THE CXCR4 INHIBITOR BL-8040 IN COMBINATION WITH CYTARABINE RESULTS IN A SIGNIFICANTLY EXTENDED OVERALL SURVIVAL OF RELAPSED/REFRACTORY AML PATIENTS
Author(s): ,
Gautam Borthakur
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
Martin S. Tallman
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Yishai Ofran
Affiliations:
Rambam Medical Center,Haifa,Israel
,
James Foran
Affiliations:
Mayo Clinic,Jacksonville,United States
,
Geoffrey Uy
Affiliations:
Washington University of St Louis,St Louis,United States
,
John Dipersio
Affiliations:
Washington University of St Louis,St Louis,United States
,
Arnon Nagler
Affiliations:
Sheba Medical Center,Ramat Gan,Israel
,
Jacob Rowe
Affiliations:
Shaarei Tzedek Medical Center,Jerusalem,Israel
,
Margaret M. Showel
Affiliations:
Johns Hopkins University,Baltimore,United States
,
Jessica K. Altman
Affiliations:
Northwestern University,Chicago,United States
,
Amnon Peled
Affiliations:
The Hebrew University of Jerusalem,Jerusalem,Israel
,
Michal Abraham
Affiliations:
The Hebrew University of Jerusalem,Jerusalem,Israel
,
Yaron Pereg
Affiliations:
BioLineRx,Modiin,Israel
,
Abi Vainstein
Affiliations:
BioLineRx,Modiin,Israel
,
Galia Oberkovitz
Affiliations:
BioLineRx,Modiin,Israel
,
Tzipora M Lustig
Affiliations:
BioLineRx,Modiin,Israel
,
Solli Brawer
Affiliations:
BioLineRx,Modiin,Israel
,
Osnat Bohana-Kashtan
Affiliations:
BioLineRx,Modiin,Israel
,
Jorge E. Cortes
Affiliations:
MD Anderson Cancer Center,Houston,United States
Michael Andreef
Affiliations:
MD Anderson Cancer Center,Houston,United States
(Abstract release date: 05/17/18) EHA Library. Borthakur G. 06/16/18; 215317; PS993
Gautam Borthakur
Gautam Borthakur
Contributions
Abstract

Abstract: PS993

Type: Poster Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00

Location: Poster area

Background

CXCR4 plays a key role in the retention and survival of human acute myeloid leukemia (AML) blasts in the bone marrow (BM) microenvironment. Interaction of AML blasts with the leukemic microenvironment is considered an important mediator of resistance to chemotherapy, disease relapse and poor survival. Blockade of the CXCR4/CXCL12 pathway using the high-affinity CXCR4 antagonist BL-8040 interrupts this interaction, thereby mobilizing and increasing the sensitivity of leukemic blasts to chemotherapy as well as inducing a direct anti-leukemic effect.

Aims

To assess the safety and efficacy of BL-8040 combined with high-dose Cytarabine (HiDAC) in adult patients with relapsed/refractory (r/r) AML.

Methods

A Phase IIa study (NCT02073019) consisting of two cohorts: (i) dose-escalation (3+3 design, 6 escalating doses, range 0.5-2.0 mg/kg) and (ii) expansion at the selected dose of 1.5 mg/kg. Patients with r/r AML (salvage 1/2) were treated daily with BL-8040 monotherapy (SC) for two days followed by combined administration of BL-8040 and HiDAC (IV; 1.5g or 3.0g/m2/d,

based on age) for 5 days for 1-2 cycles. Efficacy endpoints included response rate (CR/CRi), overall survival (OS), duration of response (DOR) and event free survival (EFS).

Results

42 patients, median age 61 (33-75) years were enrolled; 19 patients (45%) were refractory and 23 (55%) were relapsed. Overall, 26% (11/42) had secondary AML (from prior MDS), and 17% (7/42) were patients that relapsed after stem-cell transplantation.  81% (34/42) of patients had high-risk features that included primary refractory to one or two inductions or previous CR duration of less than 12 months.  Twelve subjects (28.6%) were refractory to a single induction and seven were refractory to 2 or more inductions. Eight subjects relapsed after a complete response that lasted less than a year after diagnosis and primary induction and seven relapsed after a complete response for less than a year after salvage chemotherapy following first relapse.  Median follow-up time was 213 days (1-958). BL-8040 in combination with HiDAC was safe and well tolerated. The CR/CRi rate for all dosing levels was 29% (12/42) and median OS (Kaplan-Meier estimate) was 9.1 months with 1-year and 2-year survival rates of 32.4% and 18.9%, respectively. In patients receiving the dose selected for expansion, 1.5 mg/kg (23 patients, 54.8%), the response rate (CR/CRi) was 39% (9/23) and median OS was 9.2 months with 1-year and 2-year survival rates of 31.6% and 21.1%, respectively. Median OS for responding (9/23 with CR/CRi) patients at the 1.5 mg/kg dose was 16.7 months, with 1- and 2-year survival rates of 50% and 37.5%, respectively. Median DOR for these patients was 10.1 months and EFS at 1 year and 2 years was 37.5% and 12.5%, respectively.

Conclusion
This study demonstrates that BL-8040 administered at a dose of 1.5 mg/kg in combination with HiDAC significantly improved overall survival of r/r AML patients compared with historical data[1] (overall survival of 6.1 months) for HiDAC alone. This supports continued clinical development of BL-8040 in frontline and early salvage AML patients.

 


[1] Ravandi et. al., Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 16: 1025 (2015).

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): AML, CXCR4

Abstract: PS993

Type: Poster Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 17:30 - 19:00

Location: Poster area

Background

CXCR4 plays a key role in the retention and survival of human acute myeloid leukemia (AML) blasts in the bone marrow (BM) microenvironment. Interaction of AML blasts with the leukemic microenvironment is considered an important mediator of resistance to chemotherapy, disease relapse and poor survival. Blockade of the CXCR4/CXCL12 pathway using the high-affinity CXCR4 antagonist BL-8040 interrupts this interaction, thereby mobilizing and increasing the sensitivity of leukemic blasts to chemotherapy as well as inducing a direct anti-leukemic effect.

Aims

To assess the safety and efficacy of BL-8040 combined with high-dose Cytarabine (HiDAC) in adult patients with relapsed/refractory (r/r) AML.

Methods

A Phase IIa study (NCT02073019) consisting of two cohorts: (i) dose-escalation (3+3 design, 6 escalating doses, range 0.5-2.0 mg/kg) and (ii) expansion at the selected dose of 1.5 mg/kg. Patients with r/r AML (salvage 1/2) were treated daily with BL-8040 monotherapy (SC) for two days followed by combined administration of BL-8040 and HiDAC (IV; 1.5g or 3.0g/m2/d,

based on age) for 5 days for 1-2 cycles. Efficacy endpoints included response rate (CR/CRi), overall survival (OS), duration of response (DOR) and event free survival (EFS).

Results

42 patients, median age 61 (33-75) years were enrolled; 19 patients (45%) were refractory and 23 (55%) were relapsed. Overall, 26% (11/42) had secondary AML (from prior MDS), and 17% (7/42) were patients that relapsed after stem-cell transplantation.  81% (34/42) of patients had high-risk features that included primary refractory to one or two inductions or previous CR duration of less than 12 months.  Twelve subjects (28.6%) were refractory to a single induction and seven were refractory to 2 or more inductions. Eight subjects relapsed after a complete response that lasted less than a year after diagnosis and primary induction and seven relapsed after a complete response for less than a year after salvage chemotherapy following first relapse.  Median follow-up time was 213 days (1-958). BL-8040 in combination with HiDAC was safe and well tolerated. The CR/CRi rate for all dosing levels was 29% (12/42) and median OS (Kaplan-Meier estimate) was 9.1 months with 1-year and 2-year survival rates of 32.4% and 18.9%, respectively. In patients receiving the dose selected for expansion, 1.5 mg/kg (23 patients, 54.8%), the response rate (CR/CRi) was 39% (9/23) and median OS was 9.2 months with 1-year and 2-year survival rates of 31.6% and 21.1%, respectively. Median OS for responding (9/23 with CR/CRi) patients at the 1.5 mg/kg dose was 16.7 months, with 1- and 2-year survival rates of 50% and 37.5%, respectively. Median DOR for these patients was 10.1 months and EFS at 1 year and 2 years was 37.5% and 12.5%, respectively.

Conclusion
This study demonstrates that BL-8040 administered at a dose of 1.5 mg/kg in combination with HiDAC significantly improved overall survival of r/r AML patients compared with historical data[1] (overall survival of 6.1 months) for HiDAC alone. This supports continued clinical development of BL-8040 in frontline and early salvage AML patients.

 


[1] Ravandi et. al., Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 16: 1025 (2015).

Session topic: 4. Acute myeloid leukemia - Clinical

Keyword(s): AML, CXCR4

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