Non-Hodgkin Lymphoma

Ibrutinib (Imbruvica)
Photo courtesy of
Janssen Biotech, Inc.

The US Food and Drug Administration (FDA) has approved the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica®) for the treatment of marginal zone lymphoma (MZL).

The drug is now approved to treat patients with relapsed/refractory MZL who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.

Ibrutinib has accelerated approval for this indication, based on the overall response rate the drug produced in a phase 2 trial.

Continued approval of ibrutinib as a treatment for MZL may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA’s approval of ibrutinib for MZL makes it the first treatment approved specifically for patients with this disease. It also marks the seventh FDA approval and fifth disease indication for ibrutinib since the drug was first approved in 2013.

Ibrutinib is also FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, patients with mantle cell lymphoma who have received at least 1 prior therapy, and patients with Waldenström’s macroglobulinemia. The approval for mantle cell lymphoma is an accelerated approval.

Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Phase 2 trial

The FDA’s approval of ibrutinib for MZL is based on data from the phase 2, single-arm PCYC-1121 study, in which researchers evaluated the drug in MZL patients who required systemic therapy and had received at least 1 prior anti-CD20-based therapy.

Results from this study were presented at the 2016 ASH Annual Meeting (abstract 1213).

The efficacy analysis included 63 patients with 3 subtypes of MZL: mucosa-associated lymphoid tissue (n=32), nodal (n=17), and splenic (n=14).

The overall response rate was 46%, with a partial response rate of 42.9% and a complete response rate of 3.2%. Responses were observed across all 3 MZL subtypes.

The median time to response was 4.5 months (range, 2.3-16.4 months). And the median duration of response was not reached (range, 16.7 months to not reached).

Overall, the safety data from this study was consistent with the known safety profile of ibrutinib in B-cell malignancies.

The most common adverse events of all grades (occurring in >20% of patients) were thrombocytopenia (49%), fatigue (44%), anemia (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema (24%), arthralgia (24%), neutropenia (22%), cough (22%), dyspnea (21%), and upper respiratory tract infection (21%).

The most common (>10%) grade 3 or 4 events were decreases in hemoglobin and neutrophils (13% each) and pneumonia (10%).

The risks associated with ibrutinib as listed in the Warnings and Precautions section of the prescribing information are hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, secondary primary malignancies, tumor lysis syndrome, and embryo fetal toxicities.

Ibrutinib (Imbruvica)
Photo courtesy of
Janssen Biotech, Inc.

The US Food and Drug Administration (FDA) has approved the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica®) for the treatment of marginal zone lymphoma (MZL).

The drug is now approved to treat patients with relapsed/refractory MZL who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.

Ibrutinib has accelerated approval for this indication, based on the overall response rate the drug produced in a phase 2 trial.

Continued approval of ibrutinib as a treatment for MZL may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA’s approval of ibrutinib for MZL makes it the first treatment approved specifically for patients with this disease. It also marks the seventh FDA approval and fifth disease indication for ibrutinib since the drug was first approved in 2013.

Ibrutinib is also FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, patients with mantle cell lymphoma who have received at least 1 prior therapy, and patients with Waldenström’s macroglobulinemia. The approval for mantle cell lymphoma is an accelerated approval.

Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Phase 2 trial

The FDA’s approval of ibrutinib for MZL is based on data from the phase 2, single-arm PCYC-1121 study, in which researchers evaluated the drug in MZL patients who required systemic therapy and had received at least 1 prior anti-CD20-based therapy.

Results from this study were presented at the 2016 ASH Annual Meeting (abstract 1213).

The efficacy analysis included 63 patients with 3 subtypes of MZL: mucosa-associated lymphoid tissue (n=32), nodal (n=17), and splenic (n=14).

The overall response rate was 46%, with a partial response rate of 42.9% and a complete response rate of 3.2%. Responses were observed across all 3 MZL subtypes.

The median time to response was 4.5 months (range, 2.3-16.4 months). And the median duration of response was not reached (range, 16.7 months to not reached).

Overall, the safety data from this study was consistent with the known safety profile of ibrutinib in B-cell malignancies.

The most common adverse events of all grades (occurring in >20% of patients) were thrombocytopenia (49%), fatigue (44%), anemia (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema (24%), arthralgia (24%), neutropenia (22%), cough (22%), dyspnea (21%), and upper respiratory tract infection (21%).

The most common (>10%) grade 3 or 4 events were decreases in hemoglobin and neutrophils (13% each) and pneumonia (10%).

The risks associated with ibrutinib as listed in the Warnings and Precautions section of the prescribing information are hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, secondary primary malignancies, tumor lysis syndrome, and embryo fetal toxicities.

Ibrutinib (Imbruvica)
Photo courtesy of
Janssen Biotech, Inc.

The US Food and Drug Administration (FDA) has approved the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica®) for the treatment of marginal zone lymphoma (MZL).

The drug is now approved to treat patients with relapsed/refractory MZL who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.

Ibrutinib has accelerated approval for this indication, based on the overall response rate the drug produced in a phase 2 trial.

Continued approval of ibrutinib as a treatment for MZL may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA’s approval of ibrutinib for MZL makes it the first treatment approved specifically for patients with this disease. It also marks the seventh FDA approval and fifth disease indication for ibrutinib since the drug was first approved in 2013.

Ibrutinib is also FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, patients with mantle cell lymphoma who have received at least 1 prior therapy, and patients with Waldenström’s macroglobulinemia. The approval for mantle cell lymphoma is an accelerated approval.

Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Phase 2 trial

The FDA’s approval of ibrutinib for MZL is based on data from the phase 2, single-arm PCYC-1121 study, in which researchers evaluated the drug in MZL patients who required systemic therapy and had received at least 1 prior anti-CD20-based therapy.

Results from this study were presented at the 2016 ASH Annual Meeting (abstract 1213).

The efficacy analysis included 63 patients with 3 subtypes of MZL: mucosa-associated lymphoid tissue (n=32), nodal (n=17), and splenic (n=14).

The overall response rate was 46%, with a partial response rate of 42.9% and a complete response rate of 3.2%. Responses were observed across all 3 MZL subtypes.

The median time to response was 4.5 months (range, 2.3-16.4 months). And the median duration of response was not reached (range, 16.7 months to not reached).

Overall, the safety data from this study was consistent with the known safety profile of ibrutinib in B-cell malignancies.

The most common adverse events of all grades (occurring in >20% of patients) were thrombocytopenia (49%), fatigue (44%), anemia (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema (24%), arthralgia (24%), neutropenia (22%), cough (22%), dyspnea (21%), and upper respiratory tract infection (21%).

The most common (>10%) grade 3 or 4 events were decreases in hemoglobin and neutrophils (13% each) and pneumonia (10%).

The risks associated with ibrutinib as listed in the Warnings and Precautions section of the prescribing information are hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, secondary primary malignancies, tumor lysis syndrome, and embryo fetal toxicities.

Firefighters in front of a
burning building in Quebec
Photo by Sylvain Pedneault

New research suggests that prolonged exposure to work-related stress may increase a man’s risk of several cancers.

The study showed a significant association between work-related stress lasting 15 years or more and non-Hodgkin lymphoma (NHL) as well as lung, colon, rectal, and stomach cancers.

Men who had worked as firefighters, engineers, mechanics, and repair workers were most likely to report work-related stress.

Marie-Élise Parent, PhD, of Institut national de la recherche scientifique (INRS) in Laval, Quebec, Canada, and her colleagues conducted this research and published

the results in Preventive Medicine.

The researchers studied 3103 men with 11 different types of cancer who were diagnosed from 1979 to 1985. The team compared these men to 512 control subjects from the general population.

Both cases and controls were interviewed and asked to describe each job they had during their lifetime, including the occurrence of stress related to a job and the reason for that stress.

The researchers then calculated odds ratios (OR) for the association between perceived workplace stress and its duration, and each cancer site. The analyses were adjusted for lifestyle and occupational factors.

The team found that having at least one stressful job in a lifetime was associated with increased odds of 5 cancers:

• Lung—OR=1.33
• Colon—OR=1.51
• Bladder—OR=1.37
• Rectal—OR=1.52
• Stomach—OR=1.53.

When the researchers looked at the duration of stress, they found no significant association between any of the cancers and work-related stress lasting less than 15 years.

However, there were significant associations for several cancers and work-related stress lasting 15 to 30 years or more than 30 years. These included:

• NHL—15-30 years, OR=1.47; >30 years, OR=1.69 (P=0.02)
• Lung cancer—15-30 years, OR=1.47; >30 years, OR=1.51 (P=0.01)
• Colon cancer—15-30 years, OR=1.32; >30 years, OR=1.64 (P<0.01)
• Rectal cancer—15-30 years, OR=1.84; >30 years, OR=1.48 (P=0.01)
• Stomach cancer—15-30 years, OR=2.15; >30 years, OR=1.48 (P=0.01).

The occupations with the highest prevalence of work-related stress were firefighter (40% of firefighting jobs reported as stressful), industrial and aerospace engineer (31%), and motor vehicle and rail transport mechanic/repair worker (28%).

For the same individual, stress varied depending on the job held.

The study also showed that perceived stress was not limited to high work load and time constraints. Customer service, sales commissions, responsibilities, having an anxious temperament, job insecurity, financial problems, challenging or dangerous work conditions, employee supervision, interpersonal conflict, and a difficult commute were all sources of stress listed by study participants.
 
The researchers said one of the biggest flaws in previous studies of this kind is that none of them assessed work-related stress over a full working lifetime. The team said this made it impossible to determine how the duration of exposure to work-related stress affects cancer development.

This study, on the other hand, shows the importance of measuring stress at different points in an individual’s working life, the researchers said. They added that their results raise the question of whether chronic psychological stress should be viewed as a public health issue.

However, the team also pointed out that these results are unsubstantiated because they are based on a summary assessment of work-related stress for a given job. There is a need for epidemiological studies based on reliable stress measurements, repeated over time, and that take all sources of stress into account.

Firefighters in front of a
burning building in Quebec
Photo by Sylvain Pedneault

New research suggests that prolonged exposure to work-related stress may increase a man’s risk of several cancers.

The study showed a significant association between work-related stress lasting 15 years or more and non-Hodgkin lymphoma (NHL) as well as lung, colon, rectal, and stomach cancers.

Men who had worked as firefighters, engineers, mechanics, and repair workers were most likely to report work-related stress.

Marie-Élise Parent, PhD, of Institut national de la recherche scientifique (INRS) in Laval, Quebec, Canada, and her colleagues conducted this research and published

the results in Preventive Medicine.

The researchers studied 3103 men with 11 different types of cancer who were diagnosed from 1979 to 1985. The team compared these men to 512 control subjects from the general population.

Both cases and controls were interviewed and asked to describe each job they had during their lifetime, including the occurrence of stress related to a job and the reason for that stress.

The researchers then calculated odds ratios (OR) for the association between perceived workplace stress and its duration, and each cancer site. The analyses were adjusted for lifestyle and occupational factors.

The team found that having at least one stressful job in a lifetime was associated with increased odds of 5 cancers:

• Lung—OR=1.33
• Colon—OR=1.51
• Bladder—OR=1.37
• Rectal—OR=1.52
• Stomach—OR=1.53.

When the researchers looked at the duration of stress, they found no significant association between any of the cancers and work-related stress lasting less than 15 years.

However, there were significant associations for several cancers and work-related stress lasting 15 to 30 years or more than 30 years. These included:

• NHL—15-30 years, OR=1.47; >30 years, OR=1.69 (P=0.02)
• Lung cancer—15-30 years, OR=1.47; >30 years, OR=1.51 (P=0.01)
• Colon cancer—15-30 years, OR=1.32; >30 years, OR=1.64 (P<0.01)
• Rectal cancer—15-30 years, OR=1.84; >30 years, OR=1.48 (P=0.01)
• Stomach cancer—15-30 years, OR=2.15; >30 years, OR=1.48 (P=0.01).

The occupations with the highest prevalence of work-related stress were firefighter (40% of firefighting jobs reported as stressful), industrial and aerospace engineer (31%), and motor vehicle and rail transport mechanic/repair worker (28%).

For the same individual, stress varied depending on the job held.

The study also showed that perceived stress was not limited to high work load and time constraints. Customer service, sales commissions, responsibilities, having an anxious temperament, job insecurity, financial problems, challenging or dangerous work conditions, employee supervision, interpersonal conflict, and a difficult commute were all sources of stress listed by study participants.
 
The researchers said one of the biggest flaws in previous studies of this kind is that none of them assessed work-related stress over a full working lifetime. The team said this made it impossible to determine how the duration of exposure to work-related stress affects cancer development.

This study, on the other hand, shows the importance of measuring stress at different points in an individual’s working life, the researchers said. They added that their results raise the question of whether chronic psychological stress should be viewed as a public health issue.

However, the team also pointed out that these results are unsubstantiated because they are based on a summary assessment of work-related stress for a given job. There is a need for epidemiological studies based on reliable stress measurements, repeated over time, and that take all sources of stress into account.

Firefighters in front of a
burning building in Quebec
Photo by Sylvain Pedneault

New research suggests that prolonged exposure to work-related stress may increase a man’s risk of several cancers.

The study showed a significant association between work-related stress lasting 15 years or more and non-Hodgkin lymphoma (NHL) as well as lung, colon, rectal, and stomach cancers.

Men who had worked as firefighters, engineers, mechanics, and repair workers were most likely to report work-related stress.

Marie-Élise Parent, PhD, of Institut national de la recherche scientifique (INRS) in Laval, Quebec, Canada, and her colleagues conducted this research and published

the results in Preventive Medicine.

The researchers studied 3103 men with 11 different types of cancer who were diagnosed from 1979 to 1985. The team compared these men to 512 control subjects from the general population.

Both cases and controls were interviewed and asked to describe each job they had during their lifetime, including the occurrence of stress related to a job and the reason for that stress.

The researchers then calculated odds ratios (OR) for the association between perceived workplace stress and its duration, and each cancer site. The analyses were adjusted for lifestyle and occupational factors.

The team found that having at least one stressful job in a lifetime was associated with increased odds of 5 cancers:

• Lung—OR=1.33
• Colon—OR=1.51
• Bladder—OR=1.37
• Rectal—OR=1.52
• Stomach—OR=1.53.

When the researchers looked at the duration of stress, they found no significant association between any of the cancers and work-related stress lasting less than 15 years.

However, there were significant associations for several cancers and work-related stress lasting 15 to 30 years or more than 30 years. These included:

• NHL—15-30 years, OR=1.47; >30 years, OR=1.69 (P=0.02)
• Lung cancer—15-30 years, OR=1.47; >30 years, OR=1.51 (P=0.01)
• Colon cancer—15-30 years, OR=1.32; >30 years, OR=1.64 (P<0.01)
• Rectal cancer—15-30 years, OR=1.84; >30 years, OR=1.48 (P=0.01)
• Stomach cancer—15-30 years, OR=2.15; >30 years, OR=1.48 (P=0.01).

The occupations with the highest prevalence of work-related stress were firefighter (40% of firefighting jobs reported as stressful), industrial and aerospace engineer (31%), and motor vehicle and rail transport mechanic/repair worker (28%).

For the same individual, stress varied depending on the job held.

The study also showed that perceived stress was not limited to high work load and time constraints. Customer service, sales commissions, responsibilities, having an anxious temperament, job insecurity, financial problems, challenging or dangerous work conditions, employee supervision, interpersonal conflict, and a difficult commute were all sources of stress listed by study participants.
 
The researchers said one of the biggest flaws in previous studies of this kind is that none of them assessed work-related stress over a full working lifetime. The team said this made it impossible to determine how the duration of exposure to work-related stress affects cancer development.

This study, on the other hand, shows the importance of measuring stress at different points in an individual’s working life, the researchers said. They added that their results raise the question of whether chronic psychological stress should be viewed as a public health issue.

However, the team also pointed out that these results are unsubstantiated because they are based on a summary assessment of work-related stress for a given job. There is a need for epidemiological studies based on reliable stress measurements, repeated over time, and that take all sources of stress into account.

First month’s supply of
venetoclax (US version)
Photo courtesy of Abbvie

The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).

The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.

To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).

Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.

Phase 2 trials

Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.

In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.

The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.

The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.

The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.

The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

First month’s supply of
venetoclax (US version)
Photo courtesy of Abbvie

The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).

The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.

To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).

Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.

Phase 2 trials

Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.

In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.

The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.

The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.

The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.

The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

First month’s supply of
venetoclax (US version)
Photo courtesy of Abbvie

The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).

The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.

To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).

Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.

Phase 2 trials

Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.

In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.

The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.

The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.

The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.

The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab) and TGR-1202 for the treatment of patients with chronic lymphocytic leukemia (CLL).

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody, and TGR-1202 is a next-generation PI3K delta inhibitor. Both drugs are being developed by TG Therapeutics, Inc.

Researchers have evaluated ublituximab and TGR-1202 in combination in a phase 1 trial of patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphomas (NHLs).

Results were presented at the 2015 ASH Annual Meeting.

There was a 3+3 dose-escalation portion of the study and a dose-expansion phase. The patients received  TGR-1202 at doses ranging from 400 mg to 1200 mg and 2 different doses of ublituximab—900 mg for patients with NHL and 600 mg or 900 mg for patients with CLL/SLL.

As of ASH, there were 58 patients evaluable for efficacy and 71 evaluable for safety.

There were 10 CLL/SLL patients exposed to higher doses of TGR-1202. Among these patients, the overall response rate was 80%. Seven patients achieved a partial response, 1 achieved a complete response, and the remaining 2 patients had stable disease.

For the entire safety population, the most common adverse events were nausea (46%), diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion-related reactions (25%).

Grade 3/4 adverse events included neutropenia (25%), diarrhea (3%), fatigue (3%), dyspnea (3%), pyrexia (3%), nausea (1%), infusion-related reactions (1%), sinusitis (1%), anemia (1%), hypophosphatemia (1%), and peripheral edema (1%). 

Now, the combination of ublituximab and TGR-1202 is being evaluated in the UNITY-CLL phase 3 trial for patients with previously treated or untreated CLL.

“[W]ith enrollment into our UNITY-CLL phase 3 trial currently exceeding our expectations, we expect to be able to commence a regulatory filing for the combination in 2018, and having orphan drug designation will provide certain cost-saving advantages for us during the regulatory approval process,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics. 

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab) and TGR-1202 for the treatment of patients with chronic lymphocytic leukemia (CLL).

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody, and TGR-1202 is a next-generation PI3K delta inhibitor. Both drugs are being developed by TG Therapeutics, Inc.

Researchers have evaluated ublituximab and TGR-1202 in combination in a phase 1 trial of patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphomas (NHLs).

Results were presented at the 2015 ASH Annual Meeting.

There was a 3+3 dose-escalation portion of the study and a dose-expansion phase. The patients received  TGR-1202 at doses ranging from 400 mg to 1200 mg and 2 different doses of ublituximab—900 mg for patients with NHL and 600 mg or 900 mg for patients with CLL/SLL.

As of ASH, there were 58 patients evaluable for efficacy and 71 evaluable for safety.

There were 10 CLL/SLL patients exposed to higher doses of TGR-1202. Among these patients, the overall response rate was 80%. Seven patients achieved a partial response, 1 achieved a complete response, and the remaining 2 patients had stable disease.

For the entire safety population, the most common adverse events were nausea (46%), diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion-related reactions (25%).

Grade 3/4 adverse events included neutropenia (25%), diarrhea (3%), fatigue (3%), dyspnea (3%), pyrexia (3%), nausea (1%), infusion-related reactions (1%), sinusitis (1%), anemia (1%), hypophosphatemia (1%), and peripheral edema (1%). 

Now, the combination of ublituximab and TGR-1202 is being evaluated in the UNITY-CLL phase 3 trial for patients with previously treated or untreated CLL.

“[W]ith enrollment into our UNITY-CLL phase 3 trial currently exceeding our expectations, we expect to be able to commence a regulatory filing for the combination in 2018, and having orphan drug designation will provide certain cost-saving advantages for us during the regulatory approval process,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics. 

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab) and TGR-1202 for the treatment of patients with chronic lymphocytic leukemia (CLL).

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody, and TGR-1202 is a next-generation PI3K delta inhibitor. Both drugs are being developed by TG Therapeutics, Inc.

Researchers have evaluated ublituximab and TGR-1202 in combination in a phase 1 trial of patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphomas (NHLs).

Results were presented at the 2015 ASH Annual Meeting.

There was a 3+3 dose-escalation portion of the study and a dose-expansion phase. The patients received  TGR-1202 at doses ranging from 400 mg to 1200 mg and 2 different doses of ublituximab—900 mg for patients with NHL and 600 mg or 900 mg for patients with CLL/SLL.

As of ASH, there were 58 patients evaluable for efficacy and 71 evaluable for safety.

There were 10 CLL/SLL patients exposed to higher doses of TGR-1202. Among these patients, the overall response rate was 80%. Seven patients achieved a partial response, 1 achieved a complete response, and the remaining 2 patients had stable disease.

For the entire safety population, the most common adverse events were nausea (46%), diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion-related reactions (25%).

Grade 3/4 adverse events included neutropenia (25%), diarrhea (3%), fatigue (3%), dyspnea (3%), pyrexia (3%), nausea (1%), infusion-related reactions (1%), sinusitis (1%), anemia (1%), hypophosphatemia (1%), and peripheral edema (1%). 

Now, the combination of ublituximab and TGR-1202 is being evaluated in the UNITY-CLL phase 3 trial for patients with previously treated or untreated CLL.

“[W]ith enrollment into our UNITY-CLL phase 3 trial currently exceeding our expectations, we expect to be able to commence a regulatory filing for the combination in 2018, and having orphan drug designation will provide certain cost-saving advantages for us during the regulatory approval process,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics. 

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Ofatumumab

Photo courtesy of GSK

Salvage treatment with an ofatumumab-based regimen is no better than a rituximab-based regimen for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 3 study.

The study, ORCHARRD, was a comparison of ofatumumab plus cisplatin, cytarabine, and dexamethasone (O-DHAP) and rituximab plus DHAP (R-DHAP), both followed by autologous stem cell transplant (auto-SCT), in patients with relapsed/refractory DLBCL.

The data showed no significant difference between the 2 treatment arms with regard to progression-free survival (PFS), event-free survival (EFS), or overall survival (OS).

And the incidence of serious adverse events (AEs) was similar between the arms.

Gustaaf W. van Imhoff, MD, PhD, of University Medical Center Groningen in Groningen, Netherlands, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was proposed by HOVON, sponsored by GlaxoSmithKline (GSK), and funded by GSK, Genmab A/S, and Novartis AG. Ofatumumab became an asset of Novartis AG in March 2015.

Patients and treatment

The study included 447 adults with CD20+ DLBCL who had experienced their first relapse or who were refractory to first-line treatment with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or a similar regimen.

The patients’ median age was 57 (range, 18 to 83), 63% had stage III/IV disease, and 71% of patients either did not achieve a complete response (CR) to first-line treatment or had a CR lasting less than 1 year.

The patients were randomized to receive O-DHAP (n=222) or R-DHAP (n=225). They received ofatumumab at 1000 mg or rituximab at 375 mg/m² on days 1 and 8 of cycle 1 and day 1 of cycles 2 and 3 of DHAP (4 infusions of either drug).

The patients who had responded after 2 cycles of treatment received the third cycle, followed by high-dose therapy and auto-SCT. Failure to achieve a response after cycle 2 was included as an event.

Response and survival

The response rate was 38% with O-DHAP and 42% with R-DHAP. The CR rate was 15% and 22%, respectively.

Thirty-three percent of patients in the O-DHAP arm and 37% in the R-DHAP arm underwent auto-SCT on protocol.

At 2 years, PFS was 24% with O-DHAP and 26% with R-DHAP (hazard ratio [HR]=1.12, P=0.33).

Two-year EFS was 16% with O-DHAP and 18% with R-DHAP. (HR=1.10, P=0.35). And 2-year OS was 41% with O-DHAP and 38% with R-DHAP (HR=0.90, P=0.38).

The researchers found that having a negative PET scan after cycle 3 was associated with better PFS and OS.

Two-year PFS was 32% for patients with a positive PET scan after cycle 3 and 70% for those with a negative PET scan (P=0.001). Two-year OS was 43% for patients with positive PET scan and 78% for those with a negative PET scan (P=0.0018).

Safety

Fifty-two percent of all patients had 1 or more serious AE, and the incidence of serious AEs was similar between the treatment arms. The most common serious AEs were febrile neutropenia (13%), acute renal failure (5%), thrombocytopenia (5%), and vomiting (5%).

Fatal serious AEs occurred in 6% of patients. These were mainly related to infectious complications and occurred in a similar proportion of patients in both treatment arms.

The incidence of rash was higher in the O-DHAP arm (22% vs 9%), as was the incidence of raised serum creatinine (23% vs 16%).

Dose interruptions/delays (of either anti-CD20 therapy or chemotherapy) as a result of AEs occurred in 49% of patients in the O-DHAP arm and 30% in the R-DHAP arm.

AEs causing dose delays/interruptions included (in the O-DHAP and R-DHAP arms, respectively) neutropenia (6% and 7%), rash (9% and <1%), thrombocytopenia (5% and 4%), urticaria (6% and <1%), pyrexia (4% and 2%), febrile neutropenia (4% and 1%), hypersensitivity (4% and 1%), infusion-related reactions (5% and <1%), decrease in platelet count (2% and 3%), and pruritus (4% and 0%).

Sixteen percent of all patients had AEs that led to permanent discontinuation of study treatment. The rate of such AEs was similar between the treatment arms. The most frequent event leading to discontinuation was renal toxicity (8%).

Ofatumumab

Photo courtesy of GSK

Salvage treatment with an ofatumumab-based regimen is no better than a rituximab-based regimen for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 3 study.

The study, ORCHARRD, was a comparison of ofatumumab plus cisplatin, cytarabine, and dexamethasone (O-DHAP) and rituximab plus DHAP (R-DHAP), both followed by autologous stem cell transplant (auto-SCT), in patients with relapsed/refractory DLBCL.

The data showed no significant difference between the 2 treatment arms with regard to progression-free survival (PFS), event-free survival (EFS), or overall survival (OS).

And the incidence of serious adverse events (AEs) was similar between the arms.

Gustaaf W. van Imhoff, MD, PhD, of University Medical Center Groningen in Groningen, Netherlands, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was proposed by HOVON, sponsored by GlaxoSmithKline (GSK), and funded by GSK, Genmab A/S, and Novartis AG. Ofatumumab became an asset of Novartis AG in March 2015.

Patients and treatment

The study included 447 adults with CD20+ DLBCL who had experienced their first relapse or who were refractory to first-line treatment with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or a similar regimen.

The patients’ median age was 57 (range, 18 to 83), 63% had stage III/IV disease, and 71% of patients either did not achieve a complete response (CR) to first-line treatment or had a CR lasting less than 1 year.

The patients were randomized to receive O-DHAP (n=222) or R-DHAP (n=225). They received ofatumumab at 1000 mg or rituximab at 375 mg/m² on days 1 and 8 of cycle 1 and day 1 of cycles 2 and 3 of DHAP (4 infusions of either drug).

The patients who had responded after 2 cycles of treatment received the third cycle, followed by high-dose therapy and auto-SCT. Failure to achieve a response after cycle 2 was included as an event.

Response and survival

The response rate was 38% with O-DHAP and 42% with R-DHAP. The CR rate was 15% and 22%, respectively.

Thirty-three percent of patients in the O-DHAP arm and 37% in the R-DHAP arm underwent auto-SCT on protocol.

At 2 years, PFS was 24% with O-DHAP and 26% with R-DHAP (hazard ratio [HR]=1.12, P=0.33).

Two-year EFS was 16% with O-DHAP and 18% with R-DHAP. (HR=1.10, P=0.35). And 2-year OS was 41% with O-DHAP and 38% with R-DHAP (HR=0.90, P=0.38).

The researchers found that having a negative PET scan after cycle 3 was associated with better PFS and OS.

Two-year PFS was 32% for patients with a positive PET scan after cycle 3 and 70% for those with a negative PET scan (P=0.001). Two-year OS was 43% for patients with positive PET scan and 78% for those with a negative PET scan (P=0.0018).

Safety

Fifty-two percent of all patients had 1 or more serious AE, and the incidence of serious AEs was similar between the treatment arms. The most common serious AEs were febrile neutropenia (13%), acute renal failure (5%), thrombocytopenia (5%), and vomiting (5%).

Fatal serious AEs occurred in 6% of patients. These were mainly related to infectious complications and occurred in a similar proportion of patients in both treatment arms.

The incidence of rash was higher in the O-DHAP arm (22% vs 9%), as was the incidence of raised serum creatinine (23% vs 16%).

Dose interruptions/delays (of either anti-CD20 therapy or chemotherapy) as a result of AEs occurred in 49% of patients in the O-DHAP arm and 30% in the R-DHAP arm.

AEs causing dose delays/interruptions included (in the O-DHAP and R-DHAP arms, respectively) neutropenia (6% and 7%), rash (9% and <1%), thrombocytopenia (5% and 4%), urticaria (6% and <1%), pyrexia (4% and 2%), febrile neutropenia (4% and 1%), hypersensitivity (4% and 1%), infusion-related reactions (5% and <1%), decrease in platelet count (2% and 3%), and pruritus (4% and 0%).

Sixteen percent of all patients had AEs that led to permanent discontinuation of study treatment. The rate of such AEs was similar between the treatment arms. The most frequent event leading to discontinuation was renal toxicity (8%).

Ofatumumab

Photo courtesy of GSK

Salvage treatment with an ofatumumab-based regimen is no better than a rituximab-based regimen for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to a phase 3 study.

The study, ORCHARRD, was a comparison of ofatumumab plus cisplatin, cytarabine, and dexamethasone (O-DHAP) and rituximab plus DHAP (R-DHAP), both followed by autologous stem cell transplant (auto-SCT), in patients with relapsed/refractory DLBCL.

The data showed no significant difference between the 2 treatment arms with regard to progression-free survival (PFS), event-free survival (EFS), or overall survival (OS).

And the incidence of serious adverse events (AEs) was similar between the arms.

Gustaaf W. van Imhoff, MD, PhD, of University Medical Center Groningen in Groningen, Netherlands, and his colleagues conducted this study and reported the results in the Journal of Clinical Oncology.

The study was proposed by HOVON, sponsored by GlaxoSmithKline (GSK), and funded by GSK, Genmab A/S, and Novartis AG. Ofatumumab became an asset of Novartis AG in March 2015.

Patients and treatment

The study included 447 adults with CD20+ DLBCL who had experienced their first relapse or who were refractory to first-line treatment with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) or a similar regimen.

The patients’ median age was 57 (range, 18 to 83), 63% had stage III/IV disease, and 71% of patients either did not achieve a complete response (CR) to first-line treatment or had a CR lasting less than 1 year.

The patients were randomized to receive O-DHAP (n=222) or R-DHAP (n=225). They received ofatumumab at 1000 mg or rituximab at 375 mg/m² on days 1 and 8 of cycle 1 and day 1 of cycles 2 and 3 of DHAP (4 infusions of either drug).

The patients who had responded after 2 cycles of treatment received the third cycle, followed by high-dose therapy and auto-SCT. Failure to achieve a response after cycle 2 was included as an event.

Response and survival

The response rate was 38% with O-DHAP and 42% with R-DHAP. The CR rate was 15% and 22%, respectively.

Thirty-three percent of patients in the O-DHAP arm and 37% in the R-DHAP arm underwent auto-SCT on protocol.

At 2 years, PFS was 24% with O-DHAP and 26% with R-DHAP (hazard ratio [HR]=1.12, P=0.33).

Two-year EFS was 16% with O-DHAP and 18% with R-DHAP. (HR=1.10, P=0.35). And 2-year OS was 41% with O-DHAP and 38% with R-DHAP (HR=0.90, P=0.38).

The researchers found that having a negative PET scan after cycle 3 was associated with better PFS and OS.

Two-year PFS was 32% for patients with a positive PET scan after cycle 3 and 70% for those with a negative PET scan (P=0.001). Two-year OS was 43% for patients with positive PET scan and 78% for those with a negative PET scan (P=0.0018).

Safety

Fifty-two percent of all patients had 1 or more serious AE, and the incidence of serious AEs was similar between the treatment arms. The most common serious AEs were febrile neutropenia (13%), acute renal failure (5%), thrombocytopenia (5%), and vomiting (5%).

Fatal serious AEs occurred in 6% of patients. These were mainly related to infectious complications and occurred in a similar proportion of patients in both treatment arms.

The incidence of rash was higher in the O-DHAP arm (22% vs 9%), as was the incidence of raised serum creatinine (23% vs 16%).

Dose interruptions/delays (of either anti-CD20 therapy or chemotherapy) as a result of AEs occurred in 49% of patients in the O-DHAP arm and 30% in the R-DHAP arm.

AEs causing dose delays/interruptions included (in the O-DHAP and R-DHAP arms, respectively) neutropenia (6% and 7%), rash (9% and <1%), thrombocytopenia (5% and 4%), urticaria (6% and <1%), pyrexia (4% and 2%), febrile neutropenia (4% and 1%), hypersensitivity (4% and 1%), infusion-related reactions (5% and <1%), decrease in platelet count (2% and 3%), and pruritus (4% and 0%).

Sixteen percent of all patients had AEs that led to permanent discontinuation of study treatment. The rate of such AEs was similar between the treatment arms. The most frequent event leading to discontinuation was renal toxicity (8%).

Micrograph showing CLL

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

Micrograph showing CLL

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

Micrograph showing CLL

Results of a phase 2 trial suggest a 2-drug combination may be effective in patients with chronic lymphocytic leukemia (CLL), particularly those with high-risk disease.

The combination consists of ublituximab (TG-1101), a glycoengineered anti-CD20 monoclonal antibody, and the oral BTK inhibitor ibrutinib.

Six months after starting treatment, the overall response rate was 88% among all evaluable patients and 95% among those with high-risk CLL.

Researchers said the long-term clinical benefit of the combination will be defined by an ongoing phase 3 trial.

The team reported results from the phase 2 trial in the British Journal of Haematology. The study was sponsored by TG Therapeutics, Inc., the company developing ublituximab.

The trial included 45 patients. Their median age was 71 (range, 39-86), about half were female, and the median ECOG performance score was 1.

Nearly half of patients (47%, n=21) had high-risk CLL. Twelve patients had del 17p, 12 had del 11q, 5 patients had both, and 2 had a TP53 mutation.

The patients had a median of 2 (range, 1-7) prior treatments, including purine analogues (n=22), bendamustine (n=21), idelalisib (n=2), a spleen-tyrosine kinase inhibitor (n=2), and the BTK inhibitor CC-292 (n=1).

Treatment

For this study, patients received ibrutinib at 420 mg once daily and 2 different doses of ublituximab. The study had a dose-confirmation safety run-in period that was followed by an open enrollment into phase 2.

The dose-confirmation safety assessment enrolled 6 patients in each of 2 cohorts. Patients in cohort 1 received ublituximab at 600 mg on days 1, 8, and 15 of cycle 1. If there was ≤1 dose-limiting toxicity (DLT) in this cohort, the dose escalation would proceed to cohort 2.

In cohort 2, patients’ ublituximab dose increased to 900 mg on days 1, 8, and 15 of cycle 1. If ≤ 1 DLT was reported in this cohort, the dose was considered safe for phase 2.

There were no DLTs observed in either cohort. So subsequent patients were enrolled into the open phase 2 part of the study, in which they received ublituximab at 900 mg on days 1, 8, and 15 of cycle 1, as well as on day 1 of cycles 2 to 6.

Patients had response assessments at cycles 3 and 6. After that, they continued on ibrutinib monotherapy off study.

Safety

All 45 patients were evaluable for safety. The most common adverse events (AEs) were infusion-related reactions (IRRs, 53%), diarrhea (40%), fatigue (33%), cough (27%), rash (27%), and nausea (24%).

Grade 3/4 AEs included anemia (11%), neutropenia (11%), IRRs (7%), thrombocytopenia (7%), diarrhea (4%), and arthralgia (2%).

All rash and grade 3/4 diarrhea events were attributed to ibrutinib, and all IRRs were related to ublituximab. Twenty-one patients (47%) had dose interruptions due to IRRs, and 1 patient had a dose reduction to 600 mg.

Four patients had ublituximab-related dose interruptions—2 due to neutropenia and 2 because of elevated aspartate aminotransferase.

Two patients had ibrutinib-related dose reductions (for diarrhea and dizziness). Ten patients had ibrutinib-related dose interruptions—3 due to rash, 2 due to neutropenia, and 1 each because of anemia, thrombocytopenia, nausea, hypercalcemia, and dehydration.

Efficacy

Forty-one patients were evaluable for efficacy. Two patients were lost to follow-up, and 2 discontinued due to AEs. One of the AEs, diarrhea, was considered related to ibrutinib. The other patient discontinued due to pneumonia and pleural effusion, which were not attributed to study treatment.

At 6 months, the overall response rate was 88% among evaluable patients and 95% among high-risk patients. The median time to response was 8 weeks.

Two patients had a complete response, 34 had a partial response, and 3 had stable disease.

Both complete responders and 1 of the partial responders achieved minimal residual disease negativity. All 3 of these patients had high-risk disease.

“[T]he addition of ublituximab to ibrutinib not only produced high response rates but also allowed patients to achieve deeper responses, with complete responses and minimal residual disease negativity seen, which is rare with ibrutinib alone,” said study author Jeff Sharman, MD, of Willamette Valley Cancer Institute in Eugene, Oregon.

“We look forward to exploring how the increased depth of response may affect the sequence of treatments given to patients.”

Micrograph showing MCL

Bendamustine hydrochloride (TREAKISYM®) has been approved in Japan as first-line treatment for patients with low-grade B-cell non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL).

The drug will now be available for adjunctive use with rituximab in these patients.

Bendamustine hydrochloride is already approved in Japan as monotherapy for relapsed or refractory low-grade B-cell NHL and MCL, as well as chronic lymphocytic leukemia.

Bendamustine hydrochloride is the subject of a licensing agreement concluded between Eisai Co., Ltd and SymBio Pharmaceuticals Limited. Under the licensing agreement, Eisai has been marketing the product since December 2010.

Bendamustine hydrochloride is available at doses of 25 mg and 100 mg for intravenous infusion. The recommended dosage and administration is as follows:

• For low-grade B-cell NHL and MCL

  • As first-line treatment

    When used adjunctively with rituximab, the usual adult dose of bendamustine hydrochloride is 90 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

  • For relapsed or refractory disease

    The usual adult dose of bendamustine hydrochloride is 120 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 21-day cycles.

• For chronic lymphocytic leukemia

  • The usual adult dose of bendamustine hydrochloride is 100 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

All of the aforementioned doses may be reduced appropriately according to the patient’s condition. 

Micrograph showing MCL

Bendamustine hydrochloride (TREAKISYM®) has been approved in Japan as first-line treatment for patients with low-grade B-cell non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL).

The drug will now be available for adjunctive use with rituximab in these patients.

Bendamustine hydrochloride is already approved in Japan as monotherapy for relapsed or refractory low-grade B-cell NHL and MCL, as well as chronic lymphocytic leukemia.

Bendamustine hydrochloride is the subject of a licensing agreement concluded between Eisai Co., Ltd and SymBio Pharmaceuticals Limited. Under the licensing agreement, Eisai has been marketing the product since December 2010.

Bendamustine hydrochloride is available at doses of 25 mg and 100 mg for intravenous infusion. The recommended dosage and administration is as follows:

• For low-grade B-cell NHL and MCL

  • As first-line treatment

    When used adjunctively with rituximab, the usual adult dose of bendamustine hydrochloride is 90 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

  • For relapsed or refractory disease

    The usual adult dose of bendamustine hydrochloride is 120 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 21-day cycles.

• For chronic lymphocytic leukemia

  • The usual adult dose of bendamustine hydrochloride is 100 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

All of the aforementioned doses may be reduced appropriately according to the patient’s condition. 

Micrograph showing MCL

Bendamustine hydrochloride (TREAKISYM®) has been approved in Japan as first-line treatment for patients with low-grade B-cell non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL).

The drug will now be available for adjunctive use with rituximab in these patients.

Bendamustine hydrochloride is already approved in Japan as monotherapy for relapsed or refractory low-grade B-cell NHL and MCL, as well as chronic lymphocytic leukemia.

Bendamustine hydrochloride is the subject of a licensing agreement concluded between Eisai Co., Ltd and SymBio Pharmaceuticals Limited. Under the licensing agreement, Eisai has been marketing the product since December 2010.

Bendamustine hydrochloride is available at doses of 25 mg and 100 mg for intravenous infusion. The recommended dosage and administration is as follows:

• For low-grade B-cell NHL and MCL

  • As first-line treatment

    When used adjunctively with rituximab, the usual adult dose of bendamustine hydrochloride is 90 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

  • For relapsed or refractory disease

    The usual adult dose of bendamustine hydrochloride is 120 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 21-day cycles.

• For chronic lymphocytic leukemia

  • The usual adult dose of bendamustine hydrochloride is 100 mg/m² body surface area infused intravenously over 60 minutes on days 1 and 2 of repeated 28-day cycles.

All of the aforementioned doses may be reduced appropriately according to the patient’s condition. 

Vial of obinutuzumab

SAN DIEGO—Substituting obinutuzumab for rituximab in combination with CHOP chemotherapy does not improve outcomes in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to a study presented at the 2016 ASH Annual Meeting.

In this phase 3 trial, known as GOYA, researchers compared obinutuzumab plus CHOP (G-CHOP) to rituximab plus CHOP (R-CHOP) in patients with previously untreated DLBCL.

There were no significant differences between the treatment arms with regard to response rates, progression-free survival (PFS), or overall survival (OS).

In addition, grade 3-5 adverse events (AEs) and serious AEs were more common with G-CHOP than with R-CHOP.

“Rituximab plus CHOP remains the standard of care in this setting,” said study investigator Umberto Vitolo, MD, of the Universitaria Città della Salute e della Scienza di Torino in Torino, Italy.

“Further analyses of the data from this trial will inform and shape the direction of future research activities in DLBCL.”

Dr Vitolo presented results from GOYA at ASH as abstract 470.

Obinutuzumab is a glycoengineered, type II, anti-CD20 monoclonal antibody said to have greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than rituximab.

In the phase 2 GATHER trial, G-CHOP demonstrated manageable toxicity and promising preliminary efficacy in patients with advanced, untreated DLBCL.

So with the phase 3 GOYA trial, researchers wanted to compare G-CHOP to R-CHOP in DLBCL. The trial enrolled 1418 patients (median age 62) with previously untreated DLBCL.

Patients from 207 centers around the world were randomized to receive eight 21-day cycles of obinutuzumab at 1000 mg intravenously on days 1, 8, and 15 in cycle 1 and day 1 in cycles 2 to 8 (n=706) or rituximab at 375 mg/m² intravenously on day 1 (n=712) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease.

Dr Vitolo said baseline characteristics were well balanced between the 2 treatment arms. Cell-of-origin distribution, as assessed by gene-expression profiling, was similar in both arms.

Virtually all (88%) of the patients received more than 90% of the planned cumulative dose of chemotherapy. Antibody dose delays were more common in the G-CHOP arm.

Efficacy

The median follow-up was 29 months.

For the primary endpoint of investigator-assessed PFS, there was no significant difference between the G-CHOP and R-CHOP arms. The 3-year PFS was 69.6% for G-CHOP and 66.9% for R-CHOP (hazard ratio [HR]=0.92, P=0.3868).

There were no clinically meaningful differences observed between the treatment arms in terms of secondary endpoints, including OS, end-of-treatment overall response rate, and complete response rate, with or without PET scanning.

At the end of treatment, the overall response rates, according to CT and PET, were 77.9% in the R-CHOP arm and 77.4% in the G-CHOP arm. The complete response rates were 59.5% and 56.7%, respectively.

The 3-year OS rate was 81.4% in the R-CHOP arm and 81.2% in the G-CHOP arm (HR=1.00, P=0.9982).

In a pre-specified subgroup analysis of investigator-assessed PFS, there was a slight trend toward improved PFS in favor of G-CHOP for patients with GCB DLBCL, with a 3-year PFS of 79% vs 70% for R-CHOP (HR=0.72).

Safety

No new safety signals were identified. Grade 3 or higher AEs and serious AEs were more common in the G-CHOP arm than the R-CHOP arm. The incidence of grade 3-5 AEs was 73.7% and 64.7%, respectively. The incidence of serious AEs was 42.6% and 37.6%, respectively.

Certain grade 3-5 AEs were more common with G-CHOP than R-CHOP, including neutropenia (46.2% vs 38.1%), infusion-related reactions (2.8% vs 0.6%), infections (19.2% vs 15.5%), and thrombocytopenia 4.4% vs 1.4%).

AEs resulting in withdrawal from treatment and AEs with fatal outcomes were slightly more common with G-CHOP than with R-CHOP. AEs leading to withdrawal occurred in 11.9% and 8.5% of patients, respectively.

Fatal AEs (listed by preferred term) in the G-CHOP arm included septic shock (n=6, 0.9%), pneumonia (n=5, 0.7%), death (n=3, 0.4%), pulmonary embolism (n=2, 1.3%), and cerebrovascular accident (n=2, 0.3%).

Fatal AEs in the R-CHOP arm included pneumonia (n=6, 0.9%), sepsis (n=3, 0.4%), cerebrovascular accident (n=2, 0.3%), and death (n=2, 0.3%).

Vial of obinutuzumab

SAN DIEGO—Substituting obinutuzumab for rituximab in combination with CHOP chemotherapy does not improve outcomes in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to a study presented at the 2016 ASH Annual Meeting.

In this phase 3 trial, known as GOYA, researchers compared obinutuzumab plus CHOP (G-CHOP) to rituximab plus CHOP (R-CHOP) in patients with previously untreated DLBCL.

There were no significant differences between the treatment arms with regard to response rates, progression-free survival (PFS), or overall survival (OS).

In addition, grade 3-5 adverse events (AEs) and serious AEs were more common with G-CHOP than with R-CHOP.

“Rituximab plus CHOP remains the standard of care in this setting,” said study investigator Umberto Vitolo, MD, of the Universitaria Città della Salute e della Scienza di Torino in Torino, Italy.

“Further analyses of the data from this trial will inform and shape the direction of future research activities in DLBCL.”

Dr Vitolo presented results from GOYA at ASH as abstract 470.

Obinutuzumab is a glycoengineered, type II, anti-CD20 monoclonal antibody said to have greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than rituximab.

In the phase 2 GATHER trial, G-CHOP demonstrated manageable toxicity and promising preliminary efficacy in patients with advanced, untreated DLBCL.

So with the phase 3 GOYA trial, researchers wanted to compare G-CHOP to R-CHOP in DLBCL. The trial enrolled 1418 patients (median age 62) with previously untreated DLBCL.

Patients from 207 centers around the world were randomized to receive eight 21-day cycles of obinutuzumab at 1000 mg intravenously on days 1, 8, and 15 in cycle 1 and day 1 in cycles 2 to 8 (n=706) or rituximab at 375 mg/m² intravenously on day 1 (n=712) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease.

Dr Vitolo said baseline characteristics were well balanced between the 2 treatment arms. Cell-of-origin distribution, as assessed by gene-expression profiling, was similar in both arms.

Virtually all (88%) of the patients received more than 90% of the planned cumulative dose of chemotherapy. Antibody dose delays were more common in the G-CHOP arm.

Efficacy

The median follow-up was 29 months.

For the primary endpoint of investigator-assessed PFS, there was no significant difference between the G-CHOP and R-CHOP arms. The 3-year PFS was 69.6% for G-CHOP and 66.9% for R-CHOP (hazard ratio [HR]=0.92, P=0.3868).

There were no clinically meaningful differences observed between the treatment arms in terms of secondary endpoints, including OS, end-of-treatment overall response rate, and complete response rate, with or without PET scanning.

At the end of treatment, the overall response rates, according to CT and PET, were 77.9% in the R-CHOP arm and 77.4% in the G-CHOP arm. The complete response rates were 59.5% and 56.7%, respectively.

The 3-year OS rate was 81.4% in the R-CHOP arm and 81.2% in the G-CHOP arm (HR=1.00, P=0.9982).

In a pre-specified subgroup analysis of investigator-assessed PFS, there was a slight trend toward improved PFS in favor of G-CHOP for patients with GCB DLBCL, with a 3-year PFS of 79% vs 70% for R-CHOP (HR=0.72).

Safety

No new safety signals were identified. Grade 3 or higher AEs and serious AEs were more common in the G-CHOP arm than the R-CHOP arm. The incidence of grade 3-5 AEs was 73.7% and 64.7%, respectively. The incidence of serious AEs was 42.6% and 37.6%, respectively.

Certain grade 3-5 AEs were more common with G-CHOP than R-CHOP, including neutropenia (46.2% vs 38.1%), infusion-related reactions (2.8% vs 0.6%), infections (19.2% vs 15.5%), and thrombocytopenia 4.4% vs 1.4%).

AEs resulting in withdrawal from treatment and AEs with fatal outcomes were slightly more common with G-CHOP than with R-CHOP. AEs leading to withdrawal occurred in 11.9% and 8.5% of patients, respectively.

Fatal AEs (listed by preferred term) in the G-CHOP arm included septic shock (n=6, 0.9%), pneumonia (n=5, 0.7%), death (n=3, 0.4%), pulmonary embolism (n=2, 1.3%), and cerebrovascular accident (n=2, 0.3%).

Fatal AEs in the R-CHOP arm included pneumonia (n=6, 0.9%), sepsis (n=3, 0.4%), cerebrovascular accident (n=2, 0.3%), and death (n=2, 0.3%).

Vial of obinutuzumab

SAN DIEGO—Substituting obinutuzumab for rituximab in combination with CHOP chemotherapy does not improve outcomes in patients with previously untreated diffuse large B-cell lymphoma (DLBCL), according to a study presented at the 2016 ASH Annual Meeting.

In this phase 3 trial, known as GOYA, researchers compared obinutuzumab plus CHOP (G-CHOP) to rituximab plus CHOP (R-CHOP) in patients with previously untreated DLBCL.

There were no significant differences between the treatment arms with regard to response rates, progression-free survival (PFS), or overall survival (OS).

In addition, grade 3-5 adverse events (AEs) and serious AEs were more common with G-CHOP than with R-CHOP.

“Rituximab plus CHOP remains the standard of care in this setting,” said study investigator Umberto Vitolo, MD, of the Universitaria Città della Salute e della Scienza di Torino in Torino, Italy.

“Further analyses of the data from this trial will inform and shape the direction of future research activities in DLBCL.”

Dr Vitolo presented results from GOYA at ASH as abstract 470.

Obinutuzumab is a glycoengineered, type II, anti-CD20 monoclonal antibody said to have greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than rituximab.

In the phase 2 GATHER trial, G-CHOP demonstrated manageable toxicity and promising preliminary efficacy in patients with advanced, untreated DLBCL.

So with the phase 3 GOYA trial, researchers wanted to compare G-CHOP to R-CHOP in DLBCL. The trial enrolled 1418 patients (median age 62) with previously untreated DLBCL.

Patients from 207 centers around the world were randomized to receive eight 21-day cycles of obinutuzumab at 1000 mg intravenously on days 1, 8, and 15 in cycle 1 and day 1 in cycles 2 to 8 (n=706) or rituximab at 375 mg/m² intravenously on day 1 (n=712) in combination with 6 or 8 cycles of CHOP. Preplanned radiotherapy was allowed for bulky or extranodal disease.

Dr Vitolo said baseline characteristics were well balanced between the 2 treatment arms. Cell-of-origin distribution, as assessed by gene-expression profiling, was similar in both arms.

Virtually all (88%) of the patients received more than 90% of the planned cumulative dose of chemotherapy. Antibody dose delays were more common in the G-CHOP arm.

Efficacy

The median follow-up was 29 months.

For the primary endpoint of investigator-assessed PFS, there was no significant difference between the G-CHOP and R-CHOP arms. The 3-year PFS was 69.6% for G-CHOP and 66.9% for R-CHOP (hazard ratio [HR]=0.92, P=0.3868).

There were no clinically meaningful differences observed between the treatment arms in terms of secondary endpoints, including OS, end-of-treatment overall response rate, and complete response rate, with or without PET scanning.

At the end of treatment, the overall response rates, according to CT and PET, were 77.9% in the R-CHOP arm and 77.4% in the G-CHOP arm. The complete response rates were 59.5% and 56.7%, respectively.

The 3-year OS rate was 81.4% in the R-CHOP arm and 81.2% in the G-CHOP arm (HR=1.00, P=0.9982).

In a pre-specified subgroup analysis of investigator-assessed PFS, there was a slight trend toward improved PFS in favor of G-CHOP for patients with GCB DLBCL, with a 3-year PFS of 79% vs 70% for R-CHOP (HR=0.72).

Safety

No new safety signals were identified. Grade 3 or higher AEs and serious AEs were more common in the G-CHOP arm than the R-CHOP arm. The incidence of grade 3-5 AEs was 73.7% and 64.7%, respectively. The incidence of serious AEs was 42.6% and 37.6%, respectively.

Certain grade 3-5 AEs were more common with G-CHOP than R-CHOP, including neutropenia (46.2% vs 38.1%), infusion-related reactions (2.8% vs 0.6%), infections (19.2% vs 15.5%), and thrombocytopenia 4.4% vs 1.4%).

AEs resulting in withdrawal from treatment and AEs with fatal outcomes were slightly more common with G-CHOP than with R-CHOP. AEs leading to withdrawal occurred in 11.9% and 8.5% of patients, respectively.

Fatal AEs (listed by preferred term) in the G-CHOP arm included septic shock (n=6, 0.9%), pneumonia (n=5, 0.7%), death (n=3, 0.4%), pulmonary embolism (n=2, 1.3%), and cerebrovascular accident (n=2, 0.3%).

Fatal AEs in the R-CHOP arm included pneumonia (n=6, 0.9%), sepsis (n=3, 0.4%), cerebrovascular accident (n=2, 0.3%), and death (n=2, 0.3%).

 

 

Micrograph showing DLBCL

 

The chimeric antigen receptor (CAR) T-cell therapy JCAR017 has received breakthrough therapy designation from the US Food and Drug Administration (FDA) and access to the European Medicines Agency’s (EMA) Priority Medicines (PRIME) program.

JCAR017 has gained access to the PRIME program as a treatment for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

The breakthrough designation is for JCAR017 in the treatment of patients with relapsed/refractory, aggressive, large B-cell non-Hodgkin lymphoma, including DLBCL not otherwise specified (de novo or transformed from indolent lymphoma), primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma.

JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain. The product is being developed by Juno Therapeutics, Inc. and Celgene Corporation.

The breakthrough therapy designation and PRIME eligibility for JCAR017 were granted by the FDA and EMA, respectively, on the basis of early clinical results with JCAR017 in relapsed/refractory DLBCL.

Results from a phase 1 trial of JCAR017 in relapsed/refractory DLBCL and mantle cell lymphoma were recently presented at the 2016 ASH Annual Meeting (abstract 4192).

About the PRIME program

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs.

The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

About breakthrough designation

The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

 

 

Micrograph showing DLBCL

 

The chimeric antigen receptor (CAR) T-cell therapy JCAR017 has received breakthrough therapy designation from the US Food and Drug Administration (FDA) and access to the European Medicines Agency’s (EMA) Priority Medicines (PRIME) program.

JCAR017 has gained access to the PRIME program as a treatment for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

The breakthrough designation is for JCAR017 in the treatment of patients with relapsed/refractory, aggressive, large B-cell non-Hodgkin lymphoma, including DLBCL not otherwise specified (de novo or transformed from indolent lymphoma), primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma.

JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain. The product is being developed by Juno Therapeutics, Inc. and Celgene Corporation.

The breakthrough therapy designation and PRIME eligibility for JCAR017 were granted by the FDA and EMA, respectively, on the basis of early clinical results with JCAR017 in relapsed/refractory DLBCL.

Results from a phase 1 trial of JCAR017 in relapsed/refractory DLBCL and mantle cell lymphoma were recently presented at the 2016 ASH Annual Meeting (abstract 4192).

About the PRIME program

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs.

The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

About breakthrough designation

The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

 

 

Micrograph showing DLBCL

 

The chimeric antigen receptor (CAR) T-cell therapy JCAR017 has received breakthrough therapy designation from the US Food and Drug Administration (FDA) and access to the European Medicines Agency’s (EMA) Priority Medicines (PRIME) program.

JCAR017 has gained access to the PRIME program as a treatment for relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

The breakthrough designation is for JCAR017 in the treatment of patients with relapsed/refractory, aggressive, large B-cell non-Hodgkin lymphoma, including DLBCL not otherwise specified (de novo or transformed from indolent lymphoma), primary mediastinal B-cell lymphoma, and grade 3B follicular lymphoma.

JCAR017 uses a defined CD4:CD8 cell composition and 4-1BB as the costimulatory domain. The product is being developed by Juno Therapeutics, Inc. and Celgene Corporation.

The breakthrough therapy designation and PRIME eligibility for JCAR017 were granted by the FDA and EMA, respectively, on the basis of early clinical results with JCAR017 in relapsed/refractory DLBCL.

Results from a phase 1 trial of JCAR017 in relapsed/refractory DLBCL and mantle cell lymphoma were recently presented at the 2016 ASH Annual Meeting (abstract 4192).

About the PRIME program

The goal of the EMA’s PRIME program is to accelerate the development of therapies that target unmet medical needs.

The program provides enhanced EMA support and increased interaction to developers, in order to optimize development plans and speed regulatory evaluations to potentially bring these therapies to patients more quickly.

To be accepted for PRIME, a therapy must demonstrate the potential to benefit patients with unmet medical need through early clinical or nonclinical data.

About breakthrough designation

The FDA’s breakthrough therapy designation is intended to expedite the development and review of new treatments for serious or life-threatening conditions.

Breakthrough designation entitles the company developing a therapy to more intensive FDA guidance on an efficient and accelerated development program, as well as eligibility for other actions to expedite FDA review, such as a rolling submission and priority review.

To earn breakthrough designation, a treatment must show encouraging early clinical results demonstrating substantial improvement over available therapies with regard to a clinically significant endpoint, or it must fulfill an unmet need.

Micrograph showing CLL

Image by Mary Ann Thompson

Adding an anti-CD37 molecule to treatment with bendamustine can improve outcomes in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in the British Journal of Haematology.

In a phase 2 trial, researchers found that combining the anti-CD37 molecule otlertuzumab with bendamustine significantly improved overall response rates (ORRs) and progression-free survival (PFS) when compared to bendamustine alone.

“We’re very encouraged by the phase 2 data, which demonstrated a significant increase in median progression-free survival, from approximately 10 to 16 months in patients receiving combination otlertuzumab/bendamustine therapy,” said Marvin L. White, president and chief executive officer of Aptevo Therapeutics Inc, the company developing otlertuzumab.

“These data, coupled with additional results from ongoing studies of otlertuzumab used in combination with current CLL therapies, should help position otlertuzumab for a potential partnership to advance into phase 3 clinical development.”

The phase 2 trial was sponsored by Emergent Product Development Seattle LLC. Aptevo Therapeutics is a spin-off of Emergent Biosolutions.

About otlertuzumab

Otlertuzumab (formerly TRU-016) is a humanized, monospecific ADAPTIR™ molecule that targets CD37.

Aptevo Therapeutics says the company is applying its ADAPTIR technology to develop immuno-oncology candidates that focus on redirected T-cell cytotoxicity. ADAPTIR technology can be used to generate immunotherapeutics with unique mechanisms of action, including targeted cytokine delivery, targeting 2 cell surface receptors, or neutralization of multiple soluble proteins.

According to Aptevo, otlertuzumab mediates death of CD37-expressing cells through various mechanisms, including direct cell death, antibody-dependent cell-mediated cytotoxicity, and phagocytosis. Otlertuzumab is being investigated as part of combination therapies for the treatment of CLL.

Study design

This phase 2 study enrolled 65 patients with relapsed/refractory CLL—32 who received a combination of otlertuzumab and bendamustine and 33 who received bendamustine alone.

Patients in the combination arm received otlertuzumab at 20 mg/kg weekly by intravenous infusion for two 28-day cycles, then every 14 days for four 28-day cycles.

Patients in both arms received intravenous bendamustine at 70 mg/m² on days 1 and 2 of each cycle for up to six 28-day cycles. Dosing was adjusted according to neutrophil and platelet counts.

The study’s primary endpoint was ORR (per IWCLL criteria), and secondary endpoints included PFS and safety.

Patient characteristics

The researchers said the treatment arms were generally well balanced. However, patients in the combination arm were older, had more prior treatment regimens, a longer time from diagnosis, and more bulky disease. More patients in the control arm were Rai stage III or IV.

Two patients in the combination arm and 5 in the control arm had 17p deletion. Four patients in the combination arm and 6 in the control arm had TP53 mutations.

There were 5 patients in the combination arm and 3 in the control arm who were refractory to their prior treatment.

In both arms, patients received a median of 6 cycles of study treatment. Bendamustine exposure was similar between the arms—a median of 143 days. The median treatment duration for otlertuzumab was 156 days.

Seven patients (22%) in the combination arm and 12 (36%) in the control arm discontinued treatment early.

In the combination arm, 3 patients discontinued due to adverse events (AEs), 3 due to disease progression, and 1 patient withdrew to have a stem cell transplant.

In the control arm, 7 patients discontinued due to AEs, 3 due to progression, 1 withdrew for an unspecified reason, and 1 patient died of acute heart failure.

Response and survival

The ORR was 69% in the combination arm and 39% in the control arm (P=0.025).

In the combination arm, 3 patients (9%) had a complete response (CR), 1 patient had a CR with incomplete marrow recovery, and 19 (59%) had a partial response.

In the control arm, 1 patient (3%) had a CR and 12 (36%) had a partial response.

The median PFS was 15.9 months in the combination arm and 10.2 months in the control arm (P=0.0192).

The median overall survival was not reached in either arm. After 2 years of follow-up, there were no deaths in the combination arm and 3 deaths in the control arm.

Safety

Ninety-one percent of patients in the combination arm and 100% of those in the control arm experienced an AE. Serious AEs occurred in 31% and 45%, respectively.

Severe neutropenia was more frequent in the combination arm than the control arm (56% vs 39%), as was severe thrombocytopenia (19% vs 15%).

However, there were fewer grade 3/4 infections in the combination arm than the control arm (13% vs 27%). And 2 patients in the control arm had febrile neutropenia, but there were no cases in the combination arm.

“These latest data show the combination of otlertuzumab and bendamustine is well tolerated and significantly increases the response rate and PFS in patients with relapsed or refractory CLL,” said Scott Stromatt, MD, study director and chief medical officer for Aptevo.

“Consequently, we are now exploring the utility of otlertuzumab in combination with additional CLL therapies to evaluate clinical benefit in distinct CLL patient subgroups.”

Micrograph showing CLL

Image by Mary Ann Thompson

Adding an anti-CD37 molecule to treatment with bendamustine can improve outcomes in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in the British Journal of Haematology.

In a phase 2 trial, researchers found that combining the anti-CD37 molecule otlertuzumab with bendamustine significantly improved overall response rates (ORRs) and progression-free survival (PFS) when compared to bendamustine alone.

“We’re very encouraged by the phase 2 data, which demonstrated a significant increase in median progression-free survival, from approximately 10 to 16 months in patients receiving combination otlertuzumab/bendamustine therapy,” said Marvin L. White, president and chief executive officer of Aptevo Therapeutics Inc, the company developing otlertuzumab.

“These data, coupled with additional results from ongoing studies of otlertuzumab used in combination with current CLL therapies, should help position otlertuzumab for a potential partnership to advance into phase 3 clinical development.”

The phase 2 trial was sponsored by Emergent Product Development Seattle LLC. Aptevo Therapeutics is a spin-off of Emergent Biosolutions.

About otlertuzumab

Otlertuzumab (formerly TRU-016) is a humanized, monospecific ADAPTIR™ molecule that targets CD37.

Aptevo Therapeutics says the company is applying its ADAPTIR technology to develop immuno-oncology candidates that focus on redirected T-cell cytotoxicity. ADAPTIR technology can be used to generate immunotherapeutics with unique mechanisms of action, including targeted cytokine delivery, targeting 2 cell surface receptors, or neutralization of multiple soluble proteins.

According to Aptevo, otlertuzumab mediates death of CD37-expressing cells through various mechanisms, including direct cell death, antibody-dependent cell-mediated cytotoxicity, and phagocytosis. Otlertuzumab is being investigated as part of combination therapies for the treatment of CLL.

Study design

This phase 2 study enrolled 65 patients with relapsed/refractory CLL—32 who received a combination of otlertuzumab and bendamustine and 33 who received bendamustine alone.

Patients in the combination arm received otlertuzumab at 20 mg/kg weekly by intravenous infusion for two 28-day cycles, then every 14 days for four 28-day cycles.

Patients in both arms received intravenous bendamustine at 70 mg/m² on days 1 and 2 of each cycle for up to six 28-day cycles. Dosing was adjusted according to neutrophil and platelet counts.

The study’s primary endpoint was ORR (per IWCLL criteria), and secondary endpoints included PFS and safety.

Patient characteristics

The researchers said the treatment arms were generally well balanced. However, patients in the combination arm were older, had more prior treatment regimens, a longer time from diagnosis, and more bulky disease. More patients in the control arm were Rai stage III or IV.

Two patients in the combination arm and 5 in the control arm had 17p deletion. Four patients in the combination arm and 6 in the control arm had TP53 mutations.

There were 5 patients in the combination arm and 3 in the control arm who were refractory to their prior treatment.

In both arms, patients received a median of 6 cycles of study treatment. Bendamustine exposure was similar between the arms—a median of 143 days. The median treatment duration for otlertuzumab was 156 days.

Seven patients (22%) in the combination arm and 12 (36%) in the control arm discontinued treatment early.

In the combination arm, 3 patients discontinued due to adverse events (AEs), 3 due to disease progression, and 1 patient withdrew to have a stem cell transplant.

In the control arm, 7 patients discontinued due to AEs, 3 due to progression, 1 withdrew for an unspecified reason, and 1 patient died of acute heart failure.

Response and survival

The ORR was 69% in the combination arm and 39% in the control arm (P=0.025).

In the combination arm, 3 patients (9%) had a complete response (CR), 1 patient had a CR with incomplete marrow recovery, and 19 (59%) had a partial response.

In the control arm, 1 patient (3%) had a CR and 12 (36%) had a partial response.

The median PFS was 15.9 months in the combination arm and 10.2 months in the control arm (P=0.0192).

The median overall survival was not reached in either arm. After 2 years of follow-up, there were no deaths in the combination arm and 3 deaths in the control arm.

Safety

Ninety-one percent of patients in the combination arm and 100% of those in the control arm experienced an AE. Serious AEs occurred in 31% and 45%, respectively.

Severe neutropenia was more frequent in the combination arm than the control arm (56% vs 39%), as was severe thrombocytopenia (19% vs 15%).

However, there were fewer grade 3/4 infections in the combination arm than the control arm (13% vs 27%). And 2 patients in the control arm had febrile neutropenia, but there were no cases in the combination arm.

“These latest data show the combination of otlertuzumab and bendamustine is well tolerated and significantly increases the response rate and PFS in patients with relapsed or refractory CLL,” said Scott Stromatt, MD, study director and chief medical officer for Aptevo.

“Consequently, we are now exploring the utility of otlertuzumab in combination with additional CLL therapies to evaluate clinical benefit in distinct CLL patient subgroups.”

Micrograph showing CLL

Image by Mary Ann Thompson

Adding an anti-CD37 molecule to treatment with bendamustine can improve outcomes in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to research published in the British Journal of Haematology.

In a phase 2 trial, researchers found that combining the anti-CD37 molecule otlertuzumab with bendamustine significantly improved overall response rates (ORRs) and progression-free survival (PFS) when compared to bendamustine alone.

“We’re very encouraged by the phase 2 data, which demonstrated a significant increase in median progression-free survival, from approximately 10 to 16 months in patients receiving combination otlertuzumab/bendamustine therapy,” said Marvin L. White, president and chief executive officer of Aptevo Therapeutics Inc, the company developing otlertuzumab.

“These data, coupled with additional results from ongoing studies of otlertuzumab used in combination with current CLL therapies, should help position otlertuzumab for a potential partnership to advance into phase 3 clinical development.”

The phase 2 trial was sponsored by Emergent Product Development Seattle LLC. Aptevo Therapeutics is a spin-off of Emergent Biosolutions.

About otlertuzumab

Otlertuzumab (formerly TRU-016) is a humanized, monospecific ADAPTIR™ molecule that targets CD37.

Aptevo Therapeutics says the company is applying its ADAPTIR technology to develop immuno-oncology candidates that focus on redirected T-cell cytotoxicity. ADAPTIR technology can be used to generate immunotherapeutics with unique mechanisms of action, including targeted cytokine delivery, targeting 2 cell surface receptors, or neutralization of multiple soluble proteins.

According to Aptevo, otlertuzumab mediates death of CD37-expressing cells through various mechanisms, including direct cell death, antibody-dependent cell-mediated cytotoxicity, and phagocytosis. Otlertuzumab is being investigated as part of combination therapies for the treatment of CLL.

Study design

This phase 2 study enrolled 65 patients with relapsed/refractory CLL—32 who received a combination of otlertuzumab and bendamustine and 33 who received bendamustine alone.

Patients in the combination arm received otlertuzumab at 20 mg/kg weekly by intravenous infusion for two 28-day cycles, then every 14 days for four 28-day cycles.

Patients in both arms received intravenous bendamustine at 70 mg/m² on days 1 and 2 of each cycle for up to six 28-day cycles. Dosing was adjusted according to neutrophil and platelet counts.

The study’s primary endpoint was ORR (per IWCLL criteria), and secondary endpoints included PFS and safety.

Patient characteristics

The researchers said the treatment arms were generally well balanced. However, patients in the combination arm were older, had more prior treatment regimens, a longer time from diagnosis, and more bulky disease. More patients in the control arm were Rai stage III or IV.

Two patients in the combination arm and 5 in the control arm had 17p deletion. Four patients in the combination arm and 6 in the control arm had TP53 mutations.

There were 5 patients in the combination arm and 3 in the control arm who were refractory to their prior treatment.

In both arms, patients received a median of 6 cycles of study treatment. Bendamustine exposure was similar between the arms—a median of 143 days. The median treatment duration for otlertuzumab was 156 days.

Seven patients (22%) in the combination arm and 12 (36%) in the control arm discontinued treatment early.

In the combination arm, 3 patients discontinued due to adverse events (AEs), 3 due to disease progression, and 1 patient withdrew to have a stem cell transplant.

In the control arm, 7 patients discontinued due to AEs, 3 due to progression, 1 withdrew for an unspecified reason, and 1 patient died of acute heart failure.

Response and survival

The ORR was 69% in the combination arm and 39% in the control arm (P=0.025).

In the combination arm, 3 patients (9%) had a complete response (CR), 1 patient had a CR with incomplete marrow recovery, and 19 (59%) had a partial response.

In the control arm, 1 patient (3%) had a CR and 12 (36%) had a partial response.

The median PFS was 15.9 months in the combination arm and 10.2 months in the control arm (P=0.0192).

The median overall survival was not reached in either arm. After 2 years of follow-up, there were no deaths in the combination arm and 3 deaths in the control arm.

Safety

Ninety-one percent of patients in the combination arm and 100% of those in the control arm experienced an AE. Serious AEs occurred in 31% and 45%, respectively.

Severe neutropenia was more frequent in the combination arm than the control arm (56% vs 39%), as was severe thrombocytopenia (19% vs 15%).

However, there were fewer grade 3/4 infections in the combination arm than the control arm (13% vs 27%). And 2 patients in the control arm had febrile neutropenia, but there were no cases in the combination arm.

“These latest data show the combination of otlertuzumab and bendamustine is well tolerated and significantly increases the response rate and PFS in patients with relapsed or refractory CLL,” said Scott Stromatt, MD, study director and chief medical officer for Aptevo.

“Consequently, we are now exploring the utility of otlertuzumab in combination with additional CLL therapies to evaluate clinical benefit in distinct CLL patient subgroups.”