SGN-CD33A IN COMBINATION WITH HYPOMETHYLATING AGENTS: A NOVEL, WELL-TOLERATED REGIMEN WITH HIGH REMISSION RATE IN OLDER PATIENTS WITH AML
(Abstract release date: 05/19/16)
EHA Library. Fathi A. 06/11/16; 135259; S503
Ms. Amir Fathi
Contributions
Contributions
Abstract
Abstract: S503
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:30 - 16:45
Location: Hall A3
Background
Many older patients with AML are treated with hypomethylating agents (HMAs) or other low-intensity therapy (Dombret 2015, Kantarjian 2012). SGN-CD33A (vadastuximab talirine; 33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. Enhanced cytotoxicity was observed in preclinical studies combining 33A+HMA (azacitidine or decitabine), with HMA priming upregulating CD33 and increasing incorporation of PBD dimer (Sutherland 2015).
Aims
A combination cohort in a phase 1 study (NCT01902329) was designed to evaluate the safety, tolerability, pharmacokinetics, and antileukemic activity of 33A in combination with an HMA.
Methods
Eligible patients (ECOG 0– 1) must have previously untreated CD33-positive AML, and have declined intensive therapy. 33A (10 mcg/kg) was administered via outpatient IV every 4 weeks on the last day of HMA (azacitidine or decitabine [5-day regimen], standard dosing). Patients with clinical benefit could continue treatment until relapse or unacceptable toxicity. Investigator assessment of response was per IWG criteria; CRi required either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL (Cheson 2003).
Results
Fifty-three patients (64% male) with a median age of 75 years (range 60 – 87) were treated with the combination therapy. Nineteen patients (36%) had adverse cytogenetic risk (MRC) and 30 patients (57%) had intermediate cytogenetic risk. Forty-eight patients (91%) were treatment naïve and 5 patients (9%) had received prior low-intensity therapy for MDS. At baseline, patients had a median of 45.9% BM blasts. Patients were on treatment for a median of 15.6 weeks (range 2 – 68) and 27 patients (51%) remain on study treatment; no DLTs were reported. Grade 3 or higher adverse events (AE) reported in ≥20% of patients were febrile neutropenia (47%), thrombocytopenia (42%), anemia (34%), and neutropenia (28%). Other common treatment-emergent AEs regardless of relationship to study treatment were fatigue (55%), nausea (43%), constipation (38%), decreased appetite (36%), and peripheral edema (36%). Thirty- and 60-day mortality rates were 2% and 8% respectively with no treatment-related deaths reported. Thirty-seven of the 49 efficacy evaluable patients (76%) achieved CR (17), CRi (19), or PR (1), with a median time to remission of 2 cycles (range 1 – 4); the median relapse-free survival in CR/CRi patients is currently 6.9 months (range 0+ – 11+). Thirteen of 17 patients (76%) with adverse cytogenetic risk achieved remission. Of the responding patients, 14 of 33 (42%) achieved MRD negativity by local or central flow cytometry. Thirty-seven patients (70%) were alive at the time of this data cut with a median follow-up of 4.7 months (range 0.5 – 15.6). Survival trends appear similar in patients ≥75 years as in patients <75 years.
Conclusion
The combination of 33A with HMA was well tolerated and capable of inducing deep and durable remissions. In ~50 treated patients, activity with the combination appeared greater and occurred more rapidly than what is historically expected from HMA alone in this patient population. The observed low early mortality rate and the 76% overall remission rate in AML patients with poor risk factors are particularly encouraging. A global phase 3 randomized trial of 33A+HMA vs. HMA alone is planned for 2016.
Session topic: New Compounds in AML Treatment
Keyword(s): Acute myeloid leukemia, Antibody targeting, CD33, Targeted therapy
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:30 - 16:45
Location: Hall A3
Background
Many older patients with AML are treated with hypomethylating agents (HMAs) or other low-intensity therapy (Dombret 2015, Kantarjian 2012). SGN-CD33A (vadastuximab talirine; 33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. Enhanced cytotoxicity was observed in preclinical studies combining 33A+HMA (azacitidine or decitabine), with HMA priming upregulating CD33 and increasing incorporation of PBD dimer (Sutherland 2015).
Aims
A combination cohort in a phase 1 study (NCT01902329) was designed to evaluate the safety, tolerability, pharmacokinetics, and antileukemic activity of 33A in combination with an HMA.
Methods
Eligible patients (ECOG 0– 1) must have previously untreated CD33-positive AML, and have declined intensive therapy. 33A (10 mcg/kg) was administered via outpatient IV every 4 weeks on the last day of HMA (azacitidine or decitabine [5-day regimen], standard dosing). Patients with clinical benefit could continue treatment until relapse or unacceptable toxicity. Investigator assessment of response was per IWG criteria; CRi required either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL (Cheson 2003).
Results
Fifty-three patients (64% male) with a median age of 75 years (range 60 – 87) were treated with the combination therapy. Nineteen patients (36%) had adverse cytogenetic risk (MRC) and 30 patients (57%) had intermediate cytogenetic risk. Forty-eight patients (91%) were treatment naïve and 5 patients (9%) had received prior low-intensity therapy for MDS. At baseline, patients had a median of 45.9% BM blasts. Patients were on treatment for a median of 15.6 weeks (range 2 – 68) and 27 patients (51%) remain on study treatment; no DLTs were reported. Grade 3 or higher adverse events (AE) reported in ≥20% of patients were febrile neutropenia (47%), thrombocytopenia (42%), anemia (34%), and neutropenia (28%). Other common treatment-emergent AEs regardless of relationship to study treatment were fatigue (55%), nausea (43%), constipation (38%), decreased appetite (36%), and peripheral edema (36%). Thirty- and 60-day mortality rates were 2% and 8% respectively with no treatment-related deaths reported. Thirty-seven of the 49 efficacy evaluable patients (76%) achieved CR (17), CRi (19), or PR (1), with a median time to remission of 2 cycles (range 1 – 4); the median relapse-free survival in CR/CRi patients is currently 6.9 months (range 0+ – 11+). Thirteen of 17 patients (76%) with adverse cytogenetic risk achieved remission. Of the responding patients, 14 of 33 (42%) achieved MRD negativity by local or central flow cytometry. Thirty-seven patients (70%) were alive at the time of this data cut with a median follow-up of 4.7 months (range 0.5 – 15.6). Survival trends appear similar in patients ≥75 years as in patients <75 years.
Conclusion
The combination of 33A with HMA was well tolerated and capable of inducing deep and durable remissions. In ~50 treated patients, activity with the combination appeared greater and occurred more rapidly than what is historically expected from HMA alone in this patient population. The observed low early mortality rate and the 76% overall remission rate in AML patients with poor risk factors are particularly encouraging. A global phase 3 randomized trial of 33A+HMA vs. HMA alone is planned for 2016.
Session topic: New Compounds in AML Treatment
Keyword(s): Acute myeloid leukemia, Antibody targeting, CD33, Targeted therapy
Abstract: S503
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:30 - 16:45
Location: Hall A3
Background
Many older patients with AML are treated with hypomethylating agents (HMAs) or other low-intensity therapy (Dombret 2015, Kantarjian 2012). SGN-CD33A (vadastuximab talirine; 33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. Enhanced cytotoxicity was observed in preclinical studies combining 33A+HMA (azacitidine or decitabine), with HMA priming upregulating CD33 and increasing incorporation of PBD dimer (Sutherland 2015).
Aims
A combination cohort in a phase 1 study (NCT01902329) was designed to evaluate the safety, tolerability, pharmacokinetics, and antileukemic activity of 33A in combination with an HMA.
Methods
Eligible patients (ECOG 0– 1) must have previously untreated CD33-positive AML, and have declined intensive therapy. 33A (10 mcg/kg) was administered via outpatient IV every 4 weeks on the last day of HMA (azacitidine or decitabine [5-day regimen], standard dosing). Patients with clinical benefit could continue treatment until relapse or unacceptable toxicity. Investigator assessment of response was per IWG criteria; CRi required either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL (Cheson 2003).
Results
Fifty-three patients (64% male) with a median age of 75 years (range 60 – 87) were treated with the combination therapy. Nineteen patients (36%) had adverse cytogenetic risk (MRC) and 30 patients (57%) had intermediate cytogenetic risk. Forty-eight patients (91%) were treatment naïve and 5 patients (9%) had received prior low-intensity therapy for MDS. At baseline, patients had a median of 45.9% BM blasts. Patients were on treatment for a median of 15.6 weeks (range 2 – 68) and 27 patients (51%) remain on study treatment; no DLTs were reported. Grade 3 or higher adverse events (AE) reported in ≥20% of patients were febrile neutropenia (47%), thrombocytopenia (42%), anemia (34%), and neutropenia (28%). Other common treatment-emergent AEs regardless of relationship to study treatment were fatigue (55%), nausea (43%), constipation (38%), decreased appetite (36%), and peripheral edema (36%). Thirty- and 60-day mortality rates were 2% and 8% respectively with no treatment-related deaths reported. Thirty-seven of the 49 efficacy evaluable patients (76%) achieved CR (17), CRi (19), or PR (1), with a median time to remission of 2 cycles (range 1 – 4); the median relapse-free survival in CR/CRi patients is currently 6.9 months (range 0+ – 11+). Thirteen of 17 patients (76%) with adverse cytogenetic risk achieved remission. Of the responding patients, 14 of 33 (42%) achieved MRD negativity by local or central flow cytometry. Thirty-seven patients (70%) were alive at the time of this data cut with a median follow-up of 4.7 months (range 0.5 – 15.6). Survival trends appear similar in patients ≥75 years as in patients <75 years.
Conclusion
The combination of 33A with HMA was well tolerated and capable of inducing deep and durable remissions. In ~50 treated patients, activity with the combination appeared greater and occurred more rapidly than what is historically expected from HMA alone in this patient population. The observed low early mortality rate and the 76% overall remission rate in AML patients with poor risk factors are particularly encouraging. A global phase 3 randomized trial of 33A+HMA vs. HMA alone is planned for 2016.
Session topic: New Compounds in AML Treatment
Keyword(s): Acute myeloid leukemia, Antibody targeting, CD33, Targeted therapy
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:30 - 16:45
Location: Hall A3
Background
Many older patients with AML are treated with hypomethylating agents (HMAs) or other low-intensity therapy (Dombret 2015, Kantarjian 2012). SGN-CD33A (vadastuximab talirine; 33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer. Upon binding, 33A is internalized and transported to the lysosomes where PBD dimer is released via proteolytic cleavage of the linker, crosslinking DNA, and leading to cell death. Enhanced cytotoxicity was observed in preclinical studies combining 33A+HMA (azacitidine or decitabine), with HMA priming upregulating CD33 and increasing incorporation of PBD dimer (Sutherland 2015).
Aims
A combination cohort in a phase 1 study (NCT01902329) was designed to evaluate the safety, tolerability, pharmacokinetics, and antileukemic activity of 33A in combination with an HMA.
Methods
Eligible patients (ECOG 0– 1) must have previously untreated CD33-positive AML, and have declined intensive therapy. 33A (10 mcg/kg) was administered via outpatient IV every 4 weeks on the last day of HMA (azacitidine or decitabine [5-day regimen], standard dosing). Patients with clinical benefit could continue treatment until relapse or unacceptable toxicity. Investigator assessment of response was per IWG criteria; CRi required either platelet count of ≥100,000/µL or neutrophils of ≥1,000/µL (Cheson 2003).
Results
Fifty-three patients (64% male) with a median age of 75 years (range 60 – 87) were treated with the combination therapy. Nineteen patients (36%) had adverse cytogenetic risk (MRC) and 30 patients (57%) had intermediate cytogenetic risk. Forty-eight patients (91%) were treatment naïve and 5 patients (9%) had received prior low-intensity therapy for MDS. At baseline, patients had a median of 45.9% BM blasts. Patients were on treatment for a median of 15.6 weeks (range 2 – 68) and 27 patients (51%) remain on study treatment; no DLTs were reported. Grade 3 or higher adverse events (AE) reported in ≥20% of patients were febrile neutropenia (47%), thrombocytopenia (42%), anemia (34%), and neutropenia (28%). Other common treatment-emergent AEs regardless of relationship to study treatment were fatigue (55%), nausea (43%), constipation (38%), decreased appetite (36%), and peripheral edema (36%). Thirty- and 60-day mortality rates were 2% and 8% respectively with no treatment-related deaths reported. Thirty-seven of the 49 efficacy evaluable patients (76%) achieved CR (17), CRi (19), or PR (1), with a median time to remission of 2 cycles (range 1 – 4); the median relapse-free survival in CR/CRi patients is currently 6.9 months (range 0+ – 11+). Thirteen of 17 patients (76%) with adverse cytogenetic risk achieved remission. Of the responding patients, 14 of 33 (42%) achieved MRD negativity by local or central flow cytometry. Thirty-seven patients (70%) were alive at the time of this data cut with a median follow-up of 4.7 months (range 0.5 – 15.6). Survival trends appear similar in patients ≥75 years as in patients <75 years.
Conclusion
The combination of 33A with HMA was well tolerated and capable of inducing deep and durable remissions. In ~50 treated patients, activity with the combination appeared greater and occurred more rapidly than what is historically expected from HMA alone in this patient population. The observed low early mortality rate and the 76% overall remission rate in AML patients with poor risk factors are particularly encouraging. A global phase 3 randomized trial of 33A+HMA vs. HMA alone is planned for 2016.
Session topic: New Compounds in AML Treatment
Keyword(s): Acute myeloid leukemia, Antibody targeting, CD33, Targeted therapy
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