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A PHASE 1B STUDY OF THE COMBINATION OF VADASTUXIMAB TALIRINE AND 7+3 INDUCTION THERAPY FOR PATIENTS WITH NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA (AML)
Author(s):
Moshe Y. Levy
,
Moshe Y. Levy
Affiliations:
Baylor University Medical Center,Dallas, TX,United States
Anthony S. Stein
,
Anthony S. Stein
Affiliations:
Gehr Family Center for Leukemia Research - City of Hope,Duarte, CA,United States
Sumithira Vasu
,
Sumithira Vasu
Affiliations:
Ohio State University Comprehensive Cancer Center,Columbus, OH,United States
Michael B. Maris
,
Michael B. Maris
Affiliations:
Colorado Blood Cancer Institute,Denver, CO,United States
Anjali S. Advani
,
Anjali S. Advani
Affiliations:
Cleveland Clinic,Cleveland, OH,United States
Amir T. Fathi
,
Amir T. Fathi
Affiliations:
Massachusetts General Hospital,Boston, MA,United States
Stefan Faderl
,
Stefan Faderl
Affiliations:
John Theurer Cancer Center,Hackensack, NJ,United States
Roland B. Walter
,
Roland B. Walter
Affiliations:
Fred Hutchinson Cancer Research Center,Seattle, WA,United States
Scott E. Smith
,
Scott E. Smith
Affiliations:
Loyola University Medical Center,Maywood, IL,United States
Jay Yang
,
Jay Yang
Affiliations:
Karmanos Cancer Institute,Detroit, MI,United States
William B. Donnellan
,
William B. Donnellan
Affiliations:
Sarah Cannon Research Institute,Nashville, TN,United States
Brent L. Wood
,
Brent L. Wood
Affiliations:
University of Washington Medical Center,Seattle, WA,United States
Farhad Ravandi
,
Farhad Ravandi
Affiliations:
MD Anderson Cancer Center,Houston, TX,United States
Eric J. Feldman
,
Eric J. Feldman
Affiliations:
Seattle Genetics, Inc.,Bothell, WA,United States
Jenna L. Voellinger
,
Jenna L. Voellinger
Affiliations:
Seattle Genetics, Inc.,Bothell, WA,United States
Harry Erba
Harry Erba
Affiliations:
University of Alabama-Birmingham,Birmingham, AL,United States
(Abstract release date: 05/18/17) EHA Library. Y. Levy M. 06/25/17; 182080; S793
Moshe Y. Levy
Moshe Y. Levy
Contributions
PDF Abstract
Abstract

Abstract: S793

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 09:00 - 09:15

Location: Room N101

Background
For patients <65 yrs with newly diagnosed AML, standard induction treatment is continuous infusion of cytarabine for 7 days and an anthracycline for 3 days (7+3). Although a high percentage of patients achieve a CR by morphologic criteria, some requiring a 2nd induction, many are resistant to treatment or achieve a morphologic CR with evidence of minimal residual disease (MRD). Vadastuximab talirine (SGN-CD33A; 33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine dimer. Combining 33A with 7+3 could result in enhanced and deeper (MRD negative) remissions, resulting in reduced relapse rates and improved OS.

Aims
This phase 1b study (NCT02326584) evaluated the safety and antileukemic activity of escalating doses of 33A on 2 schedules: split dose (D1 and 4) or single dose (D1) with 7+3 induction therapy (cytarabine 100 mg/m2 and daunorubicin 60 mg/m2).

Methods
AML patients must be eligible for induction therapy. Response assessments occur on D15 and 28. Second induction and post-remission therapies were per investigator choice and did not include additional 33A. MRD was assessed centrally by bone marrow exam by a multiparametric flow at D15 and D28.

Results

Split-dose cohort: 42 patients (median age 45.5 yrs [range, 18-65]) were treated with 33A on D1 and 4 (10+10 [n=4] or 20+10 [n=38] mcg/kg) with 7+3. Most patients had intermediate (50%) or adverse (36%) cytogenetic risk. 19% had secondary AML. 2 patients had hematologic DLTs (lack of recovery of platelets [25K] and/or ANC [500] by D42) and 20+10 mcg/kg was determined to be MTD. The median time to count recovery from D1 of therapy in patients who achieved CR/CRi was 4.9 wks for ANC (≥1K) and 5.1 wks for platelets (≥100K). No non-hematologic TEAEs ≥G3 were reported in >10% of patients; non-hematologic TEAEs of any grade occurring in ≥25% of patients were nausea (62%), diarrhea, and constipation (38% each). Of the 42 efficacy evaluable (EE) patients, best responses included 25 CR (60%), 7 CRi (17%), and 5 morphologic leukemia-free state (mLFS; 12%) with a CR+CRi (CRc) rate of 76%; 23 of 25 (94%) responses were achieved in the 1st cycle. Of the patients with blast clearance (CR+CRi+mLFS), 73% (27/37) achieved MRD negative status.
Single-dose cohort: To date, 25 patients (median age 58 yrs [range, 38-65]) were treated with 33A on D1 only (30 [n=14] or 40 [n=11] mcg/kg) with 7+3. Patients had intermediate (48%) or adverse (36%) cytogenetic risk. 16% had secondary AML. The median time to count recovery from D1 of therapy was 4.1 wks for ANC (≥1K) and 5.9 wks for platelets (≥100K) in patients who achieved CR/CRi. Four patients had hematologic DLTs, 1 at 30 and 3 at 40 mcg/kg. Non-hematologic TEAEs were consistent with those seen in the D1 and 4 schedule. Of the 24 EE patients, best responses included 12 CR (50%), 6 CRi (25%), and 3 mLFS (13%) with a CRc rate of 75%, achieved in 1st cycle. Of the evaluable patients with blast clearance, 89% (17/19) achieved MRD negative status. The CRc rate at the 40 mcg/kg dose level was 91% (10/11); all 11 patients had blast clearance and 90% (9/10) of evaluable patients achieved MRD negative status.
Across schedules (N=67), the CRc rate was 76%; 79% (44/56) of evaluable patients with blast clearance achieved MRD negativity. The 30- and 60-day mortality rates were 1% and 7%, respectively. Median OS is not reached for either schedule and 52 patients (78%) were alive at the time of analysis.

Conclusion
33A can be safely combined with 7+3 with acceptable count recovery in this population at the doses and schedules studied. Extramedullary AEs, including hepatotoxicity, and induction mortality rates were similar to reported rates for 7+3 alone in this AML population. A high remission rate with the 1st induction cycle was observed, the majority of which were MRD negative.

 

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Targeted therapy, Induction chemotherapy, CD33, AML

Abstract: S793

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 09:00 - 09:15

Location: Room N101

Background
For patients <65 yrs with newly diagnosed AML, standard induction treatment is continuous infusion of cytarabine for 7 days and an anthracycline for 3 days (7+3). Although a high percentage of patients achieve a CR by morphologic criteria, some requiring a 2nd induction, many are resistant to treatment or achieve a morphologic CR with evidence of minimal residual disease (MRD). Vadastuximab talirine (SGN-CD33A; 33A) is a CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine dimer. Combining 33A with 7+3 could result in enhanced and deeper (MRD negative) remissions, resulting in reduced relapse rates and improved OS.

Aims
This phase 1b study (NCT02326584) evaluated the safety and antileukemic activity of escalating doses of 33A on 2 schedules: split dose (D1 and 4) or single dose (D1) with 7+3 induction therapy (cytarabine 100 mg/m2 and daunorubicin 60 mg/m2).

Methods
AML patients must be eligible for induction therapy. Response assessments occur on D15 and 28. Second induction and post-remission therapies were per investigator choice and did not include additional 33A. MRD was assessed centrally by bone marrow exam by a multiparametric flow at D15 and D28.

Results

Split-dose cohort: 42 patients (median age 45.5 yrs [range, 18-65]) were treated with 33A on D1 and 4 (10+10 [n=4] or 20+10 [n=38] mcg/kg) with 7+3. Most patients had intermediate (50%) or adverse (36%) cytogenetic risk. 19% had secondary AML. 2 patients had hematologic DLTs (lack of recovery of platelets [25K] and/or ANC [500] by D42) and 20+10 mcg/kg was determined to be MTD. The median time to count recovery from D1 of therapy in patients who achieved CR/CRi was 4.9 wks for ANC (≥1K) and 5.1 wks for platelets (≥100K). No non-hematologic TEAEs ≥G3 were reported in >10% of patients; non-hematologic TEAEs of any grade occurring in ≥25% of patients were nausea (62%), diarrhea, and constipation (38% each). Of the 42 efficacy evaluable (EE) patients, best responses included 25 CR (60%), 7 CRi (17%), and 5 morphologic leukemia-free state (mLFS; 12%) with a CR+CRi (CRc) rate of 76%; 23 of 25 (94%) responses were achieved in the 1st cycle. Of the patients with blast clearance (CR+CRi+mLFS), 73% (27/37) achieved MRD negative status.
Single-dose cohort: To date, 25 patients (median age 58 yrs [range, 38-65]) were treated with 33A on D1 only (30 [n=14] or 40 [n=11] mcg/kg) with 7+3. Patients had intermediate (48%) or adverse (36%) cytogenetic risk. 16% had secondary AML. The median time to count recovery from D1 of therapy was 4.1 wks for ANC (≥1K) and 5.9 wks for platelets (≥100K) in patients who achieved CR/CRi. Four patients had hematologic DLTs, 1 at 30 and 3 at 40 mcg/kg. Non-hematologic TEAEs were consistent with those seen in the D1 and 4 schedule. Of the 24 EE patients, best responses included 12 CR (50%), 6 CRi (25%), and 3 mLFS (13%) with a CRc rate of 75%, achieved in 1st cycle. Of the evaluable patients with blast clearance, 89% (17/19) achieved MRD negative status. The CRc rate at the 40 mcg/kg dose level was 91% (10/11); all 11 patients had blast clearance and 90% (9/10) of evaluable patients achieved MRD negative status.
Across schedules (N=67), the CRc rate was 76%; 79% (44/56) of evaluable patients with blast clearance achieved MRD negativity. The 30- and 60-day mortality rates were 1% and 7%, respectively. Median OS is not reached for either schedule and 52 patients (78%) were alive at the time of analysis.

Conclusion
33A can be safely combined with 7+3 with acceptable count recovery in this population at the doses and schedules studied. Extramedullary AEs, including hepatotoxicity, and induction mortality rates were similar to reported rates for 7+3 alone in this AML population. A high remission rate with the 1st induction cycle was observed, the majority of which were MRD negative.

 

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): Targeted therapy, Induction chemotherapy, CD33, AML

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