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Cell therapy receives RMAT designation
The US Food and Drug Administration (FDA) has granted regenerative medicine advanced therapy (RMAT) designation for romyelocel-L, a myeloid progenitor cell therapy that doesn’t require HLA matching.
Romyelocel-L (CLT-008) is being developed as prophylaxis for serious bacterial and fungal infections in patients with de novo acute myeloid leukemia (AML) who develop neutropenia while receiving induction chemotherapy.
The FDA grants RMAT designation to therapies intended to treat serious or life-threatening conditions if there is preliminary clinical evidence that the therapies could address unmet medical needs.
RMAT designation provides similar advantages as breakthrough therapy designation, including early interactions with the FDA to discuss potential ways to accelerate the development of a therapy toward regulatory approval.
The FDA granted romyelocel-L RMAT designation based on a randomized, phase 2 trial of newly diagnosed AML patients who received induction consisting of cytarabine and an anthracycline.
Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 7043).
The trial enrolled 163 AML patients and randomized them, on the first day of induction, to receive:
- Daily granulocyte colony-stimulating factor (G-CSF) starting on day 14 (n=84)
- Romyelocel-L (7.5 x 106cells/kg) on day 9 plus daily G-CSF starting on day 14 (n=79).
Patients received G-CSF until neutrophil recovery to at least 500/µL.
Baseline characteristics were well balanced between the treatment arms.
There were 120 evaluable patients—59 in the romyelocel-L arm and 61 in the control arm.
The study’s primary endpoint was days in a febrile episode (DFE). The mean DFE from day 9 to 28 was 6.46 days in the romyelocel-L arm and 6.86 days in the control arm (P=0.350). The mean DFE for days 15 to 28 was 2.36 and 3.90, respectively (P=0.020).
The incidence of microbiologically or clinically diagnosed infection from day 9 to 28 was 35.6% in the romyelocel-L arm and 47.5% in the control arm, a decrease of 25% (P=0.089).
From day 15 to 28 the incidence of infection was 6.8% in the romyelocel-L arm and 27.9% in the control arm, a decrease of 76% (P=0.002).
There were no infectious deaths in the romyelocel-L arm but 2 deaths attributed to pneumonia in the control arm.
The mean hospital stay was 25.5 days in the romyelocel-L arm and 28.7 days in the control arm (P=0.002).
The proportion of patients with serious adverse events (AEs) was 14% in the romyelocel-L arm and 18% in the control arm. The proportion of patients with infectious serious AEs was 50% and 77%, respectively.
The most frequent treatment-emergent AEs (in the romyelocel-L and control arms, respectively) were febrile neutropenia (31.4% and 31%), diarrhea (25.7% and 32.4%), hypokalemia (31.4% and 25.4%), hypophosphatemia (21.4% and 23.9%), and pyrexia (22.9% and 22.5%).
There were no cases of graft-versus-host disease.
The US Food and Drug Administration (FDA) has granted regenerative medicine advanced therapy (RMAT) designation for romyelocel-L, a myeloid progenitor cell therapy that doesn’t require HLA matching.
Romyelocel-L (CLT-008) is being developed as prophylaxis for serious bacterial and fungal infections in patients with de novo acute myeloid leukemia (AML) who develop neutropenia while receiving induction chemotherapy.
The FDA grants RMAT designation to therapies intended to treat serious or life-threatening conditions if there is preliminary clinical evidence that the therapies could address unmet medical needs.
RMAT designation provides similar advantages as breakthrough therapy designation, including early interactions with the FDA to discuss potential ways to accelerate the development of a therapy toward regulatory approval.
The FDA granted romyelocel-L RMAT designation based on a randomized, phase 2 trial of newly diagnosed AML patients who received induction consisting of cytarabine and an anthracycline.
Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 7043).
The trial enrolled 163 AML patients and randomized them, on the first day of induction, to receive:
- Daily granulocyte colony-stimulating factor (G-CSF) starting on day 14 (n=84)
- Romyelocel-L (7.5 x 106cells/kg) on day 9 plus daily G-CSF starting on day 14 (n=79).
Patients received G-CSF until neutrophil recovery to at least 500/µL.
Baseline characteristics were well balanced between the treatment arms.
There were 120 evaluable patients—59 in the romyelocel-L arm and 61 in the control arm.
The study’s primary endpoint was days in a febrile episode (DFE). The mean DFE from day 9 to 28 was 6.46 days in the romyelocel-L arm and 6.86 days in the control arm (P=0.350). The mean DFE for days 15 to 28 was 2.36 and 3.90, respectively (P=0.020).
The incidence of microbiologically or clinically diagnosed infection from day 9 to 28 was 35.6% in the romyelocel-L arm and 47.5% in the control arm, a decrease of 25% (P=0.089).
From day 15 to 28 the incidence of infection was 6.8% in the romyelocel-L arm and 27.9% in the control arm, a decrease of 76% (P=0.002).
There were no infectious deaths in the romyelocel-L arm but 2 deaths attributed to pneumonia in the control arm.
The mean hospital stay was 25.5 days in the romyelocel-L arm and 28.7 days in the control arm (P=0.002).
The proportion of patients with serious adverse events (AEs) was 14% in the romyelocel-L arm and 18% in the control arm. The proportion of patients with infectious serious AEs was 50% and 77%, respectively.
The most frequent treatment-emergent AEs (in the romyelocel-L and control arms, respectively) were febrile neutropenia (31.4% and 31%), diarrhea (25.7% and 32.4%), hypokalemia (31.4% and 25.4%), hypophosphatemia (21.4% and 23.9%), and pyrexia (22.9% and 22.5%).
There were no cases of graft-versus-host disease.
The US Food and Drug Administration (FDA) has granted regenerative medicine advanced therapy (RMAT) designation for romyelocel-L, a myeloid progenitor cell therapy that doesn’t require HLA matching.
Romyelocel-L (CLT-008) is being developed as prophylaxis for serious bacterial and fungal infections in patients with de novo acute myeloid leukemia (AML) who develop neutropenia while receiving induction chemotherapy.
The FDA grants RMAT designation to therapies intended to treat serious or life-threatening conditions if there is preliminary clinical evidence that the therapies could address unmet medical needs.
RMAT designation provides similar advantages as breakthrough therapy designation, including early interactions with the FDA to discuss potential ways to accelerate the development of a therapy toward regulatory approval.
The FDA granted romyelocel-L RMAT designation based on a randomized, phase 2 trial of newly diagnosed AML patients who received induction consisting of cytarabine and an anthracycline.
Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 7043).
The trial enrolled 163 AML patients and randomized them, on the first day of induction, to receive:
- Daily granulocyte colony-stimulating factor (G-CSF) starting on day 14 (n=84)
- Romyelocel-L (7.5 x 106cells/kg) on day 9 plus daily G-CSF starting on day 14 (n=79).
Patients received G-CSF until neutrophil recovery to at least 500/µL.
Baseline characteristics were well balanced between the treatment arms.
There were 120 evaluable patients—59 in the romyelocel-L arm and 61 in the control arm.
The study’s primary endpoint was days in a febrile episode (DFE). The mean DFE from day 9 to 28 was 6.46 days in the romyelocel-L arm and 6.86 days in the control arm (P=0.350). The mean DFE for days 15 to 28 was 2.36 and 3.90, respectively (P=0.020).
The incidence of microbiologically or clinically diagnosed infection from day 9 to 28 was 35.6% in the romyelocel-L arm and 47.5% in the control arm, a decrease of 25% (P=0.089).
From day 15 to 28 the incidence of infection was 6.8% in the romyelocel-L arm and 27.9% in the control arm, a decrease of 76% (P=0.002).
There were no infectious deaths in the romyelocel-L arm but 2 deaths attributed to pneumonia in the control arm.
The mean hospital stay was 25.5 days in the romyelocel-L arm and 28.7 days in the control arm (P=0.002).
The proportion of patients with serious adverse events (AEs) was 14% in the romyelocel-L arm and 18% in the control arm. The proportion of patients with infectious serious AEs was 50% and 77%, respectively.
The most frequent treatment-emergent AEs (in the romyelocel-L and control arms, respectively) were febrile neutropenia (31.4% and 31%), diarrhea (25.7% and 32.4%), hypokalemia (31.4% and 25.4%), hypophosphatemia (21.4% and 23.9%), and pyrexia (22.9% and 22.5%).
There were no cases of graft-versus-host disease.
‘Very encouraging’ results in BPDCN
STOCKHOLM—Tagraxofusp (SL-401) has produced “very encouraging” results in a phase 2 trial of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to an investigator.
Tagraxofusp, a targeted therapy directed to CD123, produced an overall response rate (ORR) of 83% and a complete response (CR) rate of 62% in patients with previously untreated or relapsed/refractory BPDCN.
Common adverse events (AEs) related to tagraxofusp include hypoalbuminemia, transaminitis, and thrombocytopenia. There was 1 grade 5 AE—a case of capillary leak syndrome (CLS).
Study investigator Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S116.
The trial was sponsored by Stemline Therapeutics.
Dr Pemmaraju noted that there are no approved therapies for BPDCN, so patients may be treated with therapies intended for acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphomas.
“These are usually quite intense cytotoxic chemotherapy regimens,” he said. “But even with these regimens, most groups report median overall survival times of 8 to 14 months.”
And although stem cell transplants can be effective in BPDCN, a “vast majority” of patients are not fit for transplant, according to Dr Pemmaraju.
With this in mind, he and his colleagues are conducting this trial of tagraxofusp in BPDCN.
The trial has 4 stages. In stage 1, patients received tagraxofusp at 7, 9, 12, or 16 μg/kg on days 1 to 5 of a 21-day cycle. In stages 2 and 3, patients received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle. Stage 4 is still enrolling.
Efficacy
Dr Pemmaraju presented results in 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN. The patients’ median age at baseline was 70 (range, 22-84), and 82% were male.
Three patients received tagraxofusp at 7 μg/kg/day, and the rest received the 12 μg/kg/day dose.
Among patients who received the 12 μg/kg/day dose, the ORR was 83% (35/42). The ORR was 90% (26/29) in previously untreated patients and 69% (9/13) in relapsed/refractory patients.
“These are very encouraging results—a 90% overall response rate in the frontline setting,” Dr Pemmaraju noted.
The composite CR rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.
This included 13 patients with a CR (1 relapsed/refractory), 10 with a clinical CR (3 relapsed/refractory), and 3 with a CR with incomplete hematologic recovery (1 relapsed/refractory). A clinical CR was defined as absence of gross disease with minimal residual skin abnormality.
Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.
Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival has not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).
Dr Pemmaraju said this result is important because it contrasts with the historical expectation of a median overall survival of 8 to 14 months.
Safety
Dr Pemmaraju presented safety results in 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with AML, myelofibrosis, and chronic myelomonocytic leukemia in addition to the 45 patients with BPDCN. However, AEs were similar regardless of disease.
Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).
CLS of any grade was also a common AE, occurring in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.
Dr Pemmaraju did note that CLS has proven manageable with monitoring and pre-emptive measures. Specifically, inclusion criteria were changed so that patients must have normal cardiac function, adequate kidney function, and albumin of at least 3.2 g/dl. Investigators also began monitoring patients’ weight, albumin levels, and kidney function.
“With the combination of greater understanding of CLS, actual definitive protocol adjustments made by investigators, and monitoring, this has been a highly manageable phenomenon,” Dr Pemmaraju said.
Next steps
The investigators plan to continue enrolling patients in this study and collect additional safety and survival data, but Dr Pemmaraju and his colleagues also want to evaluate tagraxofusp in combination with other therapies.
Tagraxofusp is already under investigation in combination with azacitidine in a phase 1/2 trial of patients with high-risk myelodysplastic syndromes and AML.
Dr Pemmaraju is interested in combining hypomethylating agents with tagraxofusp for BPDCN patients as well, to build upon the encouraging results with tagraxofusp alone.
“An extraordinarily rare disease that used to not have any therapies at all now has at least one ongoing clinical trial with some encouraging activity,” he said. “I hope that gives hope to people with rare diseases, to let them know they’re not alone. There may be someone out there who’s researching their disease, no matter how rare it is.”
STOCKHOLM—Tagraxofusp (SL-401) has produced “very encouraging” results in a phase 2 trial of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to an investigator.
Tagraxofusp, a targeted therapy directed to CD123, produced an overall response rate (ORR) of 83% and a complete response (CR) rate of 62% in patients with previously untreated or relapsed/refractory BPDCN.
Common adverse events (AEs) related to tagraxofusp include hypoalbuminemia, transaminitis, and thrombocytopenia. There was 1 grade 5 AE—a case of capillary leak syndrome (CLS).
Study investigator Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S116.
The trial was sponsored by Stemline Therapeutics.
Dr Pemmaraju noted that there are no approved therapies for BPDCN, so patients may be treated with therapies intended for acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphomas.
“These are usually quite intense cytotoxic chemotherapy regimens,” he said. “But even with these regimens, most groups report median overall survival times of 8 to 14 months.”
And although stem cell transplants can be effective in BPDCN, a “vast majority” of patients are not fit for transplant, according to Dr Pemmaraju.
With this in mind, he and his colleagues are conducting this trial of tagraxofusp in BPDCN.
The trial has 4 stages. In stage 1, patients received tagraxofusp at 7, 9, 12, or 16 μg/kg on days 1 to 5 of a 21-day cycle. In stages 2 and 3, patients received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle. Stage 4 is still enrolling.
Efficacy
Dr Pemmaraju presented results in 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN. The patients’ median age at baseline was 70 (range, 22-84), and 82% were male.
Three patients received tagraxofusp at 7 μg/kg/day, and the rest received the 12 μg/kg/day dose.
Among patients who received the 12 μg/kg/day dose, the ORR was 83% (35/42). The ORR was 90% (26/29) in previously untreated patients and 69% (9/13) in relapsed/refractory patients.
“These are very encouraging results—a 90% overall response rate in the frontline setting,” Dr Pemmaraju noted.
The composite CR rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.
This included 13 patients with a CR (1 relapsed/refractory), 10 with a clinical CR (3 relapsed/refractory), and 3 with a CR with incomplete hematologic recovery (1 relapsed/refractory). A clinical CR was defined as absence of gross disease with minimal residual skin abnormality.
Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.
Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival has not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).
Dr Pemmaraju said this result is important because it contrasts with the historical expectation of a median overall survival of 8 to 14 months.
Safety
Dr Pemmaraju presented safety results in 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with AML, myelofibrosis, and chronic myelomonocytic leukemia in addition to the 45 patients with BPDCN. However, AEs were similar regardless of disease.
Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).
CLS of any grade was also a common AE, occurring in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.
Dr Pemmaraju did note that CLS has proven manageable with monitoring and pre-emptive measures. Specifically, inclusion criteria were changed so that patients must have normal cardiac function, adequate kidney function, and albumin of at least 3.2 g/dl. Investigators also began monitoring patients’ weight, albumin levels, and kidney function.
“With the combination of greater understanding of CLS, actual definitive protocol adjustments made by investigators, and monitoring, this has been a highly manageable phenomenon,” Dr Pemmaraju said.
Next steps
The investigators plan to continue enrolling patients in this study and collect additional safety and survival data, but Dr Pemmaraju and his colleagues also want to evaluate tagraxofusp in combination with other therapies.
Tagraxofusp is already under investigation in combination with azacitidine in a phase 1/2 trial of patients with high-risk myelodysplastic syndromes and AML.
Dr Pemmaraju is interested in combining hypomethylating agents with tagraxofusp for BPDCN patients as well, to build upon the encouraging results with tagraxofusp alone.
“An extraordinarily rare disease that used to not have any therapies at all now has at least one ongoing clinical trial with some encouraging activity,” he said. “I hope that gives hope to people with rare diseases, to let them know they’re not alone. There may be someone out there who’s researching their disease, no matter how rare it is.”
STOCKHOLM—Tagraxofusp (SL-401) has produced “very encouraging” results in a phase 2 trial of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), according to an investigator.
Tagraxofusp, a targeted therapy directed to CD123, produced an overall response rate (ORR) of 83% and a complete response (CR) rate of 62% in patients with previously untreated or relapsed/refractory BPDCN.
Common adverse events (AEs) related to tagraxofusp include hypoalbuminemia, transaminitis, and thrombocytopenia. There was 1 grade 5 AE—a case of capillary leak syndrome (CLS).
Study investigator Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, presented these results at the 23rd Congress of the European Hematology Association (EHA) as abstract S116.
The trial was sponsored by Stemline Therapeutics.
Dr Pemmaraju noted that there are no approved therapies for BPDCN, so patients may be treated with therapies intended for acute myeloid leukemia (AML), acute lymphoblastic leukemia, or lymphomas.
“These are usually quite intense cytotoxic chemotherapy regimens,” he said. “But even with these regimens, most groups report median overall survival times of 8 to 14 months.”
And although stem cell transplants can be effective in BPDCN, a “vast majority” of patients are not fit for transplant, according to Dr Pemmaraju.
With this in mind, he and his colleagues are conducting this trial of tagraxofusp in BPDCN.
The trial has 4 stages. In stage 1, patients received tagraxofusp at 7, 9, 12, or 16 μg/kg on days 1 to 5 of a 21-day cycle. In stages 2 and 3, patients received the drug at 12 μg/kg on days 1 to 5 of a 21-day cycle. Stage 4 is still enrolling.
Efficacy
Dr Pemmaraju presented results in 45 patients—32 with previously untreated BPDCN and 13 with relapsed/refractory BPDCN. The patients’ median age at baseline was 70 (range, 22-84), and 82% were male.
Three patients received tagraxofusp at 7 μg/kg/day, and the rest received the 12 μg/kg/day dose.
Among patients who received the 12 μg/kg/day dose, the ORR was 83% (35/42). The ORR was 90% (26/29) in previously untreated patients and 69% (9/13) in relapsed/refractory patients.
“These are very encouraging results—a 90% overall response rate in the frontline setting,” Dr Pemmaraju noted.
The composite CR rate was 62% (n=26) overall, 72% (n=21) in previously untreated patients, and 38% (n=5) in relapsed/refractory patients.
This included 13 patients with a CR (1 relapsed/refractory), 10 with a clinical CR (3 relapsed/refractory), and 3 with a CR with incomplete hematologic recovery (1 relapsed/refractory). A clinical CR was defined as absence of gross disease with minimal residual skin abnormality.
Fourteen patients went on to stem cell transplant, 1 of whom had relapsed/refractory disease at baseline.
Overall survival results were only available for the 29 previously untreated patients who received tagraxofusp at 12 μg/kg/day. In this group, the median overall survival has not been reached at a median follow-up of 13.8 months (range, 0.2 to 37.4 months).
Dr Pemmaraju said this result is important because it contrasts with the historical expectation of a median overall survival of 8 to 14 months.
Safety
Dr Pemmaraju presented safety results in 114 patients who have received tagraxofusp at 12 μg/kg/day on all trials of the drug. These data include patients with AML, myelofibrosis, and chronic myelomonocytic leukemia in addition to the 45 patients with BPDCN. However, AEs were similar regardless of disease.
Common treatment-related AEs (of any grade, occurring in at least 15% of patients) included hypoalbuminemia (49%), ALT increase (48%), AST increase (48%), thrombocytopenia (29%), nausea (27%), pyrexia (25%), chills (23%), fatigue (23%), weight increase (19%), hypotension (18%), peripheral edema (17%), and vomiting (15%).
CLS of any grade was also a common AE, occurring in 20% of patients (n=23). Most cases of CLS were grade 1 or 2, but there were grade 3 (n=5) and 4 (n=2) cases, as well as a single case of grade 5 CLS that occurred in a BPDCN patient.
Dr Pemmaraju did note that CLS has proven manageable with monitoring and pre-emptive measures. Specifically, inclusion criteria were changed so that patients must have normal cardiac function, adequate kidney function, and albumin of at least 3.2 g/dl. Investigators also began monitoring patients’ weight, albumin levels, and kidney function.
“With the combination of greater understanding of CLS, actual definitive protocol adjustments made by investigators, and monitoring, this has been a highly manageable phenomenon,” Dr Pemmaraju said.
Next steps
The investigators plan to continue enrolling patients in this study and collect additional safety and survival data, but Dr Pemmaraju and his colleagues also want to evaluate tagraxofusp in combination with other therapies.
Tagraxofusp is already under investigation in combination with azacitidine in a phase 1/2 trial of patients with high-risk myelodysplastic syndromes and AML.
Dr Pemmaraju is interested in combining hypomethylating agents with tagraxofusp for BPDCN patients as well, to build upon the encouraging results with tagraxofusp alone.
“An extraordinarily rare disease that used to not have any therapies at all now has at least one ongoing clinical trial with some encouraging activity,” he said. “I hope that gives hope to people with rare diseases, to let them know they’re not alone. There may be someone out there who’s researching their disease, no matter how rare it is.”
CHMP recommends rVWF for VWD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for vonicog alfa (Veyvondi), a recombinant von Willebrand factor (rVWF) product.
The CHMP is recommending vonicog alfa for the treatment of bleeding events and treatment/prevention of surgical bleeding in adults (age 18 and older) with von Willebrand disease (VWD) when desmopressin treatment alone is ineffective or not indicated.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s opinion of vonicog alfa is supported by a pair of phase 3 trials.
Non-surgical setting
Results from a phase 3 trial of vonicog alfa in a non-surgical setting were published in Blood in 2015.
The study included 49 patients with VWD who received vonicog alfa with or without recombinant factor VIII (FVIII).
All participants had successful treatment of bleeding episodes. Most (96.9%) treated bleeds (n=192 bleeds in 22 patients) were given an “excellent” efficacy rating (as good as or better than expected).
Most bleeds (81.8%) were resolved with a single infusion of vonicog alfa, and the treatment had a mean half-life of 21.9 hours.
There were 8 adverse events (AEs) considered related to vonicog alfa, and 2 were serious. One patient experienced 2 simultaneous serious AEs—chest discomfort and increased heart rate—but these were resolved.
There were no thrombotic events in this trial, no treatment-related binding or neutralizing antibodies against VWF, and no neutralizing antibodies against FVIII.
Surgical setting
Results from the phase 3 trial in a surgical setting were presented at the WFH 2018 World Congress.
The trial enrolled 15 adults with severe VWD who were undergoing elective surgical procedures (10 of them major procedures).
Patients received vonicog alfa at 40 to 60 IU per kg of body weight 12 to 24 hours before surgery. Within 3 hours of surgery, each patient’s FVIII level (FVIII:C) was assessed, with a target of 30 IU/dL for minor surgeries and 60 IU/dL for major surgeries.
Within an hour of surgery, patients received a dose of vonicog alfa, with or without recombinant factor VIII, depending on the target FVIII:C levels at the 3-hour assessment.
Ten patients received rVWF alone, 12 did not receive any preoperative FVIII, and 2 did not receive rVWF postoperatively.
The study’s primary endpoint was met. Vonicog alfa demonstrated overall hemostatic efficacy, as assessed 24 hours after the last perioperative infusion or the completion of the study visit, whichever occurred earlier.
Intra- and post-operative hemostasis was rated as “excellent” (as good as or better than expected) in 60% of patients and “good” (probably as good as expected) in 40% of patients.
One patient developed deep vein thrombosis 3 days after undergoing hip replacement surgery.
One patient tested positive for binding antibodies to VWF. None of the patients developed binding antibodies against potential impurities such as rFurin, CHO-protein, or mouse IgG.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for vonicog alfa (Veyvondi), a recombinant von Willebrand factor (rVWF) product.
The CHMP is recommending vonicog alfa for the treatment of bleeding events and treatment/prevention of surgical bleeding in adults (age 18 and older) with von Willebrand disease (VWD) when desmopressin treatment alone is ineffective or not indicated.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s opinion of vonicog alfa is supported by a pair of phase 3 trials.
Non-surgical setting
Results from a phase 3 trial of vonicog alfa in a non-surgical setting were published in Blood in 2015.
The study included 49 patients with VWD who received vonicog alfa with or without recombinant factor VIII (FVIII).
All participants had successful treatment of bleeding episodes. Most (96.9%) treated bleeds (n=192 bleeds in 22 patients) were given an “excellent” efficacy rating (as good as or better than expected).
Most bleeds (81.8%) were resolved with a single infusion of vonicog alfa, and the treatment had a mean half-life of 21.9 hours.
There were 8 adverse events (AEs) considered related to vonicog alfa, and 2 were serious. One patient experienced 2 simultaneous serious AEs—chest discomfort and increased heart rate—but these were resolved.
There were no thrombotic events in this trial, no treatment-related binding or neutralizing antibodies against VWF, and no neutralizing antibodies against FVIII.
Surgical setting
Results from the phase 3 trial in a surgical setting were presented at the WFH 2018 World Congress.
The trial enrolled 15 adults with severe VWD who were undergoing elective surgical procedures (10 of them major procedures).
Patients received vonicog alfa at 40 to 60 IU per kg of body weight 12 to 24 hours before surgery. Within 3 hours of surgery, each patient’s FVIII level (FVIII:C) was assessed, with a target of 30 IU/dL for minor surgeries and 60 IU/dL for major surgeries.
Within an hour of surgery, patients received a dose of vonicog alfa, with or without recombinant factor VIII, depending on the target FVIII:C levels at the 3-hour assessment.
Ten patients received rVWF alone, 12 did not receive any preoperative FVIII, and 2 did not receive rVWF postoperatively.
The study’s primary endpoint was met. Vonicog alfa demonstrated overall hemostatic efficacy, as assessed 24 hours after the last perioperative infusion or the completion of the study visit, whichever occurred earlier.
Intra- and post-operative hemostasis was rated as “excellent” (as good as or better than expected) in 60% of patients and “good” (probably as good as expected) in 40% of patients.
One patient developed deep vein thrombosis 3 days after undergoing hip replacement surgery.
One patient tested positive for binding antibodies to VWF. None of the patients developed binding antibodies against potential impurities such as rFurin, CHO-protein, or mouse IgG.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for vonicog alfa (Veyvondi), a recombinant von Willebrand factor (rVWF) product.
The CHMP is recommending vonicog alfa for the treatment of bleeding events and treatment/prevention of surgical bleeding in adults (age 18 and older) with von Willebrand disease (VWD) when desmopressin treatment alone is ineffective or not indicated.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s opinion of vonicog alfa is supported by a pair of phase 3 trials.
Non-surgical setting
Results from a phase 3 trial of vonicog alfa in a non-surgical setting were published in Blood in 2015.
The study included 49 patients with VWD who received vonicog alfa with or without recombinant factor VIII (FVIII).
All participants had successful treatment of bleeding episodes. Most (96.9%) treated bleeds (n=192 bleeds in 22 patients) were given an “excellent” efficacy rating (as good as or better than expected).
Most bleeds (81.8%) were resolved with a single infusion of vonicog alfa, and the treatment had a mean half-life of 21.9 hours.
There were 8 adverse events (AEs) considered related to vonicog alfa, and 2 were serious. One patient experienced 2 simultaneous serious AEs—chest discomfort and increased heart rate—but these were resolved.
There were no thrombotic events in this trial, no treatment-related binding or neutralizing antibodies against VWF, and no neutralizing antibodies against FVIII.
Surgical setting
Results from the phase 3 trial in a surgical setting were presented at the WFH 2018 World Congress.
The trial enrolled 15 adults with severe VWD who were undergoing elective surgical procedures (10 of them major procedures).
Patients received vonicog alfa at 40 to 60 IU per kg of body weight 12 to 24 hours before surgery. Within 3 hours of surgery, each patient’s FVIII level (FVIII:C) was assessed, with a target of 30 IU/dL for minor surgeries and 60 IU/dL for major surgeries.
Within an hour of surgery, patients received a dose of vonicog alfa, with or without recombinant factor VIII, depending on the target FVIII:C levels at the 3-hour assessment.
Ten patients received rVWF alone, 12 did not receive any preoperative FVIII, and 2 did not receive rVWF postoperatively.
The study’s primary endpoint was met. Vonicog alfa demonstrated overall hemostatic efficacy, as assessed 24 hours after the last perioperative infusion or the completion of the study visit, whichever occurred earlier.
Intra- and post-operative hemostasis was rated as “excellent” (as good as or better than expected) in 60% of patients and “good” (probably as good as expected) in 40% of patients.
One patient developed deep vein thrombosis 3 days after undergoing hip replacement surgery.
One patient tested positive for binding antibodies to VWF. None of the patients developed binding antibodies against potential impurities such as rFurin, CHO-protein, or mouse IgG.
CHMP supports authorization of drug for AML
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for CPX-351 (Vyxeos™), a liposomal formulation that delivers a fixed ratio (1:5) of daunorubicin and cytarabine.
The CHMP is recommending approval of CPX-351 (44 mg/100 mg) for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia or AML with myelodysplasia-related changes.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The marketing authorization application for CPX-351 is supported by data from 5 studies, including a phase 3 study.
Data from the phase 3 study were presented at the 2016 ASCO Annual Meeting and are available in the US prescribing information for CPX-351. (The following data are taken from the prescribing information.)
This trial enrolled 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.
They received CPX-351 (n=153) or cytarabine and daunorubicin (7+3; n=156).
The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).
The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.
The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).
All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.
Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.
The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.
The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.
The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for CPX-351 (Vyxeos™), a liposomal formulation that delivers a fixed ratio (1:5) of daunorubicin and cytarabine.
The CHMP is recommending approval of CPX-351 (44 mg/100 mg) for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia or AML with myelodysplasia-related changes.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The marketing authorization application for CPX-351 is supported by data from 5 studies, including a phase 3 study.
Data from the phase 3 study were presented at the 2016 ASCO Annual Meeting and are available in the US prescribing information for CPX-351. (The following data are taken from the prescribing information.)
This trial enrolled 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.
They received CPX-351 (n=153) or cytarabine and daunorubicin (7+3; n=156).
The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).
The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.
The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).
All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.
Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.
The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.
The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.
The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for CPX-351 (Vyxeos™), a liposomal formulation that delivers a fixed ratio (1:5) of daunorubicin and cytarabine.
The CHMP is recommending approval of CPX-351 (44 mg/100 mg) for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia or AML with myelodysplasia-related changes.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The marketing authorization application for CPX-351 is supported by data from 5 studies, including a phase 3 study.
Data from the phase 3 study were presented at the 2016 ASCO Annual Meeting and are available in the US prescribing information for CPX-351. (The following data are taken from the prescribing information.)
This trial enrolled 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.
They received CPX-351 (n=153) or cytarabine and daunorubicin (7+3; n=156).
The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).
The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.
The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).
All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.
Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.
The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.
The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.
The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.
CHMP backs approval of caplacizumab
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of caplacizumab (Cablivi) for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP).
Caplacizumab is a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.
The CHMP’s recommendation regarding caplacizumab will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s opinion of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.
TITAN trial
Results from TITAN were published in NEJM in 2016. TITAN included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care (daily plasma exchange and immunosuppressive therapy).
The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).
Among the 69 patients who had not undergone a plasma-exchange session before enrollment, the median time to response was 3.0 days in the caplacizumab arm and 4.9 days in the placebo arm.
Among the 6 patients who did undergo a plasma-exchange session before enrollment, the median time to a response was 2.4 days in the caplacizumab arm and 4.3 days in the placebo arm.
The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.
There were 541 adverse events (AEs) in 34 of the 35 evaluable patients receiving caplacizumab (97%) and 522 AEs in all 37 evaluable patients receiving placebo (100%). TTP exacerbations and relapses were not included as AEs.
The rate of AEs thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. And the rate of serious AEs was 37% and 32%, respectively.
There were no deaths in the caplacizumab arm and 2 in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.
HERCULES trial
Results from HERCULES were presented at the 2017 ASH Annual Meeting.
The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.
The study’s primary endpoint was the time to normalization of platelet count response, which was defined as an initial platelet count of at least 150 x 109/L with subsequent stop of daily plasma exchange within 5 days.
There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of caplacizumab (Cablivi) for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP).
Caplacizumab is a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.
The CHMP’s recommendation regarding caplacizumab will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s opinion of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.
TITAN trial
Results from TITAN were published in NEJM in 2016. TITAN included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care (daily plasma exchange and immunosuppressive therapy).
The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).
Among the 69 patients who had not undergone a plasma-exchange session before enrollment, the median time to response was 3.0 days in the caplacizumab arm and 4.9 days in the placebo arm.
Among the 6 patients who did undergo a plasma-exchange session before enrollment, the median time to a response was 2.4 days in the caplacizumab arm and 4.3 days in the placebo arm.
The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.
There were 541 adverse events (AEs) in 34 of the 35 evaluable patients receiving caplacizumab (97%) and 522 AEs in all 37 evaluable patients receiving placebo (100%). TTP exacerbations and relapses were not included as AEs.
The rate of AEs thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. And the rate of serious AEs was 37% and 32%, respectively.
There were no deaths in the caplacizumab arm and 2 in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.
HERCULES trial
Results from HERCULES were presented at the 2017 ASH Annual Meeting.
The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.
The study’s primary endpoint was the time to normalization of platelet count response, which was defined as an initial platelet count of at least 150 x 109/L with subsequent stop of daily plasma exchange within 5 days.
There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of caplacizumab (Cablivi) for the treatment of adults with acquired thrombotic thrombocytopenic purpura (aTTP).
Caplacizumab is a humanized bivalent nanobody that inhibits the interaction between von Willebrand factor and platelets.
The CHMP’s recommendation regarding caplacizumab will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s opinion of caplacizumab is supported by data from the phase 2 TITAN study and the phase 3 HERCULES study.
TITAN trial
Results from TITAN were published in NEJM in 2016. TITAN included 75 aTTP patients who were randomized to caplacizumab (n=36) or placebo (n=39), with all patients receiving the current standard of care (daily plasma exchange and immunosuppressive therapy).
The study’s primary endpoint was time to response (platelet count normalization). Patients in the caplacizumab arm had a 39% reduction in the median time to response compared to patients in the placebo arm (P=0.005).
Among the 69 patients who had not undergone a plasma-exchange session before enrollment, the median time to response was 3.0 days in the caplacizumab arm and 4.9 days in the placebo arm.
Among the 6 patients who did undergo a plasma-exchange session before enrollment, the median time to a response was 2.4 days in the caplacizumab arm and 4.3 days in the placebo arm.
The rate of confirmed response was 86.1% (n=31) in the caplacizumab arm and 71.8% (n=28) in the placebo arm.
There were 541 adverse events (AEs) in 34 of the 35 evaluable patients receiving caplacizumab (97%) and 522 AEs in all 37 evaluable patients receiving placebo (100%). TTP exacerbations and relapses were not included as AEs.
The rate of AEs thought to be related to the study drug was 17% in the caplacizumab arm and 11% in the placebo arm. The rate of AEs that were possibly related was 54% and 8%, respectively. And the rate of serious AEs was 37% and 32%, respectively.
There were no deaths in the caplacizumab arm and 2 in the placebo arm. One death was due to severe, refractory TTP, and the other was due to cerebral hemorrhage.
HERCULES trial
Results from HERCULES were presented at the 2017 ASH Annual Meeting.
The study enrolled patients with an acute episode of aTTP. They were randomized to receive either caplacizumab (n=72) or placebo (n=73) in addition to standard care, which consisted of plasma exchange and immunosuppression.
The study’s primary endpoint was the time to normalization of platelet count response, which was defined as an initial platelet count of at least 150 x 109/L with subsequent stop of daily plasma exchange within 5 days.
There was a significant reduction in time to platelet count response in the caplacizumab arm compared to the placebo arm. The platelet normalization rate ratio was 1.55 (P<0.01).
A secondary endpoint was the combination of aTTP-related death, aTTP recurrence, and at least 1 major thromboembolic event during study treatment. The incidence of this combined endpoint was 12.7% (n=9) in the caplacizumab arm and 49.3% (n=36) in the placebo arm (P<0.0001).
The incidence of aTTP-related death was 0% (n=0) in the caplacizumab arm and 4.1% (n=3) in the placebo arm. The incidence of aTTP recurrence was 4.2% (n=3) and 38.4% (n=28), respectively. And the incidence of at least 1 major thromboembolic event was 8.5% (n=6) and 8.2% (n=6), respectively.
The proportion of patients with at least 1 study-drug-related AE was 57.7% in the caplacizumab arm and 43.8% in the placebo arm. The proportion of patients with at least 1 study-drug-related serious AE was 14.1% (n=10) and 5.5% (n=4), respectively. The rate of discontinuation due to at least 1 AE was 7.0% and 12.3%, respectively.
During the treatment period, there were no deaths in the caplacizumab arm and 3 deaths in the placebo arm. There was 1 death in the caplacizumab arm during the follow-up period, but it was considered unrelated to caplacizumab.
CHMP recommends CAR T for ALL, DLBCL
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of tisagenlecleucel (Kymriah®, formerly CTL019) for 2 indications.
According to the CHMP, the chimeric antigen receptor (CAR) T-cell therapy should be approved to treat adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received 2 or more lines of systemic therapy and patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s recommendation is based on results from a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
Updated results from JULIET were presented at the recent 23rd Annual Congress of the European Hematology Association (EHA) as abstract S799.
The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).
Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. Of the patients in CR at month 3, 83% remained in CR at month 12. The median duration of response was not reached.
At the time of data cutoff, none of the responders had proceeded to stem cell transplant.
For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.
Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
ELIANA trial
Updated results from ELIANA were published in NEJM in February.
The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of tisagenlecleucel (Kymriah®, formerly CTL019) for 2 indications.
According to the CHMP, the chimeric antigen receptor (CAR) T-cell therapy should be approved to treat adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received 2 or more lines of systemic therapy and patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s recommendation is based on results from a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
Updated results from JULIET were presented at the recent 23rd Annual Congress of the European Hematology Association (EHA) as abstract S799.
The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).
Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. Of the patients in CR at month 3, 83% remained in CR at month 12. The median duration of response was not reached.
At the time of data cutoff, none of the responders had proceeded to stem cell transplant.
For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.
Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
ELIANA trial
Updated results from ELIANA were published in NEJM in February.
The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of tisagenlecleucel (Kymriah®, formerly CTL019) for 2 indications.
According to the CHMP, the chimeric antigen receptor (CAR) T-cell therapy should be approved to treat adults with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who have received 2 or more lines of systemic therapy and patients up to 25 years of age who have B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post-transplant, or in second or later relapse.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The CHMP’s recommendation is based on results from a pair of phase 2 trials—ELIANA and JULIET.
JULIET trial
Updated results from JULIET were presented at the recent 23rd Annual Congress of the European Hematology Association (EHA) as abstract S799.
The trial enrolled 165 adults with relapsed/refractory DLBCL, and 111 of them received a single infusion of tisagenlecleucel. Most of the patients who discontinued before dosing did so due to disease progression or clinical deterioration. The patients’ median age at baseline was 56 (range, 22-76).
Ninety-two percent of patients received bridging therapy, and 93% received lymphodepleting chemotherapy prior to tisagenlecleucel.
The median time from infusion to data cutoff was 13.9 months.
The overall response rate was 52%, and the complete response (CR) rate was 40%. Of the patients in CR at month 3, 83% remained in CR at month 12. The median duration of response was not reached.
At the time of data cutoff, none of the responders had proceeded to stem cell transplant.
For all infused patients (n=111), the 12-month overall survival (OS) rate was 49%, and the median OS was 11.7 months. The median OS was not reached for patients in CR.
Within 8 weeks of tisagenlecleucel infusion, 22% of patients had developed grade 3/4 cytokine release syndrome (CRS). Fifteen percent of patients received tocilizumab for CRS, including 3% of patients with grade 2 CRS and 50% of patients with grade 3 CRS.
Other adverse events (AEs) of interest included grade 3/4 neurologic events (12%), grade 3/4 cytopenias lasting more than 28 days (32%), grade 3/4 infections (20%), and grade 3/4 febrile neutropenia (15%).
ELIANA trial
Updated results from ELIANA were published in NEJM in February.
The trial included 75 children and young adults with relapsed/refractory ALL. The patients’ median age was 11 (range, 3 to 23).
All 75 patients received a single infusion of tisagenlecleucel, and 72 received lymphodepleting chemotherapy.
The median duration of follow-up was 13.1 months. The study’s primary endpoint was overall remission rate, which was defined as the rate of a best overall response of either CR or CR with incomplete hematologic recovery (CRi) within 3 months.
The overall remission rate was 81% (61/75), with 60% of patients (n=45) achieving a CR and 21% (n=16) achieving a CRi.
All patients whose best response was CR/CRi were negative for minimal residual disease. The median duration of response was not met.
Eight patients proceeded to transplant while in remission. At last follow-up, 4 were still in remission, and 4 had unknown disease status.
At 6 months, the event-free survival rate was 73%, and the OS rate was 90%. At 12 months, the rates were 50% and 76%, respectively.
All patients experienced at least 1 AE, and 95% had AEs thought to be related to tisagenlecleucel. The rate of grade 3/4 AEs was 88%, and the rate of related grade 3/4 AEs was 73%.
AEs of special interest included CRS (77%), neurologic events (40%), infections (43%), febrile neutropenia (35%), cytopenias not resolved by day 28 (37%), and tumor lysis syndrome (4%).
CHMP recommends CAR T for DLBCL, PMBCL
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta®, formerly KTE-C19).
The recommendation pertains to axicabtagene ciloleucel as a treatment for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or primary mediastinal large B-cell lymphoma (PMBCL) who have received 2 or more lines of systemic therapy.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The marketing authorization application for axicabtagene ciloleucel is supported by data from the ZUMA-1 trial.
Results from this phase 2 trial were presented at the 2017 ASH Annual Meeting and published simultaneously in NEJM.
The trial enrolled 111 patients with relapsed/refractory B-cell lymphomas. There were 101 patients who received axicabtagene ciloleucel—77 with DLBCL, 8 with PMBCL, and 16 with transformed follicular lymphoma (TFL).
Patients received conditioning with low-dose cyclophosphamide and fludarabine, followed by axicabtagene ciloleucel.
The objective response rate (ORR) was 82% (n=83), and the complete response (CR) rate was 54% (n=55).
Among the DLBCL patients, the ORR was 82% (63/77), and the CR rate was 49% (38/77). In the patients with PMBCL or TFL, the ORR was 83% (20/24), and the CR rate was 71% (17/24).
With a median follow-up of 15.4 months, 42% of patients retained their response, and 40% retained a CR.
At 18 months, the overall survival was 52%. Most deaths were due to disease progression.
However, 2 patients died of adverse events related to axicabtagene ciloleucel, both cytokine release syndrome (CRS).
The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), thrombocytopenia (38%), and febrile neutropenia (31%).
Grade 3 or higher CRS occurred in 13% of patients, and grade 3 or higher neurologic events occurred in 28%.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta®, formerly KTE-C19).
The recommendation pertains to axicabtagene ciloleucel as a treatment for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or primary mediastinal large B-cell lymphoma (PMBCL) who have received 2 or more lines of systemic therapy.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The marketing authorization application for axicabtagene ciloleucel is supported by data from the ZUMA-1 trial.
Results from this phase 2 trial were presented at the 2017 ASH Annual Meeting and published simultaneously in NEJM.
The trial enrolled 111 patients with relapsed/refractory B-cell lymphomas. There were 101 patients who received axicabtagene ciloleucel—77 with DLBCL, 8 with PMBCL, and 16 with transformed follicular lymphoma (TFL).
Patients received conditioning with low-dose cyclophosphamide and fludarabine, followed by axicabtagene ciloleucel.
The objective response rate (ORR) was 82% (n=83), and the complete response (CR) rate was 54% (n=55).
Among the DLBCL patients, the ORR was 82% (63/77), and the CR rate was 49% (38/77). In the patients with PMBCL or TFL, the ORR was 83% (20/24), and the CR rate was 71% (17/24).
With a median follow-up of 15.4 months, 42% of patients retained their response, and 40% retained a CR.
At 18 months, the overall survival was 52%. Most deaths were due to disease progression.
However, 2 patients died of adverse events related to axicabtagene ciloleucel, both cytokine release syndrome (CRS).
The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), thrombocytopenia (38%), and febrile neutropenia (31%).
Grade 3 or higher CRS occurred in 13% of patients, and grade 3 or higher neurologic events occurred in 28%.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta®, formerly KTE-C19).
The recommendation pertains to axicabtagene ciloleucel as a treatment for adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) or primary mediastinal large B-cell lymphoma (PMBCL) who have received 2 or more lines of systemic therapy.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
The marketing authorization application for axicabtagene ciloleucel is supported by data from the ZUMA-1 trial.
Results from this phase 2 trial were presented at the 2017 ASH Annual Meeting and published simultaneously in NEJM.
The trial enrolled 111 patients with relapsed/refractory B-cell lymphomas. There were 101 patients who received axicabtagene ciloleucel—77 with DLBCL, 8 with PMBCL, and 16 with transformed follicular lymphoma (TFL).
Patients received conditioning with low-dose cyclophosphamide and fludarabine, followed by axicabtagene ciloleucel.
The objective response rate (ORR) was 82% (n=83), and the complete response (CR) rate was 54% (n=55).
Among the DLBCL patients, the ORR was 82% (63/77), and the CR rate was 49% (38/77). In the patients with PMBCL or TFL, the ORR was 83% (20/24), and the CR rate was 71% (17/24).
With a median follow-up of 15.4 months, 42% of patients retained their response, and 40% retained a CR.
At 18 months, the overall survival was 52%. Most deaths were due to disease progression.
However, 2 patients died of adverse events related to axicabtagene ciloleucel, both cytokine release syndrome (CRS).
The most common grade 3 or higher adverse events were neutropenia (78%), anemia (43%), thrombocytopenia (38%), and febrile neutropenia (31%).
Grade 3 or higher CRS occurred in 13% of patients, and grade 3 or higher neurologic events occurred in 28%.
CHMP backs expanded approval of tocilizumab
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved use of tocilizumab (RoActemra).
The recommendation is for tocilizumab to treat adults and pediatric patients age 2 and older who have severe or life-threatening cytokine release syndrome (CRS) induced by chimeric antigen receptor (CAR) T-cell therapy.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
Tocilizumab is a humanized interleukin-6 receptor antagonist marketed by Roche Registration GmbH.
The drug is already approved by the European Commission to treat rheumatoid arthritis, active systemic juvenile idiopathic arthritis, and juvenile idiopathic polyarthritis.
The CHMP’s recommendation to expand the approved use of tocilizumab is supported by results from a retrospective analysis of data from clinical trials of CAR T-cell therapies in patients with hematologic malignancies.
For this analysis, researchers assessed 45 pediatric and adult patients treated with tocilizumab, with or without additional high-dose corticosteroids, for severe or life-threatening CRS.
Thirty-one patients (69%) achieved a response, defined as resolution of CRS within 14 days of the first dose of tocilizumab.
No more than 2 doses of tocilizumab were needed, and no drugs other than tocilizumab and corticosteroids were used for treatment.
No adverse reactions related to tocilizumab were reported.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved use of tocilizumab (RoActemra).
The recommendation is for tocilizumab to treat adults and pediatric patients age 2 and older who have severe or life-threatening cytokine release syndrome (CRS) induced by chimeric antigen receptor (CAR) T-cell therapy.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
Tocilizumab is a humanized interleukin-6 receptor antagonist marketed by Roche Registration GmbH.
The drug is already approved by the European Commission to treat rheumatoid arthritis, active systemic juvenile idiopathic arthritis, and juvenile idiopathic polyarthritis.
The CHMP’s recommendation to expand the approved use of tocilizumab is supported by results from a retrospective analysis of data from clinical trials of CAR T-cell therapies in patients with hematologic malignancies.
For this analysis, researchers assessed 45 pediatric and adult patients treated with tocilizumab, with or without additional high-dose corticosteroids, for severe or life-threatening CRS.
Thirty-one patients (69%) achieved a response, defined as resolution of CRS within 14 days of the first dose of tocilizumab.
No more than 2 doses of tocilizumab were needed, and no drugs other than tocilizumab and corticosteroids were used for treatment.
No adverse reactions related to tocilizumab were reported.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended expanding the approved use of tocilizumab (RoActemra).
The recommendation is for tocilizumab to treat adults and pediatric patients age 2 and older who have severe or life-threatening cytokine release syndrome (CRS) induced by chimeric antigen receptor (CAR) T-cell therapy.
The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.
The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.
Tocilizumab is a humanized interleukin-6 receptor antagonist marketed by Roche Registration GmbH.
The drug is already approved by the European Commission to treat rheumatoid arthritis, active systemic juvenile idiopathic arthritis, and juvenile idiopathic polyarthritis.
The CHMP’s recommendation to expand the approved use of tocilizumab is supported by results from a retrospective analysis of data from clinical trials of CAR T-cell therapies in patients with hematologic malignancies.
For this analysis, researchers assessed 45 pediatric and adult patients treated with tocilizumab, with or without additional high-dose corticosteroids, for severe or life-threatening CRS.
Thirty-one patients (69%) achieved a response, defined as resolution of CRS within 14 days of the first dose of tocilizumab.
No more than 2 doses of tocilizumab were needed, and no drugs other than tocilizumab and corticosteroids were used for treatment.
No adverse reactions related to tocilizumab were reported.
FDA lifts hold on trial of MYC inhibitor
The US Food and Drug Administration (FDA) has lifted the clinical hold on a phase 1b trial of APTO-253.
APTO-253 is a small molecule that inhibits expression of the c-Myc oncogene without causing general myelosuppression of the bone marrow, according to Aptose Biosciences Inc., the company developing the drug.
Aptose was testing APTO-253 in a phase 1b trial of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) before the FDA put the trial on hold in November 2015.
The hold was placed after an event that occurred during dosing at a clinical site. The event was stoppage of an intravenous infusion pump that was caused by back pressure resulting from clogging of the in-line filter.
Aptose said no drug-related serious adverse events were reported, and the observed pharmacokinetic levels in patients treated with APTO-253 were within the expected range.
However, a review revealed concerns about the documentation records of the manufacturing procedures associated with APTO-253. So Aptose voluntarily stopped dosing in the phase 1b trial, and the FDA placed the trial on hold.
A root cause investigation revealed that the event with the infusion pump resulted from chemistry and manufacturing-based issues.
Therefore, Aptose developed a new formulation of APTO-253 that did not cause filter clogging or pump stoppage during simulated infusion studies.
Now that the FDA has lifted the hold on the phase 1b trial, Aptose said screening and dosing will resume “as soon as practicable.”
“We are eager to return APTO-253 back into the clinic,” said William G. Rice, PhD, chairman, president and chief executive officer of Aptose.
“Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.”
The phase 1b trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of APTO-253 as a single agent and determine the recommended phase 2 dose of the drug.
APTO-253 will be administered once weekly, over a 28-day cycle. The dose-escalation cohort of the study could potentially enroll up to 20 patients with relapsed or refractory AML or high-risk MDS. The study is designed to then transition, as appropriate, to single-agent expansion cohorts in AML and MDS.
The US Food and Drug Administration (FDA) has lifted the clinical hold on a phase 1b trial of APTO-253.
APTO-253 is a small molecule that inhibits expression of the c-Myc oncogene without causing general myelosuppression of the bone marrow, according to Aptose Biosciences Inc., the company developing the drug.
Aptose was testing APTO-253 in a phase 1b trial of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) before the FDA put the trial on hold in November 2015.
The hold was placed after an event that occurred during dosing at a clinical site. The event was stoppage of an intravenous infusion pump that was caused by back pressure resulting from clogging of the in-line filter.
Aptose said no drug-related serious adverse events were reported, and the observed pharmacokinetic levels in patients treated with APTO-253 were within the expected range.
However, a review revealed concerns about the documentation records of the manufacturing procedures associated with APTO-253. So Aptose voluntarily stopped dosing in the phase 1b trial, and the FDA placed the trial on hold.
A root cause investigation revealed that the event with the infusion pump resulted from chemistry and manufacturing-based issues.
Therefore, Aptose developed a new formulation of APTO-253 that did not cause filter clogging or pump stoppage during simulated infusion studies.
Now that the FDA has lifted the hold on the phase 1b trial, Aptose said screening and dosing will resume “as soon as practicable.”
“We are eager to return APTO-253 back into the clinic,” said William G. Rice, PhD, chairman, president and chief executive officer of Aptose.
“Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.”
The phase 1b trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of APTO-253 as a single agent and determine the recommended phase 2 dose of the drug.
APTO-253 will be administered once weekly, over a 28-day cycle. The dose-escalation cohort of the study could potentially enroll up to 20 patients with relapsed or refractory AML or high-risk MDS. The study is designed to then transition, as appropriate, to single-agent expansion cohorts in AML and MDS.
The US Food and Drug Administration (FDA) has lifted the clinical hold on a phase 1b trial of APTO-253.
APTO-253 is a small molecule that inhibits expression of the c-Myc oncogene without causing general myelosuppression of the bone marrow, according to Aptose Biosciences Inc., the company developing the drug.
Aptose was testing APTO-253 in a phase 1b trial of patients with relapsed or refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) before the FDA put the trial on hold in November 2015.
The hold was placed after an event that occurred during dosing at a clinical site. The event was stoppage of an intravenous infusion pump that was caused by back pressure resulting from clogging of the in-line filter.
Aptose said no drug-related serious adverse events were reported, and the observed pharmacokinetic levels in patients treated with APTO-253 were within the expected range.
However, a review revealed concerns about the documentation records of the manufacturing procedures associated with APTO-253. So Aptose voluntarily stopped dosing in the phase 1b trial, and the FDA placed the trial on hold.
A root cause investigation revealed that the event with the infusion pump resulted from chemistry and manufacturing-based issues.
Therefore, Aptose developed a new formulation of APTO-253 that did not cause filter clogging or pump stoppage during simulated infusion studies.
Now that the FDA has lifted the hold on the phase 1b trial, Aptose said screening and dosing will resume “as soon as practicable.”
“We are eager to return APTO-253 back into the clinic,” said William G. Rice, PhD, chairman, president and chief executive officer of Aptose.
“Our understanding of this molecule has evolved dramatically, and we are excited to deliver a MYC gene expression inhibitor to patients with debilitating hematologic malignancies.”
The phase 1b trial is designed to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of APTO-253 as a single agent and determine the recommended phase 2 dose of the drug.
APTO-253 will be administered once weekly, over a 28-day cycle. The dose-escalation cohort of the study could potentially enroll up to 20 patients with relapsed or refractory AML or high-risk MDS. The study is designed to then transition, as appropriate, to single-agent expansion cohorts in AML and MDS.
Doc reports favorable results from trial on hold
STOCKHOLM—Interim trial results suggest the EZH2 inhibitor tazemetostat can produce durable responses in patients with relapsed or refractory follicular lymphoma (FL).
In patients with EZH2 mutations, the overall response rate (ORR) was 71%, and the median duration of response (DOR) was 32 weeks.
For patients with wild-type (WT) EZH2, the ORR was 33%, and the median DOR was 76 weeks.
Tazemetostat was considered generally well tolerated in this phase 2 trial, which is currently on partial clinical hold.
Gilles Salles, MD, PhD, of the University Hospital of Lyon France, presented results from the trial at the 23rd Congress of the European Hematology Association (EHA) as abstract S100.
The trial is sponsored by Epizyme, Inc.
In April, Epizyme announced that all US-based trials of tazemetostat had been placed on partial hold after a pediatric patient on a phase 1 trial developed secondary T-cell lymphoma.
Enrollment was stopped in all the trials, but patients could continue receiving tazemetostat if they had not progressed on the drug.
The phase 2 trial of tazemetostat in non-Hodgkin lymphoma has enrolled 89 adults with relapsed/refractory FL.
At EHA, Dr Salles presented results in 82 of these patients. There were 28 patients with EZH2-mutated FL and 54 with EZH2-WT FL.
The median age was 61 in both cohorts. Forty-three percent of EZH2-mutated and 63% of WT patients were male.
EZH2-mutated patients had a median of 3 prior therapies, and WT patients had a median of 4. Thirty-eight percent and 42%, respectively, were refractory to their last therapy. Eleven percent and 39%, respectively, had received prior transplant.
The median time from diagnosis was 5.1 years for EZH2-mutated patients and 6.4 years for WT patients. The median time from last prior therapy was 18.4 weeks and 28.1 weeks, respectively.
The patients received tazemetostat at 800 mg twice daily until disease progression or withdrawal.
Safety
In all 82 patients, the rate of treatment-emergent adverse events (AEs) was 95%, and the rate of treatment-related AEs was 78%. The rate of grade 3 or higher treatment-related AEs was 17%, and the rate of serious treatment-related AEs was 4%.
Six percent of patients discontinued treatment due to a related AE, 18% had a dose interruption, and 5% had a dose reduction due to a related AE.
Treatment-related AEs included nausea (20%), fatigue (13%), anemia (13%), diarrhea (11%), alopecia (11%), asthenia (10%), thrombocytopenia (10%), muscle spasms (6%), bronchitis (5%), vomiting (5%), headache (5%), abdominal pain (2%), pyrexia (1%), and cough (1%).
Grade 3 or higher treatment-related AEs included thrombocytopenia (4%), anemia (4%), fatigue (1%), and asthenia (1%).
Efficacy
In the EZH2-mutated cohort, the ORR was 71% (n=20). Eleven percent of patients (n=3) achieved a complete response, and 61% (n=17) had a partial response.
Twenty-nine percent (n=8) had stable disease as their best response. And 21% (n=6) of patients are still on study with stable disease.
All patients in this cohort experienced a reduction in tumor burden. None of the patients had progressive disease as their best response.
At the time of analysis (May 1, 2018), the median DOR was 32.3 weeks, and 55% of responders (n=11) had an ongoing response.
The median progression-free survival was 48.6 weeks.
In patients with WT EZH2 (n=54), the ORR was 33% (n=18). Six percent of patients (n=3) achieved a complete response, and 28% (n=15) had a partial response.
Thirty-one percent of patients (n=17) had stable disease as their best response, including 1 patient who is still receiving treatment.
Thirty-one percent of patients (n=17) progressed. For 4% (n=2), their response status was unknown.
At the time of analysis, the median DOR was 76 weeks, and 56% of responders (n=10) had an ongoing response.
The median progression-free survival was 29.9 weeks.
“I am impressed by the sustained clinical activity and the good tolerability of tazemetostat in this heavily pretreated patient population,” Dr Salles said. “This is important for patients with relapsed or refractory follicular lymphoma, as both the response rates and durations of response usually tend to decrease with each successive line of treatment.”
“I believe tazemetostat has the potential to fill a significant unmet need for these patients, and continued investigation of tazemetostat as a single agent or in combination with other agents is warranted.”
Epizyme’s president and chief executive officer, Robert Bazemore, said the company is still working to resolve the partial clinical hold on tazemetostat trials and is “making good progress.”
STOCKHOLM—Interim trial results suggest the EZH2 inhibitor tazemetostat can produce durable responses in patients with relapsed or refractory follicular lymphoma (FL).
In patients with EZH2 mutations, the overall response rate (ORR) was 71%, and the median duration of response (DOR) was 32 weeks.
For patients with wild-type (WT) EZH2, the ORR was 33%, and the median DOR was 76 weeks.
Tazemetostat was considered generally well tolerated in this phase 2 trial, which is currently on partial clinical hold.
Gilles Salles, MD, PhD, of the University Hospital of Lyon France, presented results from the trial at the 23rd Congress of the European Hematology Association (EHA) as abstract S100.
The trial is sponsored by Epizyme, Inc.
In April, Epizyme announced that all US-based trials of tazemetostat had been placed on partial hold after a pediatric patient on a phase 1 trial developed secondary T-cell lymphoma.
Enrollment was stopped in all the trials, but patients could continue receiving tazemetostat if they had not progressed on the drug.
The phase 2 trial of tazemetostat in non-Hodgkin lymphoma has enrolled 89 adults with relapsed/refractory FL.
At EHA, Dr Salles presented results in 82 of these patients. There were 28 patients with EZH2-mutated FL and 54 with EZH2-WT FL.
The median age was 61 in both cohorts. Forty-three percent of EZH2-mutated and 63% of WT patients were male.
EZH2-mutated patients had a median of 3 prior therapies, and WT patients had a median of 4. Thirty-eight percent and 42%, respectively, were refractory to their last therapy. Eleven percent and 39%, respectively, had received prior transplant.
The median time from diagnosis was 5.1 years for EZH2-mutated patients and 6.4 years for WT patients. The median time from last prior therapy was 18.4 weeks and 28.1 weeks, respectively.
The patients received tazemetostat at 800 mg twice daily until disease progression or withdrawal.
Safety
In all 82 patients, the rate of treatment-emergent adverse events (AEs) was 95%, and the rate of treatment-related AEs was 78%. The rate of grade 3 or higher treatment-related AEs was 17%, and the rate of serious treatment-related AEs was 4%.
Six percent of patients discontinued treatment due to a related AE, 18% had a dose interruption, and 5% had a dose reduction due to a related AE.
Treatment-related AEs included nausea (20%), fatigue (13%), anemia (13%), diarrhea (11%), alopecia (11%), asthenia (10%), thrombocytopenia (10%), muscle spasms (6%), bronchitis (5%), vomiting (5%), headache (5%), abdominal pain (2%), pyrexia (1%), and cough (1%).
Grade 3 or higher treatment-related AEs included thrombocytopenia (4%), anemia (4%), fatigue (1%), and asthenia (1%).
Efficacy
In the EZH2-mutated cohort, the ORR was 71% (n=20). Eleven percent of patients (n=3) achieved a complete response, and 61% (n=17) had a partial response.
Twenty-nine percent (n=8) had stable disease as their best response. And 21% (n=6) of patients are still on study with stable disease.
All patients in this cohort experienced a reduction in tumor burden. None of the patients had progressive disease as their best response.
At the time of analysis (May 1, 2018), the median DOR was 32.3 weeks, and 55% of responders (n=11) had an ongoing response.
The median progression-free survival was 48.6 weeks.
In patients with WT EZH2 (n=54), the ORR was 33% (n=18). Six percent of patients (n=3) achieved a complete response, and 28% (n=15) had a partial response.
Thirty-one percent of patients (n=17) had stable disease as their best response, including 1 patient who is still receiving treatment.
Thirty-one percent of patients (n=17) progressed. For 4% (n=2), their response status was unknown.
At the time of analysis, the median DOR was 76 weeks, and 56% of responders (n=10) had an ongoing response.
The median progression-free survival was 29.9 weeks.
“I am impressed by the sustained clinical activity and the good tolerability of tazemetostat in this heavily pretreated patient population,” Dr Salles said. “This is important for patients with relapsed or refractory follicular lymphoma, as both the response rates and durations of response usually tend to decrease with each successive line of treatment.”
“I believe tazemetostat has the potential to fill a significant unmet need for these patients, and continued investigation of tazemetostat as a single agent or in combination with other agents is warranted.”
Epizyme’s president and chief executive officer, Robert Bazemore, said the company is still working to resolve the partial clinical hold on tazemetostat trials and is “making good progress.”
STOCKHOLM—Interim trial results suggest the EZH2 inhibitor tazemetostat can produce durable responses in patients with relapsed or refractory follicular lymphoma (FL).
In patients with EZH2 mutations, the overall response rate (ORR) was 71%, and the median duration of response (DOR) was 32 weeks.
For patients with wild-type (WT) EZH2, the ORR was 33%, and the median DOR was 76 weeks.
Tazemetostat was considered generally well tolerated in this phase 2 trial, which is currently on partial clinical hold.
Gilles Salles, MD, PhD, of the University Hospital of Lyon France, presented results from the trial at the 23rd Congress of the European Hematology Association (EHA) as abstract S100.
The trial is sponsored by Epizyme, Inc.
In April, Epizyme announced that all US-based trials of tazemetostat had been placed on partial hold after a pediatric patient on a phase 1 trial developed secondary T-cell lymphoma.
Enrollment was stopped in all the trials, but patients could continue receiving tazemetostat if they had not progressed on the drug.
The phase 2 trial of tazemetostat in non-Hodgkin lymphoma has enrolled 89 adults with relapsed/refractory FL.
At EHA, Dr Salles presented results in 82 of these patients. There were 28 patients with EZH2-mutated FL and 54 with EZH2-WT FL.
The median age was 61 in both cohorts. Forty-three percent of EZH2-mutated and 63% of WT patients were male.
EZH2-mutated patients had a median of 3 prior therapies, and WT patients had a median of 4. Thirty-eight percent and 42%, respectively, were refractory to their last therapy. Eleven percent and 39%, respectively, had received prior transplant.
The median time from diagnosis was 5.1 years for EZH2-mutated patients and 6.4 years for WT patients. The median time from last prior therapy was 18.4 weeks and 28.1 weeks, respectively.
The patients received tazemetostat at 800 mg twice daily until disease progression or withdrawal.
Safety
In all 82 patients, the rate of treatment-emergent adverse events (AEs) was 95%, and the rate of treatment-related AEs was 78%. The rate of grade 3 or higher treatment-related AEs was 17%, and the rate of serious treatment-related AEs was 4%.
Six percent of patients discontinued treatment due to a related AE, 18% had a dose interruption, and 5% had a dose reduction due to a related AE.
Treatment-related AEs included nausea (20%), fatigue (13%), anemia (13%), diarrhea (11%), alopecia (11%), asthenia (10%), thrombocytopenia (10%), muscle spasms (6%), bronchitis (5%), vomiting (5%), headache (5%), abdominal pain (2%), pyrexia (1%), and cough (1%).
Grade 3 or higher treatment-related AEs included thrombocytopenia (4%), anemia (4%), fatigue (1%), and asthenia (1%).
Efficacy
In the EZH2-mutated cohort, the ORR was 71% (n=20). Eleven percent of patients (n=3) achieved a complete response, and 61% (n=17) had a partial response.
Twenty-nine percent (n=8) had stable disease as their best response. And 21% (n=6) of patients are still on study with stable disease.
All patients in this cohort experienced a reduction in tumor burden. None of the patients had progressive disease as their best response.
At the time of analysis (May 1, 2018), the median DOR was 32.3 weeks, and 55% of responders (n=11) had an ongoing response.
The median progression-free survival was 48.6 weeks.
In patients with WT EZH2 (n=54), the ORR was 33% (n=18). Six percent of patients (n=3) achieved a complete response, and 28% (n=15) had a partial response.
Thirty-one percent of patients (n=17) had stable disease as their best response, including 1 patient who is still receiving treatment.
Thirty-one percent of patients (n=17) progressed. For 4% (n=2), their response status was unknown.
At the time of analysis, the median DOR was 76 weeks, and 56% of responders (n=10) had an ongoing response.
The median progression-free survival was 29.9 weeks.
“I am impressed by the sustained clinical activity and the good tolerability of tazemetostat in this heavily pretreated patient population,” Dr Salles said. “This is important for patients with relapsed or refractory follicular lymphoma, as both the response rates and durations of response usually tend to decrease with each successive line of treatment.”
“I believe tazemetostat has the potential to fill a significant unmet need for these patients, and continued investigation of tazemetostat as a single agent or in combination with other agents is warranted.”
Epizyme’s president and chief executive officer, Robert Bazemore, said the company is still working to resolve the partial clinical hold on tazemetostat trials and is “making good progress.”