Multiple Myeloma

Philippe Moreau, MD

Photo courtesy of ASH

ORLANDO, FL—Adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results of the phase 3 TOURMALINE-MM1 trial.

It is not yet clear if the 3-drug combination can prolong overall survival when compared to treatment with lenalidomide and dexamethasone.

However, researchers believe the triplet shows promise and could become a new standard of care for relapsed/refractory MM.

Philippe Moreau, MD, of the University of Nantes in France, discussed this possibility while presenting results from TOURMALINE-MM1 at the 2015 ASH Annual Meeting (abstract 727*). The study was sponsored by Millennium Pharmaceuticals, Inc.

The trial included 722 MM patients enrolled at 147 centers in 26 countries. Patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).

Baseline patient characteristics were similar between the arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients in both arms were male.

Fifty percent of patients in the IRd arm and 47% in the Rd arm had an ECOG performance status of 0. Forty-three percent and 45%, respectively, had a status of 1, and 5% and 7%, respectively, had a status of 2.

Eighty-seven percent and 88%, respectively, had an ISS stage of I or II. Fifty-five percent of patients in the IRd arm had standard-risk cytogenetics, as did 60% in the Rd arm.

Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines.

Response and survival

“Ixazomib, when combined with len-dex . . . , was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and [higher] response rate as well,” Dr Moreau said.

At a median follow-up of about 15 months, the median PFS was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).

Dr Moreau said the PFS benefit was consistent across pre-specified subgroups. So the benefit was present regardless of age, ISS stage, cytogenetic risk, number of prior therapies, prior exposure to a proteasome inhibitor, prior immunomodulatory therapy, whether the patient was refractory to his last therapy, and whether the patient had relapsed or refractory disease.

Dr Moreau also pointed out that, in the IRd arm, the median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics. This suggests ixazomib may overcome the negative impact of cytogenetic alterations.

Whether IRd confers an overall survival benefit is not clear, as those data are not yet mature. At a median follow-up of about 23 months, the median overall survival was not reached in either treatment arm.

The researchers conducted a non-inferential PFS analysis at the same time point (23 months) and found the median PFS was 20 months in the IRd arm and 15.9 months in the Rd arm. The hazard ratio was 0.82.

As for other efficacy endpoints, the overall response rate was 78.3% in the IRd arm and 71.5% in the Rd arm (P=0.035). The rates of complete response were 11.7% and 6.6%, respectively (P=0.019). And the rates of very good partial response or greater were 48.1% and 39%, respectively (P=0.014).

The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15 months, respectively. And the median time to progression was 21.4 months and 15.7 months, respectively.

Adverse events

At a median follow-up of about 23 months, patients had received a median of 17 cycles of IRd and a median of 15 cycles of Rd.

The incidence of any adverse event (AE) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.

The incidence of AEs resulting in discontinuation was 17% and 14%, respectively. And the incidence of on-study deaths (occurring within 30 days of the last dose) was 4% and 6%, respectively.

Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).

“Ixazomib is adding limited toxicity to lenalidomide and dex, with a very low rate of peripheral neuropathy and no cardiovascular or renal adverse signals,” Dr Moreau said.

“This all-oral triplet regimen may become one of the new standards of care in the relapsed setting. [It has] a very safe profile, [is] a very effective combination, [and is] simple and convenient.”

*Data in the abstract differ from the presentation.

Philippe Moreau, MD

Photo courtesy of ASH

ORLANDO, FL—Adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results of the phase 3 TOURMALINE-MM1 trial.

It is not yet clear if the 3-drug combination can prolong overall survival when compared to treatment with lenalidomide and dexamethasone.

However, researchers believe the triplet shows promise and could become a new standard of care for relapsed/refractory MM.

Philippe Moreau, MD, of the University of Nantes in France, discussed this possibility while presenting results from TOURMALINE-MM1 at the 2015 ASH Annual Meeting (abstract 727*). The study was sponsored by Millennium Pharmaceuticals, Inc.

The trial included 722 MM patients enrolled at 147 centers in 26 countries. Patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).

Baseline patient characteristics were similar between the arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients in both arms were male.

Fifty percent of patients in the IRd arm and 47% in the Rd arm had an ECOG performance status of 0. Forty-three percent and 45%, respectively, had a status of 1, and 5% and 7%, respectively, had a status of 2.

Eighty-seven percent and 88%, respectively, had an ISS stage of I or II. Fifty-five percent of patients in the IRd arm had standard-risk cytogenetics, as did 60% in the Rd arm.

Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines.

Response and survival

“Ixazomib, when combined with len-dex . . . , was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and [higher] response rate as well,” Dr Moreau said.

At a median follow-up of about 15 months, the median PFS was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).

Dr Moreau said the PFS benefit was consistent across pre-specified subgroups. So the benefit was present regardless of age, ISS stage, cytogenetic risk, number of prior therapies, prior exposure to a proteasome inhibitor, prior immunomodulatory therapy, whether the patient was refractory to his last therapy, and whether the patient had relapsed or refractory disease.

Dr Moreau also pointed out that, in the IRd arm, the median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics. This suggests ixazomib may overcome the negative impact of cytogenetic alterations.

Whether IRd confers an overall survival benefit is not clear, as those data are not yet mature. At a median follow-up of about 23 months, the median overall survival was not reached in either treatment arm.

The researchers conducted a non-inferential PFS analysis at the same time point (23 months) and found the median PFS was 20 months in the IRd arm and 15.9 months in the Rd arm. The hazard ratio was 0.82.

As for other efficacy endpoints, the overall response rate was 78.3% in the IRd arm and 71.5% in the Rd arm (P=0.035). The rates of complete response were 11.7% and 6.6%, respectively (P=0.019). And the rates of very good partial response or greater were 48.1% and 39%, respectively (P=0.014).

The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15 months, respectively. And the median time to progression was 21.4 months and 15.7 months, respectively.

Adverse events

At a median follow-up of about 23 months, patients had received a median of 17 cycles of IRd and a median of 15 cycles of Rd.

The incidence of any adverse event (AE) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.

The incidence of AEs resulting in discontinuation was 17% and 14%, respectively. And the incidence of on-study deaths (occurring within 30 days of the last dose) was 4% and 6%, respectively.

Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).

“Ixazomib is adding limited toxicity to lenalidomide and dex, with a very low rate of peripheral neuropathy and no cardiovascular or renal adverse signals,” Dr Moreau said.

“This all-oral triplet regimen may become one of the new standards of care in the relapsed setting. [It has] a very safe profile, [is] a very effective combination, [and is] simple and convenient.”

*Data in the abstract differ from the presentation.

Philippe Moreau, MD

Photo courtesy of ASH

ORLANDO, FL—Adding the oral proteasome inhibitor ixazomib to treatment with lenalidomide and dexamethasone can prolong progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (MM), according to interim results of the phase 3 TOURMALINE-MM1 trial.

It is not yet clear if the 3-drug combination can prolong overall survival when compared to treatment with lenalidomide and dexamethasone.

However, researchers believe the triplet shows promise and could become a new standard of care for relapsed/refractory MM.

Philippe Moreau, MD, of the University of Nantes in France, discussed this possibility while presenting results from TOURMALINE-MM1 at the 2015 ASH Annual Meeting (abstract 727*). The study was sponsored by Millennium Pharmaceuticals, Inc.

The trial included 722 MM patients enrolled at 147 centers in 26 countries. Patients were randomized to receive ixazomib, lenalidomide, and dexamethasone (IRd, n=360) or placebo, lenalidomide, and dexamethasone (Rd, n=362).

Baseline patient characteristics were similar between the arms. The median age was 66 in both arms (overall range, 30-91), and nearly 60% of patients in both arms were male.

Fifty percent of patients in the IRd arm and 47% in the Rd arm had an ECOG performance status of 0. Forty-three percent and 45%, respectively, had a status of 1, and 5% and 7%, respectively, had a status of 2.

Eighty-seven percent and 88%, respectively, had an ISS stage of I or II. Fifty-five percent of patients in the IRd arm had standard-risk cytogenetics, as did 60% in the Rd arm.

Fifty-nine percent of patients in both arms had received 1 prior line of therapy, and 41% in both arms had 2 or 3 prior lines.

Response and survival

“Ixazomib, when combined with len-dex . . . , was associated with a significant and meaningful improvement in progression-free survival, improved time to progression, and [higher] response rate as well,” Dr Moreau said.

At a median follow-up of about 15 months, the median PFS was 20.6 months in the IRd arm and 14.7 months in the Rd arm. The hazard ratio was 0.742 (P=0.012).

Dr Moreau said the PFS benefit was consistent across pre-specified subgroups. So the benefit was present regardless of age, ISS stage, cytogenetic risk, number of prior therapies, prior exposure to a proteasome inhibitor, prior immunomodulatory therapy, whether the patient was refractory to his last therapy, and whether the patient had relapsed or refractory disease.

Dr Moreau also pointed out that, in the IRd arm, the median PFS in high-risk patients was similar to that in the overall patient population and in patients with standard-risk cytogenetics. This suggests ixazomib may overcome the negative impact of cytogenetic alterations.

Whether IRd confers an overall survival benefit is not clear, as those data are not yet mature. At a median follow-up of about 23 months, the median overall survival was not reached in either treatment arm.

The researchers conducted a non-inferential PFS analysis at the same time point (23 months) and found the median PFS was 20 months in the IRd arm and 15.9 months in the Rd arm. The hazard ratio was 0.82.

As for other efficacy endpoints, the overall response rate was 78.3% in the IRd arm and 71.5% in the Rd arm (P=0.035). The rates of complete response were 11.7% and 6.6%, respectively (P=0.019). And the rates of very good partial response or greater were 48.1% and 39%, respectively (P=0.014).

The median time to response was 1.1 months in the IRd arm and 1.9 months in the Rd arm. The median duration of response was 20.5 months and 15 months, respectively. And the median time to progression was 21.4 months and 15.7 months, respectively.

Adverse events

At a median follow-up of about 23 months, patients had received a median of 17 cycles of IRd and a median of 15 cycles of Rd.

The incidence of any adverse event (AE) was 98% in the IRd arm and 99% in the Rd arm. The incidence of grade 3 or higher AEs was 74% and 69%, respectively. The incidence of serious AEs was 47% and 49%, respectively.

The incidence of AEs resulting in discontinuation was 17% and 14%, respectively. And the incidence of on-study deaths (occurring within 30 days of the last dose) was 4% and 6%, respectively.

Common AEs in the IRd and Rd arms, respectively, were diarrhea (45% vs 39%), constipation (35% vs 26%), nausea (29% vs 22%), vomiting (23% vs 12%), rash (36% vs 23%), back pain (24% vs 17%), upper respiratory tract infection (23% vs 19%), thrombocytopenia (31% vs 16%), peripheral neuropathy (27% vs 22%), peripheral edema (28% vs 20%), thromboembolism (8% vs 11%), and neutropenia (33% vs 31%).

“Ixazomib is adding limited toxicity to lenalidomide and dex, with a very low rate of peripheral neuropathy and no cardiovascular or renal adverse signals,” Dr Moreau said.

“This all-oral triplet regimen may become one of the new standards of care in the relapsed setting. [It has] a very safe profile, [is] a very effective combination, [and is] simple and convenient.”

*Data in the abstract differ from the presentation.

Jesús San-Miguel, MD, PhD

Photo courtesy of the

University of Navarra

ORLANDO, FL—The addition of panobinostat to bortezomib-dexamethasone therapy in relapsed or refractory multiple myeloma (MM) patients can double the rate of deep responses and prolong progression-free survival (PFS), according to an updated analysis of data from the PANORMA 1 trial.

Panobinostat, a pan-deacetylase inhibitor, was the first agent of its class to produce a statistically significant and clinically meaningful increase in the median PFS of patients with relapsed/refractory MM in a phase 3 trial, noted Jesús F. San-Miguel, MD, PhD, of the University of Navarra in Pamplona, Spain.

Dr San-Miguel presented results of the updated analysis at the 2015 ASH Annual Meeting (abstract 4230).

In the PANORAMA 1 trial, patients receiving panobinostat plus bortezomib and dexamethasone had a significantly prolonged median PFS of 12 months versus 8.1 months in patients treated with placebo-bortezomib-dexamethasone.

A subgroup analysis showed that the PFS benefit was improved in patients with previous exposure to bortezomib and immunomodulatory drugs (IMiDs). The addition of panobinostat to bortezomib-dexamethasone also led to a significant increase in high-quality responses.

With their analysis, Dr San-Miguel and his colleagues set out to determine the effect of responses on clinical outcomes of patients treated in PANORAMA 1, including those with prior exposure to bortezomib and IMiDs.

The researchers conducted a landmark analysis at 12, 18, and 24 weeks to assess the median PFS in patients who achieved a complete response (CR)/near complete response (nCR) or partial response (PR).

“For the total study population, the rates of high-quality responses [CR/nCR rate] were significantly higher in the panobinostat-bortezomib-dexamethasone arm [28%] than in the control arm [16%],” Dr San-Miguel said.

Among the subgroup with prior exposure to bortezomib and IMiDs, the CR/nCR rate was also higher in the triple-drug arm (22.3%) than in the 2-drug arm (9.9%).

Among patients who took panobinostat-bortezomib-dexamethasone, the duration of response was twice as long in those who achieved CR/nCR (18.4 months) as in those who achieved a PR (9 months).

The median PFS at 12 weeks for patients who received panobinostat-bortezomib-dexamethasone was increased in patients achieving high-quality responses: 16.5 months for nCR as compared to 10.3 months for PR.

The subgroup of patients with prior exposure to bortezomib and IMiDs who achieved deeper responses also demonstrated longer PFS at 12 weeks: a median of 13.7 months for nCR and 8.1 months for PR.

“In both the overall study population and the subgroup of patients with prior exposure to bortezomib and IMiDs, a 2-fold increase in deep responses was achieved with panobinostat-bortezomib-dexamethasone compared with placebo-bortezomib-dexamethasone,” Dr San-Miguel said. “In both groups, deep responses were associated with a prolonged PFS and a longer duration of response.”

He noted that the magnitude of benefit at each time point appeared greater among patients who received the triple-drug combination.

“These data further support achievement of deeper responses as a treatment goal and a robust and consistent benefit of panobinostat in the phase 3 study in patients with relapsed/refractory multiple myeloma, including those with prior exposure to bortezomib and IMiDs,” Dr San-Miguel said.

The PANORAMA 1 trial was sponsored by Novartis, the company developing panobinostat. Three researchers involved in the current analysis are employees of Novartis, and other researchers reported having relationships (receiving research funding, consulting, etc.) with a range of other pharmaceutical companies.

Jesús San-Miguel, MD, PhD

Photo courtesy of the

University of Navarra

ORLANDO, FL—The addition of panobinostat to bortezomib-dexamethasone therapy in relapsed or refractory multiple myeloma (MM) patients can double the rate of deep responses and prolong progression-free survival (PFS), according to an updated analysis of data from the PANORMA 1 trial.

Panobinostat, a pan-deacetylase inhibitor, was the first agent of its class to produce a statistically significant and clinically meaningful increase in the median PFS of patients with relapsed/refractory MM in a phase 3 trial, noted Jesús F. San-Miguel, MD, PhD, of the University of Navarra in Pamplona, Spain.

Dr San-Miguel presented results of the updated analysis at the 2015 ASH Annual Meeting (abstract 4230).

In the PANORAMA 1 trial, patients receiving panobinostat plus bortezomib and dexamethasone had a significantly prolonged median PFS of 12 months versus 8.1 months in patients treated with placebo-bortezomib-dexamethasone.

A subgroup analysis showed that the PFS benefit was improved in patients with previous exposure to bortezomib and immunomodulatory drugs (IMiDs). The addition of panobinostat to bortezomib-dexamethasone also led to a significant increase in high-quality responses.

With their analysis, Dr San-Miguel and his colleagues set out to determine the effect of responses on clinical outcomes of patients treated in PANORAMA 1, including those with prior exposure to bortezomib and IMiDs.

The researchers conducted a landmark analysis at 12, 18, and 24 weeks to assess the median PFS in patients who achieved a complete response (CR)/near complete response (nCR) or partial response (PR).

“For the total study population, the rates of high-quality responses [CR/nCR rate] were significantly higher in the panobinostat-bortezomib-dexamethasone arm [28%] than in the control arm [16%],” Dr San-Miguel said.

Among the subgroup with prior exposure to bortezomib and IMiDs, the CR/nCR rate was also higher in the triple-drug arm (22.3%) than in the 2-drug arm (9.9%).

Among patients who took panobinostat-bortezomib-dexamethasone, the duration of response was twice as long in those who achieved CR/nCR (18.4 months) as in those who achieved a PR (9 months).

The median PFS at 12 weeks for patients who received panobinostat-bortezomib-dexamethasone was increased in patients achieving high-quality responses: 16.5 months for nCR as compared to 10.3 months for PR.

The subgroup of patients with prior exposure to bortezomib and IMiDs who achieved deeper responses also demonstrated longer PFS at 12 weeks: a median of 13.7 months for nCR and 8.1 months for PR.

“In both the overall study population and the subgroup of patients with prior exposure to bortezomib and IMiDs, a 2-fold increase in deep responses was achieved with panobinostat-bortezomib-dexamethasone compared with placebo-bortezomib-dexamethasone,” Dr San-Miguel said. “In both groups, deep responses were associated with a prolonged PFS and a longer duration of response.”

He noted that the magnitude of benefit at each time point appeared greater among patients who received the triple-drug combination.

“These data further support achievement of deeper responses as a treatment goal and a robust and consistent benefit of panobinostat in the phase 3 study in patients with relapsed/refractory multiple myeloma, including those with prior exposure to bortezomib and IMiDs,” Dr San-Miguel said.

The PANORAMA 1 trial was sponsored by Novartis, the company developing panobinostat. Three researchers involved in the current analysis are employees of Novartis, and other researchers reported having relationships (receiving research funding, consulting, etc.) with a range of other pharmaceutical companies.

Jesús San-Miguel, MD, PhD

Photo courtesy of the

University of Navarra

ORLANDO, FL—The addition of panobinostat to bortezomib-dexamethasone therapy in relapsed or refractory multiple myeloma (MM) patients can double the rate of deep responses and prolong progression-free survival (PFS), according to an updated analysis of data from the PANORMA 1 trial.

Panobinostat, a pan-deacetylase inhibitor, was the first agent of its class to produce a statistically significant and clinically meaningful increase in the median PFS of patients with relapsed/refractory MM in a phase 3 trial, noted Jesús F. San-Miguel, MD, PhD, of the University of Navarra in Pamplona, Spain.

Dr San-Miguel presented results of the updated analysis at the 2015 ASH Annual Meeting (abstract 4230).

In the PANORAMA 1 trial, patients receiving panobinostat plus bortezomib and dexamethasone had a significantly prolonged median PFS of 12 months versus 8.1 months in patients treated with placebo-bortezomib-dexamethasone.

A subgroup analysis showed that the PFS benefit was improved in patients with previous exposure to bortezomib and immunomodulatory drugs (IMiDs). The addition of panobinostat to bortezomib-dexamethasone also led to a significant increase in high-quality responses.

With their analysis, Dr San-Miguel and his colleagues set out to determine the effect of responses on clinical outcomes of patients treated in PANORAMA 1, including those with prior exposure to bortezomib and IMiDs.

The researchers conducted a landmark analysis at 12, 18, and 24 weeks to assess the median PFS in patients who achieved a complete response (CR)/near complete response (nCR) or partial response (PR).

“For the total study population, the rates of high-quality responses [CR/nCR rate] were significantly higher in the panobinostat-bortezomib-dexamethasone arm [28%] than in the control arm [16%],” Dr San-Miguel said.

Among the subgroup with prior exposure to bortezomib and IMiDs, the CR/nCR rate was also higher in the triple-drug arm (22.3%) than in the 2-drug arm (9.9%).

Among patients who took panobinostat-bortezomib-dexamethasone, the duration of response was twice as long in those who achieved CR/nCR (18.4 months) as in those who achieved a PR (9 months).

The median PFS at 12 weeks for patients who received panobinostat-bortezomib-dexamethasone was increased in patients achieving high-quality responses: 16.5 months for nCR as compared to 10.3 months for PR.

The subgroup of patients with prior exposure to bortezomib and IMiDs who achieved deeper responses also demonstrated longer PFS at 12 weeks: a median of 13.7 months for nCR and 8.1 months for PR.

“In both the overall study population and the subgroup of patients with prior exposure to bortezomib and IMiDs, a 2-fold increase in deep responses was achieved with panobinostat-bortezomib-dexamethasone compared with placebo-bortezomib-dexamethasone,” Dr San-Miguel said. “In both groups, deep responses were associated with a prolonged PFS and a longer duration of response.”

He noted that the magnitude of benefit at each time point appeared greater among patients who received the triple-drug combination.

“These data further support achievement of deeper responses as a treatment goal and a robust and consistent benefit of panobinostat in the phase 3 study in patients with relapsed/refractory multiple myeloma, including those with prior exposure to bortezomib and IMiDs,” Dr San-Miguel said.

The PANORAMA 1 trial was sponsored by Novartis, the company developing panobinostat. Three researchers involved in the current analysis are employees of Novartis, and other researchers reported having relationships (receiving research funding, consulting, etc.) with a range of other pharmaceutical companies.

Preparing treatment

for a clinical trial

Photo by Esther Dyson

Twelve factors may predict low patient accrual in cancer clinical trials, according to research published in JNCI.

Many studies have been conducted to investigate the perceived barriers to clinical trial accrual from the patient or provider perspective.

However, researchers have rarely taken a trial-level view and investigated why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants.

Caroline S. Bennette, PhD, of the University of Washington in Seattle, and her colleagues conducted their study to do just that.

They analyzed information on 787 phase 2/3 clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011.

After excluding trials that closed because of toxicity or interim results, the researchers found that 145 (18%) NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.

The team identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy.

The researchers then developed a multivariable prediction model of low accrual using 12 trial-level risk factors. The team said these factors had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.

Those 12 risk factors are:

1. The number of competing trials per 10,000 eligible patients per year (odds ratio [OR]=1.88)
2. Phase 3 vs phase 2 trial (OR=1.86)
3. Enrollment as percentage of eligible population for targeted therapy (OR=0.57)
4. Enrollment as percentage of eligible population for radiation therapy (OR=1.81)
5. Annual incidence of clinical condition(s) per 10,000 (OR=0.99)
6. Tissue sample required to assess eligibility (OR=1.26)
7. Investigational new drug (OR=0.34)
8. Metastatic setting (OR=1.46)
9. Sample size per 100 (OR=0.95)
10. More than one condition evaluated (OR=1.98)
11. Common solid cancer (prostate, breast, lung, or colon) vs liquid or rare solid cancers (OR=2.32)
12. Interaction term (phase 3 x investigational new drug, OR=2.47).

The researchers concluded that systematically considering the overall influence of these risk factors could aid in the design and prioritization of future clinical trials.

Preparing treatment

for a clinical trial

Photo by Esther Dyson

Twelve factors may predict low patient accrual in cancer clinical trials, according to research published in JNCI.

Many studies have been conducted to investigate the perceived barriers to clinical trial accrual from the patient or provider perspective.

However, researchers have rarely taken a trial-level view and investigated why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants.

Caroline S. Bennette, PhD, of the University of Washington in Seattle, and her colleagues conducted their study to do just that.

They analyzed information on 787 phase 2/3 clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011.

After excluding trials that closed because of toxicity or interim results, the researchers found that 145 (18%) NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.

The team identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy.

The researchers then developed a multivariable prediction model of low accrual using 12 trial-level risk factors. The team said these factors had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.

Those 12 risk factors are:

1. The number of competing trials per 10,000 eligible patients per year (odds ratio [OR]=1.88)
2. Phase 3 vs phase 2 trial (OR=1.86)
3. Enrollment as percentage of eligible population for targeted therapy (OR=0.57)
4. Enrollment as percentage of eligible population for radiation therapy (OR=1.81)
5. Annual incidence of clinical condition(s) per 10,000 (OR=0.99)
6. Tissue sample required to assess eligibility (OR=1.26)
7. Investigational new drug (OR=0.34)
8. Metastatic setting (OR=1.46)
9. Sample size per 100 (OR=0.95)
10. More than one condition evaluated (OR=1.98)
11. Common solid cancer (prostate, breast, lung, or colon) vs liquid or rare solid cancers (OR=2.32)
12. Interaction term (phase 3 x investigational new drug, OR=2.47).

The researchers concluded that systematically considering the overall influence of these risk factors could aid in the design and prioritization of future clinical trials.

Preparing treatment

for a clinical trial

Photo by Esther Dyson

Twelve factors may predict low patient accrual in cancer clinical trials, according to research published in JNCI.

Many studies have been conducted to investigate the perceived barriers to clinical trial accrual from the patient or provider perspective.

However, researchers have rarely taken a trial-level view and investigated why certain trials are able to accrue patients faster than expected while others fail to attract even a fraction of the intended number of participants.

Caroline S. Bennette, PhD, of the University of Washington in Seattle, and her colleagues conducted their study to do just that.

They analyzed information on 787 phase 2/3 clinical trials sponsored by the National Clinical Trials Network (NCTN; formerly the Cooperative Group Program) launched between 2000 and 2011.

After excluding trials that closed because of toxicity or interim results, the researchers found that 145 (18%) NCTN trials closed with low accrual or were accruing at less than 50% of target accrual 3 years or more after opening.

The team identified potential risk factors from the literature and interviews with clinical trial experts and found multiple trial-level factors that were associated with poor accrual to NCTN trials, such as increased competition for patients from currently ongoing trials, planning to enroll a higher proportion of the available patient population, and not evaluating a new investigational agent or targeted therapy.

The researchers then developed a multivariable prediction model of low accrual using 12 trial-level risk factors. The team said these factors had good agreement between predicted and observed risks of low accrual in a preliminary validation using 46 trials opened between 2012 and 2013.

Those 12 risk factors are:

1. The number of competing trials per 10,000 eligible patients per year (odds ratio [OR]=1.88)
2. Phase 3 vs phase 2 trial (OR=1.86)
3. Enrollment as percentage of eligible population for targeted therapy (OR=0.57)
4. Enrollment as percentage of eligible population for radiation therapy (OR=1.81)
5. Annual incidence of clinical condition(s) per 10,000 (OR=0.99)
6. Tissue sample required to assess eligibility (OR=1.26)
7. Investigational new drug (OR=0.34)
8. Metastatic setting (OR=1.46)
9. Sample size per 100 (OR=0.95)
10. More than one condition evaluated (OR=1.98)
11. Common solid cancer (prostate, breast, lung, or colon) vs liquid or rare solid cancers (OR=2.32)
12. Interaction term (phase 3 x investigational new drug, OR=2.47).

The researchers concluded that systematically considering the overall influence of these risk factors could aid in the design and prioritization of future clinical trials.

ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.

This included four very good partial responses (24%) and nine partial responses (53%).

In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).

The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.

The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.

The median duration of response among the 17 evaluable patients was 9.7 months.

The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.

The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.

“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.

Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.

The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.

In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.

After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.

The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.

Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).

The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.

Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.

In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.

[email protected]

ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.

This included four very good partial responses (24%) and nine partial responses (53%).

In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).

The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.

The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.

The median duration of response among the 17 evaluable patients was 9.7 months.

The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.

The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.

“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.

Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.

The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.

In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.

After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.

The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.

Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).

The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.

Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.

In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.

[email protected]

ORLANDO – The one-two punch of combining the programmed cell death-1 (PD-1) inhibitor pembrolizumab with the immunomodulatory drug lenalidomide and low-dose dexamethasone produced responses in 76% of 17 heavily pretreated patients with relapsed or refractory multiple myeloma in the KEYNOTE-023 study.

This included four very good partial responses (24%) and nine partial responses (53%).

In nine lenalidomide-refractory patients, the overall response rate was 56%, including two very good partial responses (22%) and three partial responses (33%).

The efficacy results are preliminary, but support the continued development of pembrolizumab (Keytruda) in patients with multiple myeloma, Dr. Jesús San Miguel of Clinica Universidad de Navarra, Pamplona, Spain, said at the annual meeting of the American Society of Hematology.

Patrice Wendling/Frontline Medical News

He closed his presentation with two illustrative cases highlighting a rapid response lasting more than a year and a half in a 49-year-old man with myeloma triple-refractory to autologous stem cell transplant (ASCT), lenalidomide (Revlimid), and dexamethasone.

The second case involved a patient with double-refractory myeloma and extramedullary disease who achieved a stringent complete response after two cycles of fourth-line pembrolizumab that was associated with a “striking” reduction in lesion volume on computed tomography scans, he said.

The median duration of response among the 17 evaluable patients was 9.7 months.

The median time to first response was 1.2 months (range 1.0 months to 6.5 months). But some patients require more time and, interestingly, the quality of the response was upgraded in 11% with continued treatment, Dr. San Miguel said.

The rationale for combining PD-1 inhibitors with immunomodulatory drugs (IMiD) lies in recent research showing that lenalidomide reduces PD-ligand 1 and PD-1 expression on multiple myeloma cells as well as on T and myeloid-derived suppressor cells, he explained. In addition, lenalidomide enhances checkpoint blockade–induced effector cytokine production in multiple myeloma bone marrow and induces cytotoxicity against myeloma cells.

“Lenalidomide will increase the number of T cells and the T-cell activation and anti-PD-1 will release the brake in order to allow these activated T cells to interact with the tumor,” Dr. San Miguel said.

Patients enrolled in KEYSTONE-023 were heavily pretreated, with 26% previously exposed to pomalidomide, 76% refractory to lenalidomide, 80% refractory to their last line of therapy, and 86% having undergone prior ASCT. Half the patients were double, triple, or quadruple refractory, he noted.

The study (Abstract 505) was designed to identify the maximum tolerated dose (MTD) of pembrolizumab and to assess its safety and tolerability when given with lenalidomide and dexamethasone in patients with multiple myeloma failing at least two prior lines of therapy including a proteasome inhibitor and an IMiD. Their median age was 62 years; 64% were male.

In the dose-determination stage, three of six patients treated with pembrolizumab 2 mg/kg plus lenalidomide 25 mg and dexamethasone 40 mg experienced dose-limiting toxicities that resolved without treatment discontinuation.

After dose adjustments, a “flat dose” of pembrolizumab 200 mg given every other week in a rapid 30-minute intravenous infusion without premedication with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg weekly did not cause any dose-limiting toxicities and was identified as the final MTD, Dr. San Miguel said.

The regimen is to continue for 24 months or until tumor progression or excessive side effects and was carried forward into the dose-expansion stage in 33 additional patients with a median follow-up of 48 days.

Among all 50 patients evaluable for safety, 72% experienced at least one treatment-related adverse event of any grade and 46% (23/50 patients) had grade 3/4 adverse events including neutropenia (22%), thrombocytopenia and anemia (8% each), hyperglycemia (6%), and fatigue, muscle spasms, and diarrhea (2% each).

The adverse events were consistent with the individual drug safety profiles, but “the incidence may be underestimated due to the limited drug exposure,” Dr. San Miguel cautioned.

Immune-mediated adverse events included two cases each of hyper- and hypothyroidism, one case of thyroiditis, and one grade 2 adrenal insufficiency. No cases of colitis or pneumonitis were reported. No dose modifications or treatment discontinuations were required to mange the immune-related side effects, he said. No treatment-related deaths occurred.

In a second study reported during the same oral myeloma session, pneumonitis cropped up in 10% of heavily pretreated patients with relapsed multiple myeloma receiving a slightly different regimen of pembrolizumab plus the IMiD pomalidomide (Pomalyst) and dexamethasone. The overall response rate in the phase II study was 60% among 27 evaluable patients and 55% in those double-refractory to IMiDs and proteasome inhibitors.

[email protected]

Doctor and cancer patient

Photo courtesy of NCI

and Matthews Media Group

A new study suggests that educating cancer patients about clinical trials—with either a general or patient-specific program—increases the likelihood that patients will enroll in such trials.

After completing either type of educational program, 21% of the cancer patients studied chose to enroll in clinical trials.

Traditionally, less than 5% of cancer patients decide to participate in trials, according to the American Cancer Society.

“Unfortunately, although clinical trials are critical for advancing cancer treatment and ultimately serve as the basis for new standards of care, very few patients participate,” said Neal J. Meropol, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio.

“We want to close the patient knowledge gap and positively affect their attitudes toward clinical trials.”

Dr Meropol and his colleagues described their effort to do just that in the Journal of Clinical Oncology.

The researchers compared a tailored video education program on clinical trials, PRE-ACT (Preparatory Education about Clinical Trials), to educational information delivered as written text.

PRE-ACT is an intervention in which patients access a website to take an online survey. The survey gauges the individual patient’s knowledge and attitudes about clinical trials, and then, based on that patient’s answers, video clips are presented addressing his or her specific concerns.

For example, patients may worry they will receive a placebo rather than active treatment, so one video clip explains how placebos are used ethically in cancer studies, and the fact that very few studies will include a placebo without any active treatment. The videos also help patients clarify their preferences in terms of quality of life or length of life.

Results

Dr Meropol and his colleagues enrolled 1255 cancer patients in the study. Half of them participated in the PRE-ACT program, and the other half received written information about clinical trials that was not specifically chosen based on their survey responses.

Both interventions improved patients’ knowledge and attitudes regarding clinical trials when compared with baseline (all P<0.001).

Patients in both arms said they felt more prepared to consider enrolling in a clinical trial after completing their assigned educational program (P<0.001), but there was a trend favoring the PRE-ACT arm (P<0.09).

Patients in the PRE-ACT arm also showed a significantly greater increase in knowledge (P<0.001) and a significantly greater decrease in attitudinal barriers (P<0.001) than patients in the text-only arm. And PRE-ACT was associated with greater patient satisfaction.

Financial concerns

During the course of this research, Dr Meropol and his colleagues made a surprising discovery. Video clips meant to address concerns about the costs of clinical trial treatment actually caused a spike in worries about the out-of-pocket costs of clinical trials.

These financial concerns generated yet another paper that appeared in the same edition of the Journal of Clinical Oncology.

“What was a surprise is that giving people information about costs in general terms made them more anxious,” Dr Meropol said. “It was not surprising to us that these concerns actually affect distress, add to decisional conflict, and interfere with decision-making.”

“This finding highlighted for us that communication about costs is both necessary and challenging. It indicates that we need to be sensitive to patients’ cost concerns as they navigate decisions about cancer care.”

The researchers are now planning to develop tools to assist patients with financial navigation. The team is also developing a web-based educational program for oncology nurses to help them discuss clinical trial participation with patients.

Doctor and cancer patient

Photo courtesy of NCI

and Matthews Media Group

A new study suggests that educating cancer patients about clinical trials—with either a general or patient-specific program—increases the likelihood that patients will enroll in such trials.

After completing either type of educational program, 21% of the cancer patients studied chose to enroll in clinical trials.

Traditionally, less than 5% of cancer patients decide to participate in trials, according to the American Cancer Society.

“Unfortunately, although clinical trials are critical for advancing cancer treatment and ultimately serve as the basis for new standards of care, very few patients participate,” said Neal J. Meropol, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio.

“We want to close the patient knowledge gap and positively affect their attitudes toward clinical trials.”

Dr Meropol and his colleagues described their effort to do just that in the Journal of Clinical Oncology.

The researchers compared a tailored video education program on clinical trials, PRE-ACT (Preparatory Education about Clinical Trials), to educational information delivered as written text.

PRE-ACT is an intervention in which patients access a website to take an online survey. The survey gauges the individual patient’s knowledge and attitudes about clinical trials, and then, based on that patient’s answers, video clips are presented addressing his or her specific concerns.

For example, patients may worry they will receive a placebo rather than active treatment, so one video clip explains how placebos are used ethically in cancer studies, and the fact that very few studies will include a placebo without any active treatment. The videos also help patients clarify their preferences in terms of quality of life or length of life.

Results

Dr Meropol and his colleagues enrolled 1255 cancer patients in the study. Half of them participated in the PRE-ACT program, and the other half received written information about clinical trials that was not specifically chosen based on their survey responses.

Both interventions improved patients’ knowledge and attitudes regarding clinical trials when compared with baseline (all P<0.001).

Patients in both arms said they felt more prepared to consider enrolling in a clinical trial after completing their assigned educational program (P<0.001), but there was a trend favoring the PRE-ACT arm (P<0.09).

Patients in the PRE-ACT arm also showed a significantly greater increase in knowledge (P<0.001) and a significantly greater decrease in attitudinal barriers (P<0.001) than patients in the text-only arm. And PRE-ACT was associated with greater patient satisfaction.

Financial concerns

During the course of this research, Dr Meropol and his colleagues made a surprising discovery. Video clips meant to address concerns about the costs of clinical trial treatment actually caused a spike in worries about the out-of-pocket costs of clinical trials.

These financial concerns generated yet another paper that appeared in the same edition of the Journal of Clinical Oncology.

“What was a surprise is that giving people information about costs in general terms made them more anxious,” Dr Meropol said. “It was not surprising to us that these concerns actually affect distress, add to decisional conflict, and interfere with decision-making.”

“This finding highlighted for us that communication about costs is both necessary and challenging. It indicates that we need to be sensitive to patients’ cost concerns as they navigate decisions about cancer care.”

The researchers are now planning to develop tools to assist patients with financial navigation. The team is also developing a web-based educational program for oncology nurses to help them discuss clinical trial participation with patients.

Doctor and cancer patient

Photo courtesy of NCI

and Matthews Media Group

A new study suggests that educating cancer patients about clinical trials—with either a general or patient-specific program—increases the likelihood that patients will enroll in such trials.

After completing either type of educational program, 21% of the cancer patients studied chose to enroll in clinical trials.

Traditionally, less than 5% of cancer patients decide to participate in trials, according to the American Cancer Society.

“Unfortunately, although clinical trials are critical for advancing cancer treatment and ultimately serve as the basis for new standards of care, very few patients participate,” said Neal J. Meropol, MD, of Case Western Reserve University School of Medicine in Cleveland, Ohio.

“We want to close the patient knowledge gap and positively affect their attitudes toward clinical trials.”

Dr Meropol and his colleagues described their effort to do just that in the Journal of Clinical Oncology.

The researchers compared a tailored video education program on clinical trials, PRE-ACT (Preparatory Education about Clinical Trials), to educational information delivered as written text.

PRE-ACT is an intervention in which patients access a website to take an online survey. The survey gauges the individual patient’s knowledge and attitudes about clinical trials, and then, based on that patient’s answers, video clips are presented addressing his or her specific concerns.

For example, patients may worry they will receive a placebo rather than active treatment, so one video clip explains how placebos are used ethically in cancer studies, and the fact that very few studies will include a placebo without any active treatment. The videos also help patients clarify their preferences in terms of quality of life or length of life.

Results

Dr Meropol and his colleagues enrolled 1255 cancer patients in the study. Half of them participated in the PRE-ACT program, and the other half received written information about clinical trials that was not specifically chosen based on their survey responses.

Both interventions improved patients’ knowledge and attitudes regarding clinical trials when compared with baseline (all P<0.001).

Patients in both arms said they felt more prepared to consider enrolling in a clinical trial after completing their assigned educational program (P<0.001), but there was a trend favoring the PRE-ACT arm (P<0.09).

Patients in the PRE-ACT arm also showed a significantly greater increase in knowledge (P<0.001) and a significantly greater decrease in attitudinal barriers (P<0.001) than patients in the text-only arm. And PRE-ACT was associated with greater patient satisfaction.

Financial concerns

During the course of this research, Dr Meropol and his colleagues made a surprising discovery. Video clips meant to address concerns about the costs of clinical trial treatment actually caused a spike in worries about the out-of-pocket costs of clinical trials.

These financial concerns generated yet another paper that appeared in the same edition of the Journal of Clinical Oncology.

“What was a surprise is that giving people information about costs in general terms made them more anxious,” Dr Meropol said. “It was not surprising to us that these concerns actually affect distress, add to decisional conflict, and interfere with decision-making.”

“This finding highlighted for us that communication about costs is both necessary and challenging. It indicates that we need to be sensitive to patients’ cost concerns as they navigate decisions about cancer care.”

The researchers are now planning to develop tools to assist patients with financial navigation. The team is also developing a web-based educational program for oncology nurses to help them discuss clinical trial participation with patients.

Vials of drug

Photo by Bill Branson

Results of the phase 3 ENDEAVOR trial suggest combination carfilzomib and dexamethasone prolongs progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (MM), when compared to bortezomib plus dexamethasone.

The median PFS was 18.7 months in the carfilzomib arm and 9.4 months in the bortezomib arm.

It is not clear whether this translates to an improvement in overall survival, as those data are not yet mature.

Treatment discontinuation due to adverse events (AEs) and on-study deaths were comparable between the treatment arms, although there were several AEs that occurred more frequently in the carfilzomib arm than the bortezomib arm.

These results were published in The Lancet Oncology. The trial was funded by Onyx Pharmaceuticals, Inc., a subsidiary of Amgen.

Patient treatment and characteristics

The ENDEAVOR trial included 929 patients with relapsed/refractory MM who had received 1 to 3 prior therapeutic regimens. They were randomized to receive carfilzomib in combination with low-dose dexamethasone (n=464) or bortezomib with low-dose dexamethasone (n=465) until progression.

Patients received carfilzomib as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 of 28-day treatment cycles, along with 20 mg of dexamethasone. For cycle 1 only, carfilzomib was administered at 20 mg/m² on days 1 and 2, followed by escalation to 56 mg/m² from day 8. Patients who tolerated 56 mg/m² in cycle 1 were kept at this dose for subsequent cycles.

Patients who received bortezomib (1.3 mg/m²) with low-dose dexamethasone (20 mg) were given bortezomib subcutaneously or intravenously at the discretion of the investigator. More than 75% of the patients received bortezomib subcutaneously.

Baseline characteristics were generally balanced between the treatment arms. Both arms had a median age of 65 (overall range, 30-89), and about half were male. Three-quarters of patients in both arms were white, a little over 10% were Asian, 2% were black, and about 10% did not report race/ethnicity.

A majority of patients in both arms (more than 90%) had an ECOG score of 0 or 1. Most patients (more than 60%) had standard-risk cytogenetics.

The median number of prior treatment regimens was 2 in both arms. Patients in both arms had received prior lenalidomide (38% in both arms), thalidomide (45% in the carfilzomib arm and 53% in the bortezomib arm), bortezomib (54% in both arms), and carfilzomib (<1% in both arms).

Results

The median PFS in the carfilzomib arm was roughly double that of the bortezomib arm—18.7 months and 9.4 months, respectively. The hazard ratio was 0.53 (P<0.0001).

Overall survival data are not mature and are still being monitored.

The overall response rate was 77% in the carfilzomib arm and 63% in the bortezomib arm (P<0.0001). The duration of response was 21.3 months and 10.4 months, respectively.

The proportion of patients achieving a very good partial response or better was 54.3% in the carfilzomib arm and 29% in the bortezomib arm (P<0.0001). The complete response rates were 13% and 6%, respectively (P<0.001).

Treatment discontinuation due to AEs and on-study deaths were comparable between the arms. There were 75 deaths in the carfilzomib arm and 88 deaths in the bortezomib arm.

Of the 263 patients in the carfilzomib arm who discontinued treatment, 65 did so because of AEs. Of the 351 patients in the bortezomib arm who discontinued treatment, 73 did so because of AEs.

A number of known AEs were reported at a higher rate in the carfilzomib arm than the bortezomib arm, including any-grade dyspnea (28% vs 13%), hypertension (25% vs 3%), pyrexia (27% vs 14%), cough (25% vs 15%), cardiac failure (8% vs 3%), and acute renal failure (8% vs 5%).

Rates of grade 3 or higher AEs were 73% in the carfilzomib arm and 67% in the bortezomib arm. Grade 3 or higher AEs of interest in the carfilzomib and bortezomib arms, respectively, were hypertension (9% vs 3%), dyspnea (5% vs 2%), cardiac failure (5% vs 2%), acute renal failure (4% vs 3%), ischemic heart disease (2% vs 2%), and pulmonary hypertension (0.6% vs 0.2%).

Vials of drug

Photo by Bill Branson

Results of the phase 3 ENDEAVOR trial suggest combination carfilzomib and dexamethasone prolongs progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (MM), when compared to bortezomib plus dexamethasone.

The median PFS was 18.7 months in the carfilzomib arm and 9.4 months in the bortezomib arm.

It is not clear whether this translates to an improvement in overall survival, as those data are not yet mature.

Treatment discontinuation due to adverse events (AEs) and on-study deaths were comparable between the treatment arms, although there were several AEs that occurred more frequently in the carfilzomib arm than the bortezomib arm.

These results were published in The Lancet Oncology. The trial was funded by Onyx Pharmaceuticals, Inc., a subsidiary of Amgen.

Patient treatment and characteristics

The ENDEAVOR trial included 929 patients with relapsed/refractory MM who had received 1 to 3 prior therapeutic regimens. They were randomized to receive carfilzomib in combination with low-dose dexamethasone (n=464) or bortezomib with low-dose dexamethasone (n=465) until progression.

Patients received carfilzomib as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 of 28-day treatment cycles, along with 20 mg of dexamethasone. For cycle 1 only, carfilzomib was administered at 20 mg/m² on days 1 and 2, followed by escalation to 56 mg/m² from day 8. Patients who tolerated 56 mg/m² in cycle 1 were kept at this dose for subsequent cycles.

Patients who received bortezomib (1.3 mg/m²) with low-dose dexamethasone (20 mg) were given bortezomib subcutaneously or intravenously at the discretion of the investigator. More than 75% of the patients received bortezomib subcutaneously.

Baseline characteristics were generally balanced between the treatment arms. Both arms had a median age of 65 (overall range, 30-89), and about half were male. Three-quarters of patients in both arms were white, a little over 10% were Asian, 2% were black, and about 10% did not report race/ethnicity.

A majority of patients in both arms (more than 90%) had an ECOG score of 0 or 1. Most patients (more than 60%) had standard-risk cytogenetics.

The median number of prior treatment regimens was 2 in both arms. Patients in both arms had received prior lenalidomide (38% in both arms), thalidomide (45% in the carfilzomib arm and 53% in the bortezomib arm), bortezomib (54% in both arms), and carfilzomib (<1% in both arms).

Results

The median PFS in the carfilzomib arm was roughly double that of the bortezomib arm—18.7 months and 9.4 months, respectively. The hazard ratio was 0.53 (P<0.0001).

Overall survival data are not mature and are still being monitored.

The overall response rate was 77% in the carfilzomib arm and 63% in the bortezomib arm (P<0.0001). The duration of response was 21.3 months and 10.4 months, respectively.

The proportion of patients achieving a very good partial response or better was 54.3% in the carfilzomib arm and 29% in the bortezomib arm (P<0.0001). The complete response rates were 13% and 6%, respectively (P<0.001).

Treatment discontinuation due to AEs and on-study deaths were comparable between the arms. There were 75 deaths in the carfilzomib arm and 88 deaths in the bortezomib arm.

Of the 263 patients in the carfilzomib arm who discontinued treatment, 65 did so because of AEs. Of the 351 patients in the bortezomib arm who discontinued treatment, 73 did so because of AEs.

A number of known AEs were reported at a higher rate in the carfilzomib arm than the bortezomib arm, including any-grade dyspnea (28% vs 13%), hypertension (25% vs 3%), pyrexia (27% vs 14%), cough (25% vs 15%), cardiac failure (8% vs 3%), and acute renal failure (8% vs 5%).

Rates of grade 3 or higher AEs were 73% in the carfilzomib arm and 67% in the bortezomib arm. Grade 3 or higher AEs of interest in the carfilzomib and bortezomib arms, respectively, were hypertension (9% vs 3%), dyspnea (5% vs 2%), cardiac failure (5% vs 2%), acute renal failure (4% vs 3%), ischemic heart disease (2% vs 2%), and pulmonary hypertension (0.6% vs 0.2%).

Vials of drug

Photo by Bill Branson

Results of the phase 3 ENDEAVOR trial suggest combination carfilzomib and dexamethasone prolongs progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (MM), when compared to bortezomib plus dexamethasone.

The median PFS was 18.7 months in the carfilzomib arm and 9.4 months in the bortezomib arm.

It is not clear whether this translates to an improvement in overall survival, as those data are not yet mature.

Treatment discontinuation due to adverse events (AEs) and on-study deaths were comparable between the treatment arms, although there were several AEs that occurred more frequently in the carfilzomib arm than the bortezomib arm.

These results were published in The Lancet Oncology. The trial was funded by Onyx Pharmaceuticals, Inc., a subsidiary of Amgen.

Patient treatment and characteristics

The ENDEAVOR trial included 929 patients with relapsed/refractory MM who had received 1 to 3 prior therapeutic regimens. They were randomized to receive carfilzomib in combination with low-dose dexamethasone (n=464) or bortezomib with low-dose dexamethasone (n=465) until progression.

Patients received carfilzomib as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 of 28-day treatment cycles, along with 20 mg of dexamethasone. For cycle 1 only, carfilzomib was administered at 20 mg/m² on days 1 and 2, followed by escalation to 56 mg/m² from day 8. Patients who tolerated 56 mg/m² in cycle 1 were kept at this dose for subsequent cycles.

Patients who received bortezomib (1.3 mg/m²) with low-dose dexamethasone (20 mg) were given bortezomib subcutaneously or intravenously at the discretion of the investigator. More than 75% of the patients received bortezomib subcutaneously.

Baseline characteristics were generally balanced between the treatment arms. Both arms had a median age of 65 (overall range, 30-89), and about half were male. Three-quarters of patients in both arms were white, a little over 10% were Asian, 2% were black, and about 10% did not report race/ethnicity.

A majority of patients in both arms (more than 90%) had an ECOG score of 0 or 1. Most patients (more than 60%) had standard-risk cytogenetics.

The median number of prior treatment regimens was 2 in both arms. Patients in both arms had received prior lenalidomide (38% in both arms), thalidomide (45% in the carfilzomib arm and 53% in the bortezomib arm), bortezomib (54% in both arms), and carfilzomib (<1% in both arms).

Results

The median PFS in the carfilzomib arm was roughly double that of the bortezomib arm—18.7 months and 9.4 months, respectively. The hazard ratio was 0.53 (P<0.0001).

Overall survival data are not mature and are still being monitored.

The overall response rate was 77% in the carfilzomib arm and 63% in the bortezomib arm (P<0.0001). The duration of response was 21.3 months and 10.4 months, respectively.

The proportion of patients achieving a very good partial response or better was 54.3% in the carfilzomib arm and 29% in the bortezomib arm (P<0.0001). The complete response rates were 13% and 6%, respectively (P<0.001).

Treatment discontinuation due to AEs and on-study deaths were comparable between the arms. There were 75 deaths in the carfilzomib arm and 88 deaths in the bortezomib arm.

Of the 263 patients in the carfilzomib arm who discontinued treatment, 65 did so because of AEs. Of the 351 patients in the bortezomib arm who discontinued treatment, 73 did so because of AEs.

A number of known AEs were reported at a higher rate in the carfilzomib arm than the bortezomib arm, including any-grade dyspnea (28% vs 13%), hypertension (25% vs 3%), pyrexia (27% vs 14%), cough (25% vs 15%), cardiac failure (8% vs 3%), and acute renal failure (8% vs 5%).

Rates of grade 3 or higher AEs were 73% in the carfilzomib arm and 67% in the bortezomib arm. Grade 3 or higher AEs of interest in the carfilzomib and bortezomib arms, respectively, were hypertension (9% vs 3%), dyspnea (5% vs 2%), cardiac failure (5% vs 2%), acute renal failure (4% vs 3%), ischemic heart disease (2% vs 2%), and pulmonary hypertension (0.6% vs 0.2%).

Doctor and cancer patient

Photo courtesy of the

National Cancer Institute

and Mathews Media Group

End-of-life (EOL) discussions often occur “too late” for patients with hematologic malignancies, according to a survey of US hematologists.

The researchers who conducted the survey speculate that physicians may delay EOL discussions with these patients because, unlike most solid tumors,

which are incurable when they reach an advanced stage, many advanced hematologic malignancies remain curable.

So it may not be clear that a patient has entered the EOL phase.

Oreofe O. Odejide, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues conducted the survey and reported the results in a letter to JAMA Internal Medicine.

The researchers mailed their survey on EOL discussions to US hematologists found in the clinical directory of the American Society of Hematology. The individuals surveyed provide direct care for adults with hematologic malignancies.

Three hundred and forty-nine hematologists completed the survey. Most were men (75.4%), and they had a median age of 52. More than half (55.4%) practiced in community centers, and 42.9% practiced primarily in tertiary centers.

Three hundred and forty-five individuals answered the question about typical timing of EOL discussions, and 55.9% said these discussions occur too late.

Hematologists practicing in tertiary centers were more likely to report late EOL discussions than those practicing in community centers—64.9% and 48.7%, respectively (P=0.003). This difference was still significant in multivariable analysis, with an odds ratio of 1.92 (P=0.004).

When it comes to specific aspects of EOL care, 42.5% of the hematologists reported conducting their first conversation about resuscitation status at less than optimal times; 23.2% reported waiting until death was clearly imminent before having an initial conversation about hospice care; and 39.9% reported waiting until death was clearly imminent before having an initial conversation about the preferred site of death.

The researchers said the lack of a clear distinction between the curative and EOL phases of hematologic malignancies may explain these findings. Additionally, physicians may hesitate to have EOL discussions because they don’t want to affect a patient’s mentality or because they themselves find it difficult to “give up” on patients who might still be cured.

Doctor and cancer patient

Photo courtesy of the

National Cancer Institute

and Mathews Media Group

End-of-life (EOL) discussions often occur “too late” for patients with hematologic malignancies, according to a survey of US hematologists.

The researchers who conducted the survey speculate that physicians may delay EOL discussions with these patients because, unlike most solid tumors,

which are incurable when they reach an advanced stage, many advanced hematologic malignancies remain curable.

So it may not be clear that a patient has entered the EOL phase.

Oreofe O. Odejide, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues conducted the survey and reported the results in a letter to JAMA Internal Medicine.

The researchers mailed their survey on EOL discussions to US hematologists found in the clinical directory of the American Society of Hematology. The individuals surveyed provide direct care for adults with hematologic malignancies.

Three hundred and forty-nine hematologists completed the survey. Most were men (75.4%), and they had a median age of 52. More than half (55.4%) practiced in community centers, and 42.9% practiced primarily in tertiary centers.

Three hundred and forty-five individuals answered the question about typical timing of EOL discussions, and 55.9% said these discussions occur too late.

Hematologists practicing in tertiary centers were more likely to report late EOL discussions than those practicing in community centers—64.9% and 48.7%, respectively (P=0.003). This difference was still significant in multivariable analysis, with an odds ratio of 1.92 (P=0.004).

When it comes to specific aspects of EOL care, 42.5% of the hematologists reported conducting their first conversation about resuscitation status at less than optimal times; 23.2% reported waiting until death was clearly imminent before having an initial conversation about hospice care; and 39.9% reported waiting until death was clearly imminent before having an initial conversation about the preferred site of death.

The researchers said the lack of a clear distinction between the curative and EOL phases of hematologic malignancies may explain these findings. Additionally, physicians may hesitate to have EOL discussions because they don’t want to affect a patient’s mentality or because they themselves find it difficult to “give up” on patients who might still be cured.

Doctor and cancer patient

Photo courtesy of the

National Cancer Institute

and Mathews Media Group

End-of-life (EOL) discussions often occur “too late” for patients with hematologic malignancies, according to a survey of US hematologists.

The researchers who conducted the survey speculate that physicians may delay EOL discussions with these patients because, unlike most solid tumors,

which are incurable when they reach an advanced stage, many advanced hematologic malignancies remain curable.

So it may not be clear that a patient has entered the EOL phase.

Oreofe O. Odejide, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues conducted the survey and reported the results in a letter to JAMA Internal Medicine.

The researchers mailed their survey on EOL discussions to US hematologists found in the clinical directory of the American Society of Hematology. The individuals surveyed provide direct care for adults with hematologic malignancies.

Three hundred and forty-nine hematologists completed the survey. Most were men (75.4%), and they had a median age of 52. More than half (55.4%) practiced in community centers, and 42.9% practiced primarily in tertiary centers.

Three hundred and forty-five individuals answered the question about typical timing of EOL discussions, and 55.9% said these discussions occur too late.

Hematologists practicing in tertiary centers were more likely to report late EOL discussions than those practicing in community centers—64.9% and 48.7%, respectively (P=0.003). This difference was still significant in multivariable analysis, with an odds ratio of 1.92 (P=0.004).

When it comes to specific aspects of EOL care, 42.5% of the hematologists reported conducting their first conversation about resuscitation status at less than optimal times; 23.2% reported waiting until death was clearly imminent before having an initial conversation about hospice care; and 39.9% reported waiting until death was clearly imminent before having an initial conversation about the preferred site of death.

The researchers said the lack of a clear distinction between the curative and EOL phases of hematologic malignancies may explain these findings. Additionally, physicians may hesitate to have EOL discussions because they don’t want to affect a patient’s mentality or because they themselves find it difficult to “give up” on patients who might still be cured.

ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy-resistant multiple myeloma.

The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant.

CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable 14 weeks after infusion.

“We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.

A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion.

The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr. Kochenderfer said.

The complete responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said.

The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all completely resolved.

Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.

Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.

Other responses among the 12 patients treated thus far include 1 transient very good partial response of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease.

While three new drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma.

“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comoderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview.

Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.

BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr. Kochenderfer said. Multiple myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly expressed in 60% to 70% of cases.

Preclinical studies by the team also show that BCMA is not detectable in normal human tissues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells.

The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr. Kochenderfer observed.

The 12 patients received 300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine (Fludara) daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 10⁶ to 9 x 10⁶ T cells/kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease.

It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.

“I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against really previously refractory diseases like acute lymphocytic leukemia,” noted Dr. George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukemia to other types of diseases.”

The study is still ongoing and accruing patients, but a multicenter trial is also being initiated in myeloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr. Kochenderfer said.

[email protected]

ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy-resistant multiple myeloma.

The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant.

CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable 14 weeks after infusion.

“We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.

A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion.

The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr. Kochenderfer said.

The complete responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said.

The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all completely resolved.

Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.

Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.

Other responses among the 12 patients treated thus far include 1 transient very good partial response of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease.

While three new drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma.

“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comoderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview.

Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.

BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr. Kochenderfer said. Multiple myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly expressed in 60% to 70% of cases.

Preclinical studies by the team also show that BCMA is not detectable in normal human tissues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells.

The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr. Kochenderfer observed.

The 12 patients received 300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine (Fludara) daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 10⁶ to 9 x 10⁶ T cells/kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease.

It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.

“I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against really previously refractory diseases like acute lymphocytic leukemia,” noted Dr. George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukemia to other types of diseases.”

The study is still ongoing and accruing patients, but a multicenter trial is also being initiated in myeloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr. Kochenderfer said.

[email protected]

ORLANDO – Chimeric antigen receptor (CAR) T cells targeting BCMA eradicated myeloma cells in a patient with a heavy burden of chemotherapy-resistant multiple myeloma.

The patient had received three prior myeloma therapies and relapsed with myeloma making up more than 90% of his bone marrow cells just 3 months after autologous transplant.

CD138-positive plasma cells were completely absent, however, one month after infusion of CAR T cells directed against the B-cell maturation antigen (BCMA), and remain undetectable 14 weeks after infusion.

“We have demonstrated for the first time that CAR T cells can have powerful activity against measurable multiple myeloma,” Dr. James N. Kochenderfer of the National Cancer Institute in Bethesda, Md., said at the annual meeting of the American Society of Hematology.

A second patient, who had five prior lines of myeloma therapy and myeloma in 80% of his bone marrow cells, also experienced a dramatic reduction in myeloma, resulting so far in a partial response. The patient has returned to full-time work and myeloma cells continue to decrease 6 weeks after infusion.

The two ongoing responses, however, were associated with the most severe clinical signs of cytokine release syndrome in the late-breaking abstract study (LBA-1), Dr. Kochenderfer said.

The complete responder experienced cytokine release toxicities including fever, tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase that resolved. The patient was also platelet transfusion-dependent for 9 weeks after infusion and a baseline absolute neutrophil count of less than 500 microliters remained at that level for 40 days after infusion. All symptoms resolved within two weeks, he said.

The ongoing partial responder experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia and all completely resolved.

Both patients had much higher serum levels of interleukin-6 than the other patients, he noted.

Both patients also received the highest dose level of anti-BCMA CAR T cells. Going forward, that dose will now only be administered to patients with less than 50% bone marrow plasma cells, Dr. Kochenderfer said.

Other responses among the 12 patients treated thus far include 1 transient very good partial response of 8-week duration, 1 transient partial response lasting 2 weeks, and 8 responses of stable disease.

While three new drugs (elotuzumab, daratumumab, ixazomib) were approved for the treatment of multiple myeloma in the month of November alone, this is early days for CAR T-cell therapy in multiple myeloma.

“Almost all of the CAR T-cell work has been in B-cell malignancies, acute lymphocytic leukemia, and chronic lymphocytic leukemia, so is this the right antigen, we don’t know? Is this the right construct, we don’t know? But there’s clearly activity and that is very exciting,” session comoderator Dr. David P. Steensma of the Dana-Farber Cancer Institute in Boston, said in an interview.

Dana-Farber is conducting a CAR T cell trial in myeloma using a different target and NKG2D ligands. Other centers are also using CAR T cells with different targets. “So maybe other targets would have different results and a better safety profile,” he added.

BCMA is an appropriate target for CAR T cell therapy for multiple reasons, Dr. Kochenderfer said. Multiple myeloma is still an incurable disease and BCMA, a member of the tumor necrosis factor superfamily, is uniformly expressed in 60% to 70% of cases.

Preclinical studies by the team also show that BCMA is not detectable in normal human tissues, but is selectively expressed only in bone marrow, lymphoid organs, and organs known to have plasma cells in their lamina propria and by plasma cells and a small fraction of B cells.

The investigators genetically modified autologous T cells to express an anti-BCMA CAR and ligated it into a replication-incompetent gamma retrovirus. The T cells were stimulated with the anti-CD3 monoclonal antibody OKT3 before transduction, with the entire culture process taking 9 days from start to finish. T cells expressing this CAR recognize BCMA with great specificity, Dr. Kochenderfer observed.

The 12 patients received 300 mg/m² of cyclophosphamide and 30 mg/m² of fludarabine (Fludara) daily for 3 days before a single infusion of anti-BCMA CAR at dose levels of 0.3 x 10⁶ to 9 x 10⁶ T cells/kg. All patients had at least 3 prior therapies and normal organ function. Five had amyloid light chain only, 4 had immunoglobulin gamma disease, and 4 patients, including the complete responder, had immunoglobulin alpha disease.

It’s unclear why only a few patients responded to the CAR T cells, but dose level was likely a big factor and there is a lot of patient variability with T-cell therapies, Dr. Kochenderfer said at a press briefing.

“I wish we knew exactly why some patients respond and some don’t,” he added. “The CAR T cells have shown remarkable activity against really previously refractory diseases like acute lymphocytic leukemia,” noted Dr. George Daley of Harvard Medical School, Boston, in an interview at the meeting. “There’s been a lot of excitement that maybe we can extend the principles that work in leukemia to other types of diseases.”

The study is still ongoing and accruing patients, but a multicenter trial is also being initiated in myeloma with Bluebird Bio using “a closely related, but slightly different CAR,” Dr. Kochenderfer said.

[email protected]

James Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.

The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.

In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.

The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.

The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.

The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA

single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.

Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m² daily for 3 days and fludarabine at 30 mg/m² daily for 3 days.

Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 10⁶, 1 x 10⁶, 3 x 10⁶, and 9 x 10⁶ CAR-positive T cells/kg.

Response and toxicity

“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”

One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 10⁶). This response is ongoing and has lasted longer than 12 weeks.

Patient 8, who received a CAR-BCMA T-cell dose of 3 x 10⁶, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.

Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 10⁶) and lasted 2 weeks.

The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.

The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.

Best responders

Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.

“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.

Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.

Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.

Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.

The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.

Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.

Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.

“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”

James Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.

The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.

In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.

The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.

The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.

The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA

single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.

Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m² daily for 3 days and fludarabine at 30 mg/m² daily for 3 days.

Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 10⁶, 1 x 10⁶, 3 x 10⁶, and 9 x 10⁶ CAR-positive T cells/kg.

Response and toxicity

“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”

One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 10⁶). This response is ongoing and has lasted longer than 12 weeks.

Patient 8, who received a CAR-BCMA T-cell dose of 3 x 10⁶, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.

Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 10⁶) and lasted 2 weeks.

The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.

The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.

Best responders

Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.

“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.

Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.

Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.

Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.

The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.

Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.

Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.

“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”

James Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.

The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.

In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.

The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.

The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.

The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA

single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.

Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m² daily for 3 days and fludarabine at 30 mg/m² daily for 3 days.

Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 10⁶, 1 x 10⁶, 3 x 10⁶, and 9 x 10⁶ CAR-positive T cells/kg.

Response and toxicity

“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”

One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 10⁶). This response is ongoing and has lasted longer than 12 weeks.

Patient 8, who received a CAR-BCMA T-cell dose of 3 x 10⁶, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.

Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 10⁶) and lasted 2 weeks.

The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.

The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.

Best responders

Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.

“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.

Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.

Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.

Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.

The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.

Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.

Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.

“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”

Genome sequencing

Photo courtesy of NIGMS

Researchers say they have identified substantial differences in the procedures and quality of cancer genome sequencing between sequencing centers.

And this led to dramatic discrepancies in the number and types of somatic mutations detected when using the same cancer genome sequences for analysis.

The group’s study involved 83 researchers from 78 institutions participating in the International Cancer Genomics Consortium (ICGC).

The ICGC is an international effort to establish a comprehensive description of genomic, transcriptomic, and epigenomic changes in 50 different tumor types and/or subtypes that are thought to be of clinical and societal importance across the globe.

The consortium is characterizing more than 25,000 cancer genomes and carrying out 78 projects supported by different national and international funding agencies.

For the current project, which was published in Nature Communications, researchers studied a patient with chronic lymphocytic leukemia and a patient with medulloblastoma.

The team analyzed the entire tumor genome of each patient and compared it to the normal genome of the same patient to decipher the molecular causes for these cancers.

The researchers said they saw “widely varying mutation call rates and low concordance among analysis pipelines.”

So they established a reference mutation dataset to assess analytical procedures. They said this “gold-set” reference database has helped the ICGC community improve procedures for identifying more true somatic mutations in cancer genomes and making fewer false-positive calls.

“The findings of our study have far-reaching implications for cancer genome analysis,” said Ivo Gut, of Centro Nacional de Analisis Genómico in Barcelona, Spain.

“We have found many inconsistencies in both the sequencing of cancer genomes and the data analysis at different sites. We are making our findings available to the scientific and diagnostic community so that they can improve their systems and generate more standardized and consistent results.”

Genome sequencing

Photo courtesy of NIGMS

Researchers say they have identified substantial differences in the procedures and quality of cancer genome sequencing between sequencing centers.

And this led to dramatic discrepancies in the number and types of somatic mutations detected when using the same cancer genome sequences for analysis.

The group’s study involved 83 researchers from 78 institutions participating in the International Cancer Genomics Consortium (ICGC).

The ICGC is an international effort to establish a comprehensive description of genomic, transcriptomic, and epigenomic changes in 50 different tumor types and/or subtypes that are thought to be of clinical and societal importance across the globe.

The consortium is characterizing more than 25,000 cancer genomes and carrying out 78 projects supported by different national and international funding agencies.

For the current project, which was published in Nature Communications, researchers studied a patient with chronic lymphocytic leukemia and a patient with medulloblastoma.

The team analyzed the entire tumor genome of each patient and compared it to the normal genome of the same patient to decipher the molecular causes for these cancers.

The researchers said they saw “widely varying mutation call rates and low concordance among analysis pipelines.”

So they established a reference mutation dataset to assess analytical procedures. They said this “gold-set” reference database has helped the ICGC community improve procedures for identifying more true somatic mutations in cancer genomes and making fewer false-positive calls.

“The findings of our study have far-reaching implications for cancer genome analysis,” said Ivo Gut, of Centro Nacional de Analisis Genómico in Barcelona, Spain.

“We have found many inconsistencies in both the sequencing of cancer genomes and the data analysis at different sites. We are making our findings available to the scientific and diagnostic community so that they can improve their systems and generate more standardized and consistent results.”

Genome sequencing

Photo courtesy of NIGMS

Researchers say they have identified substantial differences in the procedures and quality of cancer genome sequencing between sequencing centers.

And this led to dramatic discrepancies in the number and types of somatic mutations detected when using the same cancer genome sequences for analysis.

The group’s study involved 83 researchers from 78 institutions participating in the International Cancer Genomics Consortium (ICGC).

The ICGC is an international effort to establish a comprehensive description of genomic, transcriptomic, and epigenomic changes in 50 different tumor types and/or subtypes that are thought to be of clinical and societal importance across the globe.

The consortium is characterizing more than 25,000 cancer genomes and carrying out 78 projects supported by different national and international funding agencies.

For the current project, which was published in Nature Communications, researchers studied a patient with chronic lymphocytic leukemia and a patient with medulloblastoma.

The team analyzed the entire tumor genome of each patient and compared it to the normal genome of the same patient to decipher the molecular causes for these cancers.

The researchers said they saw “widely varying mutation call rates and low concordance among analysis pipelines.”

So they established a reference mutation dataset to assess analytical procedures. They said this “gold-set” reference database has helped the ICGC community improve procedures for identifying more true somatic mutations in cancer genomes and making fewer false-positive calls.

“The findings of our study have far-reaching implications for cancer genome analysis,” said Ivo Gut, of Centro Nacional de Analisis Genómico in Barcelona, Spain.

“We have found many inconsistencies in both the sequencing of cancer genomes and the data analysis at different sites. We are making our findings available to the scientific and diagnostic community so that they can improve their systems and generate more standardized and consistent results.”