HT Staff

Chemotherapy drugs

Photo by Bill Branson

Long-term results of the HD2000 trial reveal similar survival rates in patients with previously untreated, aggressive Hodgkin lymphoma (HL) who received 3 different combination treatment regimens.

At 10 years of follow-up, there was no significant difference in overall survival (OS) or progression-free survival (PFS) whether patients received ABVD, BEACOPP, or CEC.

However, patients who received ABVD were significantly less likely than those who received BEACOPP or CEC to develop second malignancies.

Francesco Merli, MD, of Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) in Italy, and his colleagues reported these results in the Journal of Clinical Oncology.

The trial enrolled 307 patients with advanced-stage HL. Patients were randomized to receive 1 of 3 treatment regimens:

• Six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)
• Four escalated plus 2 standard cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone)
• Six cycles of CEC (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin).

Some patients also received radiotherapy, but there was no significant difference in the proportion of patients receiving radiotherapy across the treatment arms—46% in the ABVD arm, 44% in the BEACOPP arm, and 43% in the CEC arm (P=0.871).

Results

At the end of all therapy, the complete response rate was 84% with ABVD, 91% with BEACOPP, and 83% with CEC.

There were 84 patients who did not achieve a complete response, and salvage data were available for 73 of these patients. Three patients (4%) died before salvage therapy could begin, 26 (36%) received conventional chemotherapy, 40 (55%) received a hematopoietic stem cell transplant, and 4 (5%) received radiotherapy.

The median follow-up was 120 months (range, 4 to 169 months), and 295 patients were evaluable.

In a previous analysis, at a median follow-up of 42 months, patients who received BEACOPP had superior PFS compared to patients who received ABVD.

However, in the current analysis, there was no significant difference in PFS between the 3 treatment arms. The 10-year PFS was 69% in the ABVD arm, 75% in the BEACOPP arm, and 76% in the CEC arm (P=0.471).

Likewise, there was no significant difference in OS between the treatment arms. The 10-year OS was 85% in the ABVD arm, 84% in the BEACOPP arm, and 86% in the CEC arm (P=0.892).

There were a total of 13 second malignancies—1 in the ABVD arm and 6 each in the BEACOPP and CEC arms.

The cumulative risk of developing a second malignancy at 10 years was 0.9% in the ABVD arm, 6.6% in the BEACOPP arm, and 6% in the CEC arm. So the risk with either BEACOPP or CEC was significantly higher than with ABVD (P=0.027 and 0.02, respectively).

The researchers said these results suggest BEACOPP provides better disease control than ABVD, but this benefit is counterbalanced by a higher rate of late major events with BEACOPP, particularly second malignancies, which resulted in patient deaths.

So the team concluded that BEACOPP is a viable treatment option for advanced HL, but it should not be considered the standard for all patients because 70% of these patients may be cured with ABVD and limited radiotherapy. A careful assessment of the risk-benefit ratio of the initial treatment choice is warranted.

Chemotherapy drugs

Photo by Bill Branson

Long-term results of the HD2000 trial reveal similar survival rates in patients with previously untreated, aggressive Hodgkin lymphoma (HL) who received 3 different combination treatment regimens.

At 10 years of follow-up, there was no significant difference in overall survival (OS) or progression-free survival (PFS) whether patients received ABVD, BEACOPP, or CEC.

However, patients who received ABVD were significantly less likely than those who received BEACOPP or CEC to develop second malignancies.

Francesco Merli, MD, of Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) in Italy, and his colleagues reported these results in the Journal of Clinical Oncology.

The trial enrolled 307 patients with advanced-stage HL. Patients were randomized to receive 1 of 3 treatment regimens:

• Six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)
• Four escalated plus 2 standard cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone)
• Six cycles of CEC (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin).

Some patients also received radiotherapy, but there was no significant difference in the proportion of patients receiving radiotherapy across the treatment arms—46% in the ABVD arm, 44% in the BEACOPP arm, and 43% in the CEC arm (P=0.871).

Results

At the end of all therapy, the complete response rate was 84% with ABVD, 91% with BEACOPP, and 83% with CEC.

There were 84 patients who did not achieve a complete response, and salvage data were available for 73 of these patients. Three patients (4%) died before salvage therapy could begin, 26 (36%) received conventional chemotherapy, 40 (55%) received a hematopoietic stem cell transplant, and 4 (5%) received radiotherapy.

The median follow-up was 120 months (range, 4 to 169 months), and 295 patients were evaluable.

In a previous analysis, at a median follow-up of 42 months, patients who received BEACOPP had superior PFS compared to patients who received ABVD.

However, in the current analysis, there was no significant difference in PFS between the 3 treatment arms. The 10-year PFS was 69% in the ABVD arm, 75% in the BEACOPP arm, and 76% in the CEC arm (P=0.471).

Likewise, there was no significant difference in OS between the treatment arms. The 10-year OS was 85% in the ABVD arm, 84% in the BEACOPP arm, and 86% in the CEC arm (P=0.892).

There were a total of 13 second malignancies—1 in the ABVD arm and 6 each in the BEACOPP and CEC arms.

The cumulative risk of developing a second malignancy at 10 years was 0.9% in the ABVD arm, 6.6% in the BEACOPP arm, and 6% in the CEC arm. So the risk with either BEACOPP or CEC was significantly higher than with ABVD (P=0.027 and 0.02, respectively).

The researchers said these results suggest BEACOPP provides better disease control than ABVD, but this benefit is counterbalanced by a higher rate of late major events with BEACOPP, particularly second malignancies, which resulted in patient deaths.

So the team concluded that BEACOPP is a viable treatment option for advanced HL, but it should not be considered the standard for all patients because 70% of these patients may be cured with ABVD and limited radiotherapy. A careful assessment of the risk-benefit ratio of the initial treatment choice is warranted.

Chemotherapy drugs

Photo by Bill Branson

Long-term results of the HD2000 trial reveal similar survival rates in patients with previously untreated, aggressive Hodgkin lymphoma (HL) who received 3 different combination treatment regimens.

At 10 years of follow-up, there was no significant difference in overall survival (OS) or progression-free survival (PFS) whether patients received ABVD, BEACOPP, or CEC.

However, patients who received ABVD were significantly less likely than those who received BEACOPP or CEC to develop second malignancies.

Francesco Merli, MD, of Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) in Italy, and his colleagues reported these results in the Journal of Clinical Oncology.

The trial enrolled 307 patients with advanced-stage HL. Patients were randomized to receive 1 of 3 treatment regimens:

• Six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)
• Four escalated plus 2 standard cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone)
• Six cycles of CEC (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin).

Some patients also received radiotherapy, but there was no significant difference in the proportion of patients receiving radiotherapy across the treatment arms—46% in the ABVD arm, 44% in the BEACOPP arm, and 43% in the CEC arm (P=0.871).

Results

At the end of all therapy, the complete response rate was 84% with ABVD, 91% with BEACOPP, and 83% with CEC.

There were 84 patients who did not achieve a complete response, and salvage data were available for 73 of these patients. Three patients (4%) died before salvage therapy could begin, 26 (36%) received conventional chemotherapy, 40 (55%) received a hematopoietic stem cell transplant, and 4 (5%) received radiotherapy.

The median follow-up was 120 months (range, 4 to 169 months), and 295 patients were evaluable.

In a previous analysis, at a median follow-up of 42 months, patients who received BEACOPP had superior PFS compared to patients who received ABVD.

However, in the current analysis, there was no significant difference in PFS between the 3 treatment arms. The 10-year PFS was 69% in the ABVD arm, 75% in the BEACOPP arm, and 76% in the CEC arm (P=0.471).

Likewise, there was no significant difference in OS between the treatment arms. The 10-year OS was 85% in the ABVD arm, 84% in the BEACOPP arm, and 86% in the CEC arm (P=0.892).

There were a total of 13 second malignancies—1 in the ABVD arm and 6 each in the BEACOPP and CEC arms.

The cumulative risk of developing a second malignancy at 10 years was 0.9% in the ABVD arm, 6.6% in the BEACOPP arm, and 6% in the CEC arm. So the risk with either BEACOPP or CEC was significantly higher than with ABVD (P=0.027 and 0.02, respectively).

The researchers said these results suggest BEACOPP provides better disease control than ABVD, but this benefit is counterbalanced by a higher rate of late major events with BEACOPP, particularly second malignancies, which resulted in patient deaths.

So the team concluded that BEACOPP is a viable treatment option for advanced HL, but it should not be considered the standard for all patients because 70% of these patients may be cured with ABVD and limited radiotherapy. A careful assessment of the risk-benefit ratio of the initial treatment choice is warranted.

Team performing surgery

Photo by Piotr Bodzek

CHICAGO—Updated results from the RE-VERSE AD trial suggest idarucizumab, a humanized antibody fragment, can reverse the anticoagulant effect of dabigatran in emergency settings.

In this ongoing phase 3 trial, idarucizumab has normalized diluted thrombin time (dTT) and ecarin clotting time (ECT) in a majority of patients with uncontrolled or life-threatening bleeding and patients who required emergency surgery or an invasive procedure.

In addition, researchers said there have been no safety concerns related to idarucizumab in this trial.

These results were presented at the American College of Cardiology’s 65th Annual Scientific Session (abstract 1130M-05). The study was sponsored by Boehringer Ingelheim, the company that developed idarucizumab and dabigatran.

“The data from this new RE-VERSE AD interim analysis, of the first 123 patients, support earlier findings that show idarucizumab reverses the anticoagulant effect of dabigatran, including reversal in critically ill, high-risk patients in emergency care,” said Charles Pollack, MD, of Thomas Jefferson University in Philadelphia, Pennsylvania.

Dr Pollack and his colleagues presented data on 123 patients—66 with uncontrolled or life-threatening bleeding complications (Group A) and 57 patients requiring emergency surgery or an invasive procedure (Group B).

All of these patients received 5 g of idarucizumab. The primary endpoint of the study is the degree to which idarucizumab reversed the anticoagulant effect of dabigatran within 4 hours, measured by dTT and ECT.

Overall, 94 patients were evaluable for dTT and 112 for ECT. So 97% of evaluable patients (91/94) achieved full reversal of dTT, and 87% (97/112) achieved full reversal of ECT.

Among evaluable patients in Group A (n=48), the median subjective investigator-reported time to cessation of bleeding was 9.8 hours. For 92% of patients (44/48), bleeding stopped within 72 hours of idarucizumab administration.

Among evaluable patients in Group B (n=52), the mean time to surgery was 1.7 hours after receiving idarucizumab. Normal hemostasis during surgery was reported in 92% of patients (48/52).

Thromboembolic events occurred in 5 patients after idarucizumab administration—1 each at 48 hours, 7 days, 9 days, 13 days, and 24 days. None of these patients were receiving antithrombotic therapy at the time of their event.

However, most patients in both groups restarted anticoagulation after receiving idarucizumab—47 of 66 patients in Group A and 49 of 57 patients in Group B.

There were a total of 26 deaths—13 in each group. All of the deaths appeared to be related to the original reason for emergency admission to the hospital and/or to comorbidities.

Team performing surgery

Photo by Piotr Bodzek

CHICAGO—Updated results from the RE-VERSE AD trial suggest idarucizumab, a humanized antibody fragment, can reverse the anticoagulant effect of dabigatran in emergency settings.

In this ongoing phase 3 trial, idarucizumab has normalized diluted thrombin time (dTT) and ecarin clotting time (ECT) in a majority of patients with uncontrolled or life-threatening bleeding and patients who required emergency surgery or an invasive procedure.

In addition, researchers said there have been no safety concerns related to idarucizumab in this trial.

These results were presented at the American College of Cardiology’s 65th Annual Scientific Session (abstract 1130M-05). The study was sponsored by Boehringer Ingelheim, the company that developed idarucizumab and dabigatran.

“The data from this new RE-VERSE AD interim analysis, of the first 123 patients, support earlier findings that show idarucizumab reverses the anticoagulant effect of dabigatran, including reversal in critically ill, high-risk patients in emergency care,” said Charles Pollack, MD, of Thomas Jefferson University in Philadelphia, Pennsylvania.

Dr Pollack and his colleagues presented data on 123 patients—66 with uncontrolled or life-threatening bleeding complications (Group A) and 57 patients requiring emergency surgery or an invasive procedure (Group B).

All of these patients received 5 g of idarucizumab. The primary endpoint of the study is the degree to which idarucizumab reversed the anticoagulant effect of dabigatran within 4 hours, measured by dTT and ECT.

Overall, 94 patients were evaluable for dTT and 112 for ECT. So 97% of evaluable patients (91/94) achieved full reversal of dTT, and 87% (97/112) achieved full reversal of ECT.

Among evaluable patients in Group A (n=48), the median subjective investigator-reported time to cessation of bleeding was 9.8 hours. For 92% of patients (44/48), bleeding stopped within 72 hours of idarucizumab administration.

Among evaluable patients in Group B (n=52), the mean time to surgery was 1.7 hours after receiving idarucizumab. Normal hemostasis during surgery was reported in 92% of patients (48/52).

Thromboembolic events occurred in 5 patients after idarucizumab administration—1 each at 48 hours, 7 days, 9 days, 13 days, and 24 days. None of these patients were receiving antithrombotic therapy at the time of their event.

However, most patients in both groups restarted anticoagulation after receiving idarucizumab—47 of 66 patients in Group A and 49 of 57 patients in Group B.

There were a total of 26 deaths—13 in each group. All of the deaths appeared to be related to the original reason for emergency admission to the hospital and/or to comorbidities.

Team performing surgery

Photo by Piotr Bodzek

CHICAGO—Updated results from the RE-VERSE AD trial suggest idarucizumab, a humanized antibody fragment, can reverse the anticoagulant effect of dabigatran in emergency settings.

In this ongoing phase 3 trial, idarucizumab has normalized diluted thrombin time (dTT) and ecarin clotting time (ECT) in a majority of patients with uncontrolled or life-threatening bleeding and patients who required emergency surgery or an invasive procedure.

In addition, researchers said there have been no safety concerns related to idarucizumab in this trial.

These results were presented at the American College of Cardiology’s 65th Annual Scientific Session (abstract 1130M-05). The study was sponsored by Boehringer Ingelheim, the company that developed idarucizumab and dabigatran.

“The data from this new RE-VERSE AD interim analysis, of the first 123 patients, support earlier findings that show idarucizumab reverses the anticoagulant effect of dabigatran, including reversal in critically ill, high-risk patients in emergency care,” said Charles Pollack, MD, of Thomas Jefferson University in Philadelphia, Pennsylvania.

Dr Pollack and his colleagues presented data on 123 patients—66 with uncontrolled or life-threatening bleeding complications (Group A) and 57 patients requiring emergency surgery or an invasive procedure (Group B).

All of these patients received 5 g of idarucizumab. The primary endpoint of the study is the degree to which idarucizumab reversed the anticoagulant effect of dabigatran within 4 hours, measured by dTT and ECT.

Overall, 94 patients were evaluable for dTT and 112 for ECT. So 97% of evaluable patients (91/94) achieved full reversal of dTT, and 87% (97/112) achieved full reversal of ECT.

Among evaluable patients in Group A (n=48), the median subjective investigator-reported time to cessation of bleeding was 9.8 hours. For 92% of patients (44/48), bleeding stopped within 72 hours of idarucizumab administration.

Among evaluable patients in Group B (n=52), the mean time to surgery was 1.7 hours after receiving idarucizumab. Normal hemostasis during surgery was reported in 92% of patients (48/52).

Thromboembolic events occurred in 5 patients after idarucizumab administration—1 each at 48 hours, 7 days, 9 days, 13 days, and 24 days. None of these patients were receiving antithrombotic therapy at the time of their event.

However, most patients in both groups restarted anticoagulation after receiving idarucizumab—47 of 66 patients in Group A and 49 of 57 patients in Group B.

There were a total of 26 deaths—13 in each group. All of the deaths appeared to be related to the original reason for emergency admission to the hospital and/or to comorbidities.

Researcher in the lab

Photo by Daniel Sone

SAN DIEGO—Researchers say they have discovered a way to make the anticoagulant heparin using human cells.

The team found they could produce heparin from human embryonic kidney cells transfected with the serglycin gene.

They believe this new method could offer a safer alternative to current heparin production methods, which rely on animal byproducts that are largely sourced in China.

However, the researchers noted that their recombinant human heparin was substantially less potent than porcine heparin. So more work must be done to increase the anticoagulant activity of the human heparin.

John Whitelock, PhD, of the University of New South Wales in Sydney, Australia, and his colleagues generated the recombinant human heparin and described their work in a poster presented at Experimental Biology 2016.

“What we’ve done is looked at the way our cells naturally make heparin in our bodies, taken that gene, and expressed it in cells in the laboratory,” Dr Whitelock explained. “The result is a natural product that is not synthetic, which makes it safer than the animal-sourced material.”

Specifically, the researchers increased the expression of serglycin in human embryonic kidney (HEK-293) cells and were able to produce heparin.

The team compared the anticoagulant activity of this heparin and unfractionated porcine mucosal heparin, and they found the porcine heparin was approximately 20 times more potent than the human heparin, on a weight basis.

However, the recombinant human heparin was able to significantly delay fibrin clot formation in plasma when compared to no heparin.

“Frankly, we were surprised that there was any anticoagulant effect at all,” Dr Whitelock said. “People in this field have been working with serglycin for upwards of 20 years, and, usually, you get a sort of heparin ‘cousin’ but not real heparin. It’s been a great source of frustration, and our study is an important step toward an alternative source of heparin that could have distinct advantages for patient safety.”

The team’s next steps are to refine the engineered cells to increase the amount and potency of the heparin they produce.

Dr Whitelock estimates heparin produced with the new method could hit the market within 10 to 15 years, although he cautioned that the drug will likely be more expensive than traditional animal-derived heparin because of the economies of scale that are already built into the existing supply chain.

However, human-cell-derived heparin could potentially be safer, less prone to contamination and adverse reactions, and a better option for patients who cannot use animal-derived heparin due to religious or dietary restrictions.

Researcher in the lab

Photo by Daniel Sone

SAN DIEGO—Researchers say they have discovered a way to make the anticoagulant heparin using human cells.

The team found they could produce heparin from human embryonic kidney cells transfected with the serglycin gene.

They believe this new method could offer a safer alternative to current heparin production methods, which rely on animal byproducts that are largely sourced in China.

However, the researchers noted that their recombinant human heparin was substantially less potent than porcine heparin. So more work must be done to increase the anticoagulant activity of the human heparin.

John Whitelock, PhD, of the University of New South Wales in Sydney, Australia, and his colleagues generated the recombinant human heparin and described their work in a poster presented at Experimental Biology 2016.

“What we’ve done is looked at the way our cells naturally make heparin in our bodies, taken that gene, and expressed it in cells in the laboratory,” Dr Whitelock explained. “The result is a natural product that is not synthetic, which makes it safer than the animal-sourced material.”

Specifically, the researchers increased the expression of serglycin in human embryonic kidney (HEK-293) cells and were able to produce heparin.

The team compared the anticoagulant activity of this heparin and unfractionated porcine mucosal heparin, and they found the porcine heparin was approximately 20 times more potent than the human heparin, on a weight basis.

However, the recombinant human heparin was able to significantly delay fibrin clot formation in plasma when compared to no heparin.

“Frankly, we were surprised that there was any anticoagulant effect at all,” Dr Whitelock said. “People in this field have been working with serglycin for upwards of 20 years, and, usually, you get a sort of heparin ‘cousin’ but not real heparin. It’s been a great source of frustration, and our study is an important step toward an alternative source of heparin that could have distinct advantages for patient safety.”

The team’s next steps are to refine the engineered cells to increase the amount and potency of the heparin they produce.

Dr Whitelock estimates heparin produced with the new method could hit the market within 10 to 15 years, although he cautioned that the drug will likely be more expensive than traditional animal-derived heparin because of the economies of scale that are already built into the existing supply chain.

However, human-cell-derived heparin could potentially be safer, less prone to contamination and adverse reactions, and a better option for patients who cannot use animal-derived heparin due to religious or dietary restrictions.

Researcher in the lab

Photo by Daniel Sone

SAN DIEGO—Researchers say they have discovered a way to make the anticoagulant heparin using human cells.

The team found they could produce heparin from human embryonic kidney cells transfected with the serglycin gene.

They believe this new method could offer a safer alternative to current heparin production methods, which rely on animal byproducts that are largely sourced in China.

However, the researchers noted that their recombinant human heparin was substantially less potent than porcine heparin. So more work must be done to increase the anticoagulant activity of the human heparin.

John Whitelock, PhD, of the University of New South Wales in Sydney, Australia, and his colleagues generated the recombinant human heparin and described their work in a poster presented at Experimental Biology 2016.

“What we’ve done is looked at the way our cells naturally make heparin in our bodies, taken that gene, and expressed it in cells in the laboratory,” Dr Whitelock explained. “The result is a natural product that is not synthetic, which makes it safer than the animal-sourced material.”

Specifically, the researchers increased the expression of serglycin in human embryonic kidney (HEK-293) cells and were able to produce heparin.

The team compared the anticoagulant activity of this heparin and unfractionated porcine mucosal heparin, and they found the porcine heparin was approximately 20 times more potent than the human heparin, on a weight basis.

However, the recombinant human heparin was able to significantly delay fibrin clot formation in plasma when compared to no heparin.

“Frankly, we were surprised that there was any anticoagulant effect at all,” Dr Whitelock said. “People in this field have been working with serglycin for upwards of 20 years, and, usually, you get a sort of heparin ‘cousin’ but not real heparin. It’s been a great source of frustration, and our study is an important step toward an alternative source of heparin that could have distinct advantages for patient safety.”

The team’s next steps are to refine the engineered cells to increase the amount and potency of the heparin they produce.

Dr Whitelock estimates heparin produced with the new method could hit the market within 10 to 15 years, although he cautioned that the drug will likely be more expensive than traditional animal-derived heparin because of the economies of scale that are already built into the existing supply chain.

However, human-cell-derived heparin could potentially be safer, less prone to contamination and adverse reactions, and a better option for patients who cannot use animal-derived heparin due to religious or dietary restrictions.

Micrograph showing AML

The European Medicines Agency (EMA) has recommended orphan designation for the WT1 cancer vaccine galinpepimut-S as a treatment for patients

with acute myeloid leukemia (AML) and patients with malignant pleural mesothelioma (MPM).

The EMA’s opinion has been forwarded to the European Commission (EC), which makes the final decision.

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.

Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.

About the vaccine

The WT1 vaccine consists of 4 modified peptide chains that induce an innate immune response (CD4+/CD8+ T cells) against the WT1 antigen. The vaccine is administered in combination with an adjuvant and an immune modulator to improve the immune response to the target.

Based on the vaccine’s mechanism and the accumulating evidence of activity in mid-stage trials, researchers believe the WT1 vaccine may have the potential to complement currently available therapies by destroying residual tumor cells of cancers in remission and providing ongoing immune surveillance for recurrent tumors.

The WT1 vaccine could potentially target more than 20 cancers that overexpress WT1, many of which are associated with relapse rates of up to 80% or more, as seen in patients with AML and MPM.

The vaccine is being developed by SELLAS Life Sciences Group. The company said that, in a phase 1 study, AML patients treated with the vaccine had a median overall survival of more than 3 years.

In a phase 2 trial of the vaccine, adult AML patients had a median overall survival of around 4 years. Data from the phase 2 trial are scheduled to be presented at the 2016 ASCO Annual Meeting.

SELLAS said it expects to begin a phase 3 trial of the vaccine in AML patients later this year.

Micrograph showing AML

The European Medicines Agency (EMA) has recommended orphan designation for the WT1 cancer vaccine galinpepimut-S as a treatment for patients

with acute myeloid leukemia (AML) and patients with malignant pleural mesothelioma (MPM).

The EMA’s opinion has been forwarded to the European Commission (EC), which makes the final decision.

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.

Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.

About the vaccine

The WT1 vaccine consists of 4 modified peptide chains that induce an innate immune response (CD4+/CD8+ T cells) against the WT1 antigen. The vaccine is administered in combination with an adjuvant and an immune modulator to improve the immune response to the target.

Based on the vaccine’s mechanism and the accumulating evidence of activity in mid-stage trials, researchers believe the WT1 vaccine may have the potential to complement currently available therapies by destroying residual tumor cells of cancers in remission and providing ongoing immune surveillance for recurrent tumors.

The WT1 vaccine could potentially target more than 20 cancers that overexpress WT1, many of which are associated with relapse rates of up to 80% or more, as seen in patients with AML and MPM.

The vaccine is being developed by SELLAS Life Sciences Group. The company said that, in a phase 1 study, AML patients treated with the vaccine had a median overall survival of more than 3 years.

In a phase 2 trial of the vaccine, adult AML patients had a median overall survival of around 4 years. Data from the phase 2 trial are scheduled to be presented at the 2016 ASCO Annual Meeting.

SELLAS said it expects to begin a phase 3 trial of the vaccine in AML patients later this year.

Micrograph showing AML

The European Medicines Agency (EMA) has recommended orphan designation for the WT1 cancer vaccine galinpepimut-S as a treatment for patients

with acute myeloid leukemia (AML) and patients with malignant pleural mesothelioma (MPM).

The EMA’s opinion has been forwarded to the European Commission (EC), which makes the final decision.

The EC grants orphan designation to products intended to treat, prevent, or diagnose a life-threatening condition affecting up to 5 in 10,000 people in the European Union. The product must provide significant benefit to those affected by the condition.

Orphan designation from the EC provides companies with certain development incentives, including protocol assistance, a type of scientific advice specific for orphan drugs, and 10 years of market exclusivity once the drug is approved for use.

About the vaccine

The WT1 vaccine consists of 4 modified peptide chains that induce an innate immune response (CD4+/CD8+ T cells) against the WT1 antigen. The vaccine is administered in combination with an adjuvant and an immune modulator to improve the immune response to the target.

Based on the vaccine’s mechanism and the accumulating evidence of activity in mid-stage trials, researchers believe the WT1 vaccine may have the potential to complement currently available therapies by destroying residual tumor cells of cancers in remission and providing ongoing immune surveillance for recurrent tumors.

The WT1 vaccine could potentially target more than 20 cancers that overexpress WT1, many of which are associated with relapse rates of up to 80% or more, as seen in patients with AML and MPM.

The vaccine is being developed by SELLAS Life Sciences Group. The company said that, in a phase 1 study, AML patients treated with the vaccine had a median overall survival of more than 3 years.

In a phase 2 trial of the vaccine, adult AML patients had a median overall survival of around 4 years. Data from the phase 2 trial are scheduled to be presented at the 2016 ASCO Annual Meeting.

SELLAS said it expects to begin a phase 3 trial of the vaccine in AML patients later this year.

T cells

Image courtesy of NIAID

VALENCIA, SPAIN—Interim results of a phase 1/2 trial suggest the adjunct T-cell therapy BPX-501 can safely accelerate immune recovery after haploidentical hematopoietic stem cell transplant (haplo-HSCT) in pediatric patients with nonmalignant disorders.

Twenty-four such patients received BPX-501 after haplo-HSCT on this trial.

At a median follow-up of 7 months, all 24 were still alive and disease-free.

In addition, the incidence of graft-versus-host disease (GVHD) was considered “very low.”

Pietro Merli, MD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results during the Presidential Symposium of the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) as abstract O007.*

The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate cells in the event of toxicity.

The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.

The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About BP-004

In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.

At the EBMT meeting, investigators reported results in 41 patients treated on this trial.

Dr Merli presented data on the 24 patients with nonmalignant disorders, including Fanconi anemia (n=5), beta-thalassemia major (n=5), severe combined immunodeficiency (n=5), Wiskott-Aldrich syndrome (n=4), Diamond-Blackfan anemia (n=1), hemophagocytic lymphohistiocytosis (n=1), immune deficiency due to mutation of XIAP gene (n=1), osteopetrosis (n=1), and sickle cell disease (n=1).

All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis.

The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 10⁵, 5 x 10⁵, and 1 x 10⁶ cells/kg.

In the phase 2 portion, patients received 1 X 10⁶ BPX-501 cells/kg. Rimiducid was only to be used in the event of uncontrollable GVHD.

Results

The median time to platelet recovery was 10 days (range, 7-16), and the median time to neutrophil recovery was 15 days (range, 10-33).

At a median follow-up of 220 days (range, 61-486), there were no reports of transplant-related mortality.

All 24 patients were still alive and disease-free. And none of the patients developed post-transplant lymphoproliferative disorder.

The cumulative incidence of skin-only acute GVHD was 16.6% (n=4), and the cumulative incidence of mild chronic GVHD was 5% (n=1).

This trial also included 17 patients with acute leukemias. Results in these patients were presented at the EBMT meeting as abstract WP16.

*Information in the abstract differs from that presented at the meeting.

T cells

Image courtesy of NIAID

VALENCIA, SPAIN—Interim results of a phase 1/2 trial suggest the adjunct T-cell therapy BPX-501 can safely accelerate immune recovery after haploidentical hematopoietic stem cell transplant (haplo-HSCT) in pediatric patients with nonmalignant disorders.

Twenty-four such patients received BPX-501 after haplo-HSCT on this trial.

At a median follow-up of 7 months, all 24 were still alive and disease-free.

In addition, the incidence of graft-versus-host disease (GVHD) was considered “very low.”

Pietro Merli, MD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results during the Presidential Symposium of the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) as abstract O007.*

The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate cells in the event of toxicity.

The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.

The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About BP-004

In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.

At the EBMT meeting, investigators reported results in 41 patients treated on this trial.

Dr Merli presented data on the 24 patients with nonmalignant disorders, including Fanconi anemia (n=5), beta-thalassemia major (n=5), severe combined immunodeficiency (n=5), Wiskott-Aldrich syndrome (n=4), Diamond-Blackfan anemia (n=1), hemophagocytic lymphohistiocytosis (n=1), immune deficiency due to mutation of XIAP gene (n=1), osteopetrosis (n=1), and sickle cell disease (n=1).

All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis.

The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 10⁵, 5 x 10⁵, and 1 x 10⁶ cells/kg.

In the phase 2 portion, patients received 1 X 10⁶ BPX-501 cells/kg. Rimiducid was only to be used in the event of uncontrollable GVHD.

Results

The median time to platelet recovery was 10 days (range, 7-16), and the median time to neutrophil recovery was 15 days (range, 10-33).

At a median follow-up of 220 days (range, 61-486), there were no reports of transplant-related mortality.

All 24 patients were still alive and disease-free. And none of the patients developed post-transplant lymphoproliferative disorder.

The cumulative incidence of skin-only acute GVHD was 16.6% (n=4), and the cumulative incidence of mild chronic GVHD was 5% (n=1).

This trial also included 17 patients with acute leukemias. Results in these patients were presented at the EBMT meeting as abstract WP16.

*Information in the abstract differs from that presented at the meeting.

T cells

Image courtesy of NIAID

VALENCIA, SPAIN—Interim results of a phase 1/2 trial suggest the adjunct T-cell therapy BPX-501 can safely accelerate immune recovery after haploidentical hematopoietic stem cell transplant (haplo-HSCT) in pediatric patients with nonmalignant disorders.

Twenty-four such patients received BPX-501 after haplo-HSCT on this trial.

At a median follow-up of 7 months, all 24 were still alive and disease-free.

In addition, the incidence of graft-versus-host disease (GVHD) was considered “very low.”

Pietro Merli, MD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results during the Presidential Symposium of the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT) as abstract O007.*

The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate cells in the event of toxicity.

The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.

The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About BP-004

In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.

At the EBMT meeting, investigators reported results in 41 patients treated on this trial.

Dr Merli presented data on the 24 patients with nonmalignant disorders, including Fanconi anemia (n=5), beta-thalassemia major (n=5), severe combined immunodeficiency (n=5), Wiskott-Aldrich syndrome (n=4), Diamond-Blackfan anemia (n=1), hemophagocytic lymphohistiocytosis (n=1), immune deficiency due to mutation of XIAP gene (n=1), osteopetrosis (n=1), and sickle cell disease (n=1).

All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis.

The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 10⁵, 5 x 10⁵, and 1 x 10⁶ cells/kg.

In the phase 2 portion, patients received 1 X 10⁶ BPX-501 cells/kg. Rimiducid was only to be used in the event of uncontrollable GVHD.

Results

The median time to platelet recovery was 10 days (range, 7-16), and the median time to neutrophil recovery was 15 days (range, 10-33).

At a median follow-up of 220 days (range, 61-486), there were no reports of transplant-related mortality.

All 24 patients were still alive and disease-free. And none of the patients developed post-transplant lymphoproliferative disorder.

The cumulative incidence of skin-only acute GVHD was 16.6% (n=4), and the cumulative incidence of mild chronic GVHD was 5% (n=1).

This trial also included 17 patients with acute leukemias. Results in these patients were presented at the EBMT meeting as abstract WP16.

*Information in the abstract differs from that presented at the meeting.

Leukemia patient

Photo by Bill Branson

VALENCIA, SPAIN—The adjunct T-cell therapy BPX-501 can make haploidentical hematopoietic stem cell transplant (haplo-HSCT) an “attractive option” for pediatric patients with acute leukemia, according to a presentation at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).

Acute leukemia patients who received BPX-501 after haplo-HSCT in a phase 1/2 trial tended to have favorable outcomes.

At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free.

There were several cases of graft-versus-host disease (GVHD), but nearly all of these resolved.

Franco Locatelli, MD, PhD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results at the EBMT meeting as abstract WP16.*

The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate cells in the event of toxicity.

The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.

The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About BP-004

In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.

At the EBMT meeting, researchers reported results in 41 patients treated on this trial.

Dr Locatelli presented data on 17 patients with acute leukemias—13 with acute lymphoblastic leukemia and 4 with acute myeloid leukemia. Their median age at HSCT was 6.5 years (range, 0.9-16.1)

All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis. All were in complete remission at the time of transplant.

The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 10⁵, 5 x 10⁵, and 1 x 10⁶ cells/kg.

In the phase 2 portion, patients received 1 X 10⁶ BPX-501 cells/kg. Rimiducid was only used in the event of uncontrollable GVHD.

Results

The median follow-up was 7 months (range, 1-15.6). The median time to platelet recovery was 11 days (range, 9-13), and the median time to neutrophil recovery was 17 days (range, 10-22).

Three patients developed skin-only acute GVHD, were treated with topical steroids, and the GVHD resolved. Two patients developed acute grade 3 GVHD, were treated with systemic steroids, and the GVHD resolved.

Two patients developed mild chronic GVHD, received systemic steroids, and the GVHD resolved. And 1 patient developed severe chronic GVHD, received systemic steroids and rimiducid, and the GVHD improved.

One patient relapsed. The estimated 1-year disease-free survival was 92.9%. Dr Locatelli noted that, although the follow-up is still limited, these results compare favorably to results in historical controls.

“These interim results continue to be very encouraging and indicate that a haploidentical transplant, with the addition of BPX-501-modified donor T cells, can be an attractive option for children in need of a transplant,” he said.

“Future studies will address the role of repeated infusions or higher numbers of BPX-501 cells in malignant patients with resistant disease.”

The BP-004 trial also included 24 patients with nonmalignant disorders. Results in these patients were presented at the EBMT meeting as abstract O007.

*Information in the abstract differs from that presented at the meeting.

Leukemia patient

Photo by Bill Branson

VALENCIA, SPAIN—The adjunct T-cell therapy BPX-501 can make haploidentical hematopoietic stem cell transplant (haplo-HSCT) an “attractive option” for pediatric patients with acute leukemia, according to a presentation at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).

Acute leukemia patients who received BPX-501 after haplo-HSCT in a phase 1/2 trial tended to have favorable outcomes.

At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free.

There were several cases of graft-versus-host disease (GVHD), but nearly all of these resolved.

Franco Locatelli, MD, PhD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results at the EBMT meeting as abstract WP16.*

The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate cells in the event of toxicity.

The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.

The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About BP-004

In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.

At the EBMT meeting, researchers reported results in 41 patients treated on this trial.

Dr Locatelli presented data on 17 patients with acute leukemias—13 with acute lymphoblastic leukemia and 4 with acute myeloid leukemia. Their median age at HSCT was 6.5 years (range, 0.9-16.1)

All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis. All were in complete remission at the time of transplant.

The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 10⁵, 5 x 10⁵, and 1 x 10⁶ cells/kg.

In the phase 2 portion, patients received 1 X 10⁶ BPX-501 cells/kg. Rimiducid was only used in the event of uncontrollable GVHD.

Results

The median follow-up was 7 months (range, 1-15.6). The median time to platelet recovery was 11 days (range, 9-13), and the median time to neutrophil recovery was 17 days (range, 10-22).

Three patients developed skin-only acute GVHD, were treated with topical steroids, and the GVHD resolved. Two patients developed acute grade 3 GVHD, were treated with systemic steroids, and the GVHD resolved.

Two patients developed mild chronic GVHD, received systemic steroids, and the GVHD resolved. And 1 patient developed severe chronic GVHD, received systemic steroids and rimiducid, and the GVHD improved.

One patient relapsed. The estimated 1-year disease-free survival was 92.9%. Dr Locatelli noted that, although the follow-up is still limited, these results compare favorably to results in historical controls.

“These interim results continue to be very encouraging and indicate that a haploidentical transplant, with the addition of BPX-501-modified donor T cells, can be an attractive option for children in need of a transplant,” he said.

“Future studies will address the role of repeated infusions or higher numbers of BPX-501 cells in malignant patients with resistant disease.”

The BP-004 trial also included 24 patients with nonmalignant disorders. Results in these patients were presented at the EBMT meeting as abstract O007.

*Information in the abstract differs from that presented at the meeting.

Leukemia patient

Photo by Bill Branson

VALENCIA, SPAIN—The adjunct T-cell therapy BPX-501 can make haploidentical hematopoietic stem cell transplant (haplo-HSCT) an “attractive option” for pediatric patients with acute leukemia, according to a presentation at the 42nd Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT).

Acute leukemia patients who received BPX-501 after haplo-HSCT in a phase 1/2 trial tended to have favorable outcomes.

At a median follow-up of 7 months, 16 of the 17 patients were alive and disease-free.

There were several cases of graft-versus-host disease (GVHD), but nearly all of these resolved.

Franco Locatelli, MD, PhD, of Bambino Gesù Children’s Hospital in Rome, Italy, presented these results at the EBMT meeting as abstract WP16.*

The trial, known as BP-004, was sponsored by Bellicum Pharmaceuticals, the company developing BPX-501.

About BPX-501

BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate cells in the event of toxicity.

The goal is to allow physicians to more safely perform haplo-HSCTs by giving patients BPX-501 to speed immune reconstitution and provide control over viral infections. But the technology is designed to provide a safety net to eliminate BPX-501 alloreactive T cells if severe GVHD occurs.

The CaspaCIDe switch consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway. The idea is that, if a patient develops severe GVHD, he can receive an infusion with the small molecule rimiducid. And this will trigger activation of the domain of caspase-9, which leads to selective apoptosis of the CaspaCIDe-containing cells.

About BP-004

In late 2014, Bellicum initiated BP-004, a phase 1/2 trial in children with leukemias, lymphomas, or orphan inherited blood disorders. The trial is being conducted in European and US pediatric transplant centers and is set to enroll up to 90 patients.

At the EBMT meeting, researchers reported results in 41 patients treated on this trial.

Dr Locatelli presented data on 17 patients with acute leukemias—13 with acute lymphoblastic leukemia and 4 with acute myeloid leukemia. Their median age at HSCT was 6.5 years (range, 0.9-16.1)

All of these patients received a T-cell-depleted haplo-HSCT without post-transplant GVHD prophylaxis. All were in complete remission at the time of transplant.

The patients received BPX-501 within 14 ± 4 days after haplo-HSCT. The phase 1 portion of the trial consisted of a classical 3+3 design, with 3 cohorts receiving escalating doses of BPX-501 cells—2.5 x 10⁵, 5 x 10⁵, and 1 x 10⁶ cells/kg.

In the phase 2 portion, patients received 1 X 10⁶ BPX-501 cells/kg. Rimiducid was only used in the event of uncontrollable GVHD.

Results

The median follow-up was 7 months (range, 1-15.6). The median time to platelet recovery was 11 days (range, 9-13), and the median time to neutrophil recovery was 17 days (range, 10-22).

Three patients developed skin-only acute GVHD, were treated with topical steroids, and the GVHD resolved. Two patients developed acute grade 3 GVHD, were treated with systemic steroids, and the GVHD resolved.

Two patients developed mild chronic GVHD, received systemic steroids, and the GVHD resolved. And 1 patient developed severe chronic GVHD, received systemic steroids and rimiducid, and the GVHD improved.

One patient relapsed. The estimated 1-year disease-free survival was 92.9%. Dr Locatelli noted that, although the follow-up is still limited, these results compare favorably to results in historical controls.

“These interim results continue to be very encouraging and indicate that a haploidentical transplant, with the addition of BPX-501-modified donor T cells, can be an attractive option for children in need of a transplant,” he said.

“Future studies will address the role of repeated infusions or higher numbers of BPX-501 cells in malignant patients with resistant disease.”

The BP-004 trial also included 24 patients with nonmalignant disorders. Results in these patients were presented at the EBMT meeting as abstract O007.

*Information in the abstract differs from that presented at the meeting.

VALENCIA, SPAIN—Results of a phase 2 trial suggest a personalized T-cell immunotherapy may improve outcomes in patients undergoing T-cell-depleted haploidentical hematopoietic stem cell transplant (HSCT).

Patients who received the therapy, ATIR101, after HSCT had significant improvements in transplant-related mortality (TRM) and overall survival (OS) when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 graft-versus-host disease (GVHD), despite the fact that they had not received any prophylactic immunosuppressants. Still, there were a few cases of grade 2 GVHD reported.

Denis-Claude Roy, MD, of the University of Montreal in Québec, Canada, presented the results of this trial at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation (abstract O042*). The trial was sponsored by Kiadis Pharma, the company developing ATIR101.

Patients and treatment

The trial included 23 leukemia patients with a median age of 41 (range, 21-64). They were eligible for an allogeneic HSCT but could not find a matching donor in time. Sixteen patients had acute myeloid leukemia, and 7 had acute lymphoblastic leukemia.

All patients were in complete remission (CR) at the time of the HSCT. Fifteen were in CR1, and 8 were in CR2/3. The majority of patients (57%) had a poor prognosis based on their disease risk index and cytogenetic profile.

A myeloablative conditioning regimen was used, which consisted of total body irradiation (1200 cGy; n=11) or melphalan (120 mg/m²; n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m² x 5d), and anti-thymocyte globulin (2.5 mg/kg x 4d).

Patients then received a CD34⁺ selected graft from a haploidentical donor, containing 11 x 10⁶ CD34⁺ cells/kg (range, 4.7-24.4) and 0.29 x 10⁴ CD3⁺ cells/kg (range, 0-1.8).

The patients achieved neutrophil and platelet engraftment at a median of 12 days post-HSCT (range, 8-34 and 9-35, respectively). They did not receive any post-transplant GVHD prophylaxis.

At a median of 28 days post-transplant (range, 28-73), ATIR101 was infused, at a fixed dose of 2 x 10⁶ CD3⁺ cells/kg.

ATIR101 is a personalized T-cell immunotherapy based on a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with a compound known as TH9402, which is selectively retained in activated T cells. Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

Primary endpoint: TRM

The median follow-up, on March 24, 2016, was 414 days (range, 110-742) post-HSCT. At that point, all patients were beyond 6 months post-HSCT. This allowed for assessment of the primary endpoint, which is TRM at 6 months.

Three cases of TRM were reported, for a rate of 13%. In all cases, the cause of death was an infection.

The researchers compared these results to those in a historic control group. It consisted of 35 patients who matched the inclusion and exclusion criteria of this trial and underwent a similar HSCT procedure from haploidentical family members but without the addition of ATIR101.

TRM was significantly lower (P=0.005) in patients who received ATIR101 after a T-cell-depleted haploidentical transplant than in the historical controls. The 6-month TRM for HSCT + ATIR101 was 13%, compared to 37% for HSCT only.

Relapse and survival

Two patients experienced disease relapse within the first 12 months after HSCT—at days 61 and 90. And 1 patient died from disease relapse within the first 6 months.

The researchers said the low rates of relapse and TRM translated into significantly improved OS for patients undergoing HSCT + ATIR101 compared to the historical controls.

Based on Kaplan-Meier estimates, the 1-year OS was 64% in the HSCT + ATIR101 group and 20% in the historical control group (P=0.0026).

GVHD

None of the patients in this trial (0/23) developed grade 3-4 GVHD upon infusion of ATIR101.

However, 3 cases of grade 2 acute GVHD were reported. One case occurred before ATIR101 infusion, and the other 2 cases had a delayed onset, at day 173 and day 247 post-HSCT (145 and 219 days post-ATIR101 infusion).

In the patient who developed GVHD before ATIR101 infusion, GVHD resolved quickly. The patient then received ATIR101 and did not experience any further GVHD.

“With this latest data, we can confirm the safety of ATIR101, without any incidents of grade 3-4 GVHD, significant reduction in transplant-related mortality, low relapse rates, and very good event-free survival, which we believe confirms the efficiency of photodepletion-based elimination of allo-reactive T cells,” Dr Roy said.

“Indeed, the data of patients receiving transplants with a haploidentical donor and an ATIR101 infusion are very similar to those from patients with a matched donor. As a doctor, I am very excited about this development and its potential to change patient fates.”

Dr Roy and his colleagues will continue to follow patients in this trial to collect further long-term outcome data.

Kiadis Pharma is planning to proceed with the development of ATIR101 as an adjunctive immuno-therapeutic treatment to a haploidentical HSCT for patients with acute leukemia, initiating a randomized phase 3 trial in the second half of 2016.

*Information in the abstract differs from that presented at the meeting.

VALENCIA, SPAIN—Results of a phase 2 trial suggest a personalized T-cell immunotherapy may improve outcomes in patients undergoing T-cell-depleted haploidentical hematopoietic stem cell transplant (HSCT).

Patients who received the therapy, ATIR101, after HSCT had significant improvements in transplant-related mortality (TRM) and overall survival (OS) when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 graft-versus-host disease (GVHD), despite the fact that they had not received any prophylactic immunosuppressants. Still, there were a few cases of grade 2 GVHD reported.

Denis-Claude Roy, MD, of the University of Montreal in Québec, Canada, presented the results of this trial at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation (abstract O042*). The trial was sponsored by Kiadis Pharma, the company developing ATIR101.

Patients and treatment

The trial included 23 leukemia patients with a median age of 41 (range, 21-64). They were eligible for an allogeneic HSCT but could not find a matching donor in time. Sixteen patients had acute myeloid leukemia, and 7 had acute lymphoblastic leukemia.

All patients were in complete remission (CR) at the time of the HSCT. Fifteen were in CR1, and 8 were in CR2/3. The majority of patients (57%) had a poor prognosis based on their disease risk index and cytogenetic profile.

A myeloablative conditioning regimen was used, which consisted of total body irradiation (1200 cGy; n=11) or melphalan (120 mg/m²; n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m² x 5d), and anti-thymocyte globulin (2.5 mg/kg x 4d).

Patients then received a CD34⁺ selected graft from a haploidentical donor, containing 11 x 10⁶ CD34⁺ cells/kg (range, 4.7-24.4) and 0.29 x 10⁴ CD3⁺ cells/kg (range, 0-1.8).

The patients achieved neutrophil and platelet engraftment at a median of 12 days post-HSCT (range, 8-34 and 9-35, respectively). They did not receive any post-transplant GVHD prophylaxis.

At a median of 28 days post-transplant (range, 28-73), ATIR101 was infused, at a fixed dose of 2 x 10⁶ CD3⁺ cells/kg.

ATIR101 is a personalized T-cell immunotherapy based on a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with a compound known as TH9402, which is selectively retained in activated T cells. Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

Primary endpoint: TRM

The median follow-up, on March 24, 2016, was 414 days (range, 110-742) post-HSCT. At that point, all patients were beyond 6 months post-HSCT. This allowed for assessment of the primary endpoint, which is TRM at 6 months.

Three cases of TRM were reported, for a rate of 13%. In all cases, the cause of death was an infection.

The researchers compared these results to those in a historic control group. It consisted of 35 patients who matched the inclusion and exclusion criteria of this trial and underwent a similar HSCT procedure from haploidentical family members but without the addition of ATIR101.

TRM was significantly lower (P=0.005) in patients who received ATIR101 after a T-cell-depleted haploidentical transplant than in the historical controls. The 6-month TRM for HSCT + ATIR101 was 13%, compared to 37% for HSCT only.

Relapse and survival

Two patients experienced disease relapse within the first 12 months after HSCT—at days 61 and 90. And 1 patient died from disease relapse within the first 6 months.

The researchers said the low rates of relapse and TRM translated into significantly improved OS for patients undergoing HSCT + ATIR101 compared to the historical controls.

Based on Kaplan-Meier estimates, the 1-year OS was 64% in the HSCT + ATIR101 group and 20% in the historical control group (P=0.0026).

GVHD

None of the patients in this trial (0/23) developed grade 3-4 GVHD upon infusion of ATIR101.

However, 3 cases of grade 2 acute GVHD were reported. One case occurred before ATIR101 infusion, and the other 2 cases had a delayed onset, at day 173 and day 247 post-HSCT (145 and 219 days post-ATIR101 infusion).

In the patient who developed GVHD before ATIR101 infusion, GVHD resolved quickly. The patient then received ATIR101 and did not experience any further GVHD.

“With this latest data, we can confirm the safety of ATIR101, without any incidents of grade 3-4 GVHD, significant reduction in transplant-related mortality, low relapse rates, and very good event-free survival, which we believe confirms the efficiency of photodepletion-based elimination of allo-reactive T cells,” Dr Roy said.

“Indeed, the data of patients receiving transplants with a haploidentical donor and an ATIR101 infusion are very similar to those from patients with a matched donor. As a doctor, I am very excited about this development and its potential to change patient fates.”

Dr Roy and his colleagues will continue to follow patients in this trial to collect further long-term outcome data.

Kiadis Pharma is planning to proceed with the development of ATIR101 as an adjunctive immuno-therapeutic treatment to a haploidentical HSCT for patients with acute leukemia, initiating a randomized phase 3 trial in the second half of 2016.

*Information in the abstract differs from that presented at the meeting.

VALENCIA, SPAIN—Results of a phase 2 trial suggest a personalized T-cell immunotherapy may improve outcomes in patients undergoing T-cell-depleted haploidentical hematopoietic stem cell transplant (HSCT).

Patients who received the therapy, ATIR101, after HSCT had significant improvements in transplant-related mortality (TRM) and overall survival (OS) when compared to historical controls who received a T-cell-depleted haploidentical HSCT without ATIR101.

None of the patients who received ATIR101 developed grade 3-4 graft-versus-host disease (GVHD), despite the fact that they had not received any prophylactic immunosuppressants. Still, there were a few cases of grade 2 GVHD reported.

Denis-Claude Roy, MD, of the University of Montreal in Québec, Canada, presented the results of this trial at the 42nd Annual Meeting of the European Society of Blood and Marrow Transplantation (abstract O042*). The trial was sponsored by Kiadis Pharma, the company developing ATIR101.

Patients and treatment

The trial included 23 leukemia patients with a median age of 41 (range, 21-64). They were eligible for an allogeneic HSCT but could not find a matching donor in time. Sixteen patients had acute myeloid leukemia, and 7 had acute lymphoblastic leukemia.

All patients were in complete remission (CR) at the time of the HSCT. Fifteen were in CR1, and 8 were in CR2/3. The majority of patients (57%) had a poor prognosis based on their disease risk index and cytogenetic profile.

A myeloablative conditioning regimen was used, which consisted of total body irradiation (1200 cGy; n=11) or melphalan (120 mg/m²; n=12), along with thiotepa (10 mg/kg), fludarabine (30 mg/m² x 5d), and anti-thymocyte globulin (2.5 mg/kg x 4d).

Patients then received a CD34⁺ selected graft from a haploidentical donor, containing 11 x 10⁶ CD34⁺ cells/kg (range, 4.7-24.4) and 0.29 x 10⁴ CD3⁺ cells/kg (range, 0-1.8).

The patients achieved neutrophil and platelet engraftment at a median of 12 days post-HSCT (range, 8-34 and 9-35, respectively). They did not receive any post-transplant GVHD prophylaxis.

At a median of 28 days post-transplant (range, 28-73), ATIR101 was infused, at a fixed dose of 2 x 10⁶ CD3⁺ cells/kg.

ATIR101 is a personalized T-cell immunotherapy based on a donor lymphocyte preparation selectively depleted of host-alloreactive T cells through the use of photo-dynamic therapy.

Recipient-reactive T cells from the donor are activated in a unidirectional mixed-lymphocyte reaction. The cells are then treated with a compound known as TH9402, which is selectively retained in activated T cells. Subsequent light exposure eliminates the activated recipient-reactive T cells but preserves the other T cells.

Primary endpoint: TRM

The median follow-up, on March 24, 2016, was 414 days (range, 110-742) post-HSCT. At that point, all patients were beyond 6 months post-HSCT. This allowed for assessment of the primary endpoint, which is TRM at 6 months.

Three cases of TRM were reported, for a rate of 13%. In all cases, the cause of death was an infection.

The researchers compared these results to those in a historic control group. It consisted of 35 patients who matched the inclusion and exclusion criteria of this trial and underwent a similar HSCT procedure from haploidentical family members but without the addition of ATIR101.

TRM was significantly lower (P=0.005) in patients who received ATIR101 after a T-cell-depleted haploidentical transplant than in the historical controls. The 6-month TRM for HSCT + ATIR101 was 13%, compared to 37% for HSCT only.

Relapse and survival

Two patients experienced disease relapse within the first 12 months after HSCT—at days 61 and 90. And 1 patient died from disease relapse within the first 6 months.

The researchers said the low rates of relapse and TRM translated into significantly improved OS for patients undergoing HSCT + ATIR101 compared to the historical controls.

Based on Kaplan-Meier estimates, the 1-year OS was 64% in the HSCT + ATIR101 group and 20% in the historical control group (P=0.0026).

GVHD

None of the patients in this trial (0/23) developed grade 3-4 GVHD upon infusion of ATIR101.

However, 3 cases of grade 2 acute GVHD were reported. One case occurred before ATIR101 infusion, and the other 2 cases had a delayed onset, at day 173 and day 247 post-HSCT (145 and 219 days post-ATIR101 infusion).

In the patient who developed GVHD before ATIR101 infusion, GVHD resolved quickly. The patient then received ATIR101 and did not experience any further GVHD.

“With this latest data, we can confirm the safety of ATIR101, without any incidents of grade 3-4 GVHD, significant reduction in transplant-related mortality, low relapse rates, and very good event-free survival, which we believe confirms the efficiency of photodepletion-based elimination of allo-reactive T cells,” Dr Roy said.

“Indeed, the data of patients receiving transplants with a haploidentical donor and an ATIR101 infusion are very similar to those from patients with a matched donor. As a doctor, I am very excited about this development and its potential to change patient fates.”

Dr Roy and his colleagues will continue to follow patients in this trial to collect further long-term outcome data.

Kiadis Pharma is planning to proceed with the development of ATIR101 as an adjunctive immuno-therapeutic treatment to a haploidentical HSCT for patients with acute leukemia, initiating a randomized phase 3 trial in the second half of 2016.

*Information in the abstract differs from that presented at the meeting.

Lab mice

Photo by Aaron Logan

Two research teams have found evidence to suggest that mutations in PIK3CA, a gene linked to cancer, may drive venous malformations (VMs) in some patients.

Both groups of researchers showed that PIK3CA mutations give rise to VMs in mice, and PIK3CA mutations are present in humans with VMs.

Subsequent experiments with the mice suggested that PIK3CA inhibitors could be used to treat VMs.

Both groups reported their findings in Science Translational Medicine.

Pau Castel, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues were originally studying the role of PIK3CA in uterine cancer when they noticed that mice harboring PIK3CA mutations developed defective blood vessels that closely resembled VMs.

Sandra Castillo, PhD, of University College London in the UK, and her colleagues generated mice with PIK3CA-activating mutations that also mimicked the human disease, including during mouse embryonic development.

Both teams found the mutations spurred uncontrolled growth of endothelial cells, which formed abnormal clusters and faulty blood vessels.

To verify their mouse models, the researchers analyzed samples from patients with VMs. Dr Castillo and her colleagues looked at samples from 13 children, while Castel and his colleagues evaluated samples from 32 patients (both adults and children).

Dr Castillo and her colleagues found PIK3CA mutations in 25% of patients, and Castel and his colleagues found mutations in PIK3CA and related genes of the PI3K/AKT pathway in about 30% of patients.

Both groups of researchers then tested PI3K inhibitors in their mouse models and found these drugs could stunt blood vessel overgrowth.

“Rapamycin is a drug that blocks a signaling process that happens downstream of PIK3CA, so it stops one of PIK3CA’s effects but does not block it at the source,” Dr Castillo said. “When we gave rapamycin to the mice, it showed clinical benefit, but, in patients, it can have serious side effects and compromise the immune system.”

“Our colleagues at MSK [Memorial Sloan Kettering] then tested drugs on the mice that directly inhibit PIK3CA, developed to treat cancer. These drugs worked well and significantly reduced the size of the malformations, not only when given through the bloodstream but also when applied directly to the skin as a cream.”

Lab mice

Photo by Aaron Logan

Two research teams have found evidence to suggest that mutations in PIK3CA, a gene linked to cancer, may drive venous malformations (VMs) in some patients.

Both groups of researchers showed that PIK3CA mutations give rise to VMs in mice, and PIK3CA mutations are present in humans with VMs.

Subsequent experiments with the mice suggested that PIK3CA inhibitors could be used to treat VMs.

Both groups reported their findings in Science Translational Medicine.

Pau Castel, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues were originally studying the role of PIK3CA in uterine cancer when they noticed that mice harboring PIK3CA mutations developed defective blood vessels that closely resembled VMs.

Sandra Castillo, PhD, of University College London in the UK, and her colleagues generated mice with PIK3CA-activating mutations that also mimicked the human disease, including during mouse embryonic development.

Both teams found the mutations spurred uncontrolled growth of endothelial cells, which formed abnormal clusters and faulty blood vessels.

To verify their mouse models, the researchers analyzed samples from patients with VMs. Dr Castillo and her colleagues looked at samples from 13 children, while Castel and his colleagues evaluated samples from 32 patients (both adults and children).

Dr Castillo and her colleagues found PIK3CA mutations in 25% of patients, and Castel and his colleagues found mutations in PIK3CA and related genes of the PI3K/AKT pathway in about 30% of patients.

Both groups of researchers then tested PI3K inhibitors in their mouse models and found these drugs could stunt blood vessel overgrowth.

“Rapamycin is a drug that blocks a signaling process that happens downstream of PIK3CA, so it stops one of PIK3CA’s effects but does not block it at the source,” Dr Castillo said. “When we gave rapamycin to the mice, it showed clinical benefit, but, in patients, it can have serious side effects and compromise the immune system.”

“Our colleagues at MSK [Memorial Sloan Kettering] then tested drugs on the mice that directly inhibit PIK3CA, developed to treat cancer. These drugs worked well and significantly reduced the size of the malformations, not only when given through the bloodstream but also when applied directly to the skin as a cream.”

Lab mice

Photo by Aaron Logan

Two research teams have found evidence to suggest that mutations in PIK3CA, a gene linked to cancer, may drive venous malformations (VMs) in some patients.

Both groups of researchers showed that PIK3CA mutations give rise to VMs in mice, and PIK3CA mutations are present in humans with VMs.

Subsequent experiments with the mice suggested that PIK3CA inhibitors could be used to treat VMs.

Both groups reported their findings in Science Translational Medicine.

Pau Castel, of Memorial Sloan Kettering Cancer Center in New York, New York, and his colleagues were originally studying the role of PIK3CA in uterine cancer when they noticed that mice harboring PIK3CA mutations developed defective blood vessels that closely resembled VMs.

Sandra Castillo, PhD, of University College London in the UK, and her colleagues generated mice with PIK3CA-activating mutations that also mimicked the human disease, including during mouse embryonic development.

Both teams found the mutations spurred uncontrolled growth of endothelial cells, which formed abnormal clusters and faulty blood vessels.

To verify their mouse models, the researchers analyzed samples from patients with VMs. Dr Castillo and her colleagues looked at samples from 13 children, while Castel and his colleagues evaluated samples from 32 patients (both adults and children).

Dr Castillo and her colleagues found PIK3CA mutations in 25% of patients, and Castel and his colleagues found mutations in PIK3CA and related genes of the PI3K/AKT pathway in about 30% of patients.

Both groups of researchers then tested PI3K inhibitors in their mouse models and found these drugs could stunt blood vessel overgrowth.

“Rapamycin is a drug that blocks a signaling process that happens downstream of PIK3CA, so it stops one of PIK3CA’s effects but does not block it at the source,” Dr Castillo said. “When we gave rapamycin to the mice, it showed clinical benefit, but, in patients, it can have serious side effects and compromise the immune system.”

“Our colleagues at MSK [Memorial Sloan Kettering] then tested drugs on the mice that directly inhibit PIK3CA, developed to treat cancer. These drugs worked well and significantly reduced the size of the malformations, not only when given through the bloodstream but also when applied directly to the skin as a cream.”

 

 

Micrograph showing DLBCL

 

The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.

In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).

And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.

However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.

These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.

“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.

CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.

Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).

Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).

Treatment

CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.

Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.

Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).

Safety

Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.

The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).

Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.

AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).

Efficacy

Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.

Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.

The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.

Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.

Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule.

 

 

Micrograph showing DLBCL

 

The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.

In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).

And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.

However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.

These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.

“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.

CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.

Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).

Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).

Treatment

CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.

Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.

Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).

Safety

Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.

The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).

Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.

AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).

Efficacy

Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.

Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.

The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.

Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.

Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule.

 

 

Micrograph showing DLBCL

 

The small-molecule inhibitor CUDC-907 can provide disease control in patients with relapsed or refractory lymphoma and multiple myeloma (MM), according to researchers.

In a phase 1 trial, CUDC-907 produced responses in a small number of patients with diffuse large B-cell lymphoma (DLBCL).

And more than half of patients had stable disease while on CUDC-907, including those with MM, DLBCL, Hodgkin lymphoma (HL), and other lymphomas.

However, a majority of patients in this trial—84%—discontinued treatment due to confirmed progressive disease or signs of progression.

These results were published in The Lancet. The trial was sponsored by Curis, Inc., the company developing CUDC-907, and the Leukemia and Lymphoma Society.

“The data from the phase 1 monotherapy trial for CUDC-907, especially in heavily pretreated patients with relapsed/refractory DLBCL are very encouraging, and we look forward to data emerging from the current phase 2 trial in patients with MYC-altered DLBCL,” said study author Anas Younes, MD, of the Memorial Sloan Kettering Cancer Center in New York, New York.

CUDC-907 is an oral, dual inhibitor of class I and II histone deacetylases (HDACs), as well as class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6, and 10 and PI3K-alpha, delta, and beta isoforms.

Between Jan 23, 2013, and July 27, 2015, the phase 1 trial of CUDC-907 enrolled 44 patients who were refractory to or had relapsed after 2 or more previous regimens. The patients’ median age was 63 (range, 22-83), and they had received a median of 5 prior treatments (range, 2-10).

Four patients had MM, 12 had HL, and 12 had DLBCL. The remaining 16 patients had other types of lymphoma, including lymphoplasmacytic lymphoma (n=3), small lymphocytic lymphoma (n=3), mantle cell lymphoma (n=3), follicular lymphoma (n=2), T-cell lymphoma (n=2), marginal zone lymphoma (n=1), Burkitt lymphoma (n=1), and gray zone lymphoma (n=1).

Treatment

CUDC-907 was given in a standard 3 + 3 dose-escalation design at 4 different dosing schedules—once daily, twice weekly, 3 times weekly, and daily for 5 days followed by a 2-day break (5/2)—in 21-day cycles.

Patients continued to receive CUDC-907 until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose.

Ten patients were sequentially assigned to CUDC-907 once-daily (MTD 60 mg), 12 to twice-weekly (MTD 150 mg), 15 to 3-times-weekly (MTD 150 mg), and 7 to the 5/2 dosing schedule (MTD 60 mg).

Safety

Four dose-limiting toxicities (DLTs) occurred in 3 of 40 DLT-evaluable patients. The DLTs were diarrhea and hyperglycemia in 1 patient on 60 mg once daily, hyperglycemia in 1 patient on 150 mg twice weekly, and diarrhea in 1 patient on 150 mg 3 times weekly. There were no DLTs in patients on the 5/2 schedule.

The incidence of grade 3 or higher adverse events (AEs) was 43% (19/44). The most common of these AEs were thrombocytopenia (20%, n=9), neutropenia (7%, n=3), and hyperglycemia (7%, n=3).

Twenty-five percent of patients (11/44) had serious AEs. Three of these events were considered treatment-related. They were epistaxis and the DLTs of diarrhea and hyperglycemia.

AEs led to dose reductions in 6 patients (14%) and treatment discontinuation in 7 patients (16%).

Efficacy

Thirty-seven patients were evaluable for response, and 5 of these patients responded (14%). All responses—2 complete and 3 partial responses—occurred in patients with DLBCL.

Twenty-one of the response-evaluable patients (57%) had stable disease. This included 1 patient with DLBCL, 2 with MM, 8 with HL, and 10 with the “other” types of lymphoma.

The remaining 11 patients progressed (30%)—3 with DLBCL, 2 with MM, 2 with HL, and 4 with other lymphomas.

Thirty-seven patients (84%) discontinued CUDC-907 because of progressive disease or clinical signs of progressive disease at the data cutoff.

Based on the clinical activity of CUDC-907 in patients with relapsed/refractory DLBCL, particularly those with MYC alterations, Curis has initiated a phase 2 trial of the drug in these patients. The recommended phase 2 dose is 60 mg on the 5/2 dosing schedule.

Macaque

Photo by Sakurai Midori

The parasite responsible for a form of malaria now spreading from macaques to humans in South Asia could evolve to infect humans more efficiently, according to a study published in Nature Communications.

Researchers identified a sugar variant on the surface of human red blood cells (RBCs) that currently limits the ability of the parasite Plasmodium knowlesi to invade.

But the team also found the parasite can evolve to get around this barrier and pass into the human population in a more virulent form.

“With increasing concern about the spread of P knowlesi into human populations, it is great to be able to gain insight into what the molecular stumbling blocks are for P knowlesi infection of humans and how the parasite can potentially overcome them,” said study author Selasi Dankwa, PhD, of Harvard T.H. Chan School of Public Health in Boston, Massachusetts.

The macaque malaria parasite P knowlesi has emerged as a major source of human infections in Southeast Asia. While most human infections are mild, increasing numbers of severe infections are being reported, leading to concerns that the parasite is adapting to infect humans more efficiently.

With this in mind, Dr Dankwa and her colleagues decided to explore the parasite’s ability to invade and adapt.

The team introduced the macaque sugar variant onto the human RBC surface and demonstrated that the parasite normally dependent on the macaque variant for invasion was unable to use the human version.

Specifically, macaques synthesize the sialic acid variant N-glycolylneuraminic acid (Neu5Gc), but humans lack Neu5Gc because of an Alu-mediated exon deletion in the gene encoding CMAH, which converts N-acetylneuraminic acid (Neu5Ac) to Neu5Gc.

So the absence of Neu5Gc on human RBCs limits P knowlesi invasion, but the researchers found that parasites can evolve to invade human RBCs via sialic acid-independent pathways.

Following prolonged adaptation to growth on human RBCs, P knowlesi invaded human RBCs independently of Neu5Gc. This occurred via duplication of the region containing the sialic acid-independent gene PkDBPα and complete deletion of the sialic acid-dependent gene PkDBPγ.

Based on these findings, the researchers are calling for continued monitoring of the P knowlesi parasite to ensure that it has not switched to using a sialic acid-independent pathway to invade human RBCs.

Macaque

Photo by Sakurai Midori

The parasite responsible for a form of malaria now spreading from macaques to humans in South Asia could evolve to infect humans more efficiently, according to a study published in Nature Communications.

Researchers identified a sugar variant on the surface of human red blood cells (RBCs) that currently limits the ability of the parasite Plasmodium knowlesi to invade.

But the team also found the parasite can evolve to get around this barrier and pass into the human population in a more virulent form.

“With increasing concern about the spread of P knowlesi into human populations, it is great to be able to gain insight into what the molecular stumbling blocks are for P knowlesi infection of humans and how the parasite can potentially overcome them,” said study author Selasi Dankwa, PhD, of Harvard T.H. Chan School of Public Health in Boston, Massachusetts.

The macaque malaria parasite P knowlesi has emerged as a major source of human infections in Southeast Asia. While most human infections are mild, increasing numbers of severe infections are being reported, leading to concerns that the parasite is adapting to infect humans more efficiently.

With this in mind, Dr Dankwa and her colleagues decided to explore the parasite’s ability to invade and adapt.

The team introduced the macaque sugar variant onto the human RBC surface and demonstrated that the parasite normally dependent on the macaque variant for invasion was unable to use the human version.

Specifically, macaques synthesize the sialic acid variant N-glycolylneuraminic acid (Neu5Gc), but humans lack Neu5Gc because of an Alu-mediated exon deletion in the gene encoding CMAH, which converts N-acetylneuraminic acid (Neu5Ac) to Neu5Gc.

So the absence of Neu5Gc on human RBCs limits P knowlesi invasion, but the researchers found that parasites can evolve to invade human RBCs via sialic acid-independent pathways.

Following prolonged adaptation to growth on human RBCs, P knowlesi invaded human RBCs independently of Neu5Gc. This occurred via duplication of the region containing the sialic acid-independent gene PkDBPα and complete deletion of the sialic acid-dependent gene PkDBPγ.

Based on these findings, the researchers are calling for continued monitoring of the P knowlesi parasite to ensure that it has not switched to using a sialic acid-independent pathway to invade human RBCs.

Macaque

Photo by Sakurai Midori

The parasite responsible for a form of malaria now spreading from macaques to humans in South Asia could evolve to infect humans more efficiently, according to a study published in Nature Communications.

Researchers identified a sugar variant on the surface of human red blood cells (RBCs) that currently limits the ability of the parasite Plasmodium knowlesi to invade.

But the team also found the parasite can evolve to get around this barrier and pass into the human population in a more virulent form.

“With increasing concern about the spread of P knowlesi into human populations, it is great to be able to gain insight into what the molecular stumbling blocks are for P knowlesi infection of humans and how the parasite can potentially overcome them,” said study author Selasi Dankwa, PhD, of Harvard T.H. Chan School of Public Health in Boston, Massachusetts.

The macaque malaria parasite P knowlesi has emerged as a major source of human infections in Southeast Asia. While most human infections are mild, increasing numbers of severe infections are being reported, leading to concerns that the parasite is adapting to infect humans more efficiently.

With this in mind, Dr Dankwa and her colleagues decided to explore the parasite’s ability to invade and adapt.

The team introduced the macaque sugar variant onto the human RBC surface and demonstrated that the parasite normally dependent on the macaque variant for invasion was unable to use the human version.

Specifically, macaques synthesize the sialic acid variant N-glycolylneuraminic acid (Neu5Gc), but humans lack Neu5Gc because of an Alu-mediated exon deletion in the gene encoding CMAH, which converts N-acetylneuraminic acid (Neu5Ac) to Neu5Gc.

So the absence of Neu5Gc on human RBCs limits P knowlesi invasion, but the researchers found that parasites can evolve to invade human RBCs via sialic acid-independent pathways.

Following prolonged adaptation to growth on human RBCs, P knowlesi invaded human RBCs independently of Neu5Gc. This occurred via duplication of the region containing the sialic acid-independent gene PkDBPα and complete deletion of the sialic acid-dependent gene PkDBPγ.

Based on these findings, the researchers are calling for continued monitoring of the P knowlesi parasite to ensure that it has not switched to using a sialic acid-independent pathway to invade human RBCs.