EHA Library - The official digital education library of European Hematology Association (EHA)

PHASE 1B/2 COMBINATION STUDY OF APR-246 AND AZACITIDINE (AZA) IN PATIENTS WITH TP53 MUTANT MYELODYSPLASTIC SYNDROMES (MDS) AND ACUTE MYELOID LEUKEMIA (AML)
Author(s): ,
David Sallman
Affiliations:
Malignant Hematology Department,H. Lee Moffitt Cancer Center and Research Institute,Tampa, FL,United States
,
Amy Dezern
Affiliations:
Sidney Kimmel Comprehensive Cancer Center,Johns Hopkins University,Baltimore, MD,United States
,
Kendra Sweet
Affiliations:
Malignant Hematology Department,H. Lee Moffitt Cancer Center and Research Institute,Tampa, FL,United States
,
David Steensma
Affiliations:
Department of Medical Oncology,Dana-Farber Cancer Institute, Harvard Medical School,Boston, MA,United States
,
Thomas Cluzeau
Affiliations:
Hematology Department,Cote D'azur University, Nice Sophia Antipolis University,Nice,France
,
Mikkael Sekeres
Affiliations:
Department of Hematology and Medical Oncology,Cleveland Clinic,Cleveland, OH,United States
,
Guillermo Garcia-Manero
Affiliations:
Department of Leukemia,MD Anderson Cancer Center,Houston, TX,United States
,
Gail Roboz
Affiliations:
Weill Cornell Medical College,New York, NY,United States
,
Amy McLemore
Affiliations:
Malignant Hematology Department,H. Lee Moffitt Cancer Center and Research Institute,Tampa, FL,United States
,
Kathy McGraw
Affiliations:
Malignant Hematology Department,H. Lee Moffitt Cancer Center and Research Institute,Tampa, FL,United States
,
John Puskas
Affiliations:
Malignant Hematology Department,H. Lee Moffitt Cancer Center and Research Institute,Tampa, FL,United States
,
Ling Zhang
Affiliations:
Malignant Hematology Department,H. Lee Moffitt Cancer Center and Research Institute,Tampa, FL,United States
,
Chirag Bhagat
Affiliations:
Medical Affairs,Genoptix, Inc.,Carlsbad, CA,United States
,
Armin Graber
Affiliations:
Medical Affairs,Genoptix, Inc.,Carlsbad, CA,United States
,
Najla Al Ali
Affiliations:
Malignant Hematology Department,H. Lee Moffitt Cancer Center and Research Institute,Tampa, FL,United States
,
Eric Padron
Affiliations:
Malignant Hematology Department,H. Lee Moffitt Cancer Center and Research Institute,Tampa, FL,United States
,
Roger Tell
Affiliations:
,Aprea Therapeutics,Stockholm,Sweden
,
Jeffrey Lancet
Affiliations:
Malignant Hematology Department,H. Lee Moffitt Cancer Center and Research Institute,Tampa, FL,United States
,
Pierre Fenaux
Affiliations:
Hospital St Louis, Paris 7 University,Paris,France
,
Alan List
Affiliations:
Malignant Hematology Department,H. Lee Moffitt Cancer Center and Research Institute,Tampa, FL,United States
Rami Komrokji
Affiliations:
Malignant Hematology Department,H. Lee Moffitt Cancer Center and Research Institute,Tampa, FL,United States
(Abstract release date: 05/17/18) EHA Library. Sallman D. 06/17/18; 214477; S1558
David Sallman
David Sallman
Contributions
Abstract

Abstract: S1558

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 08:45 - 09:00

Location: Room A4

Background
TP53 mutant (mTP53) MDS and AML represent a distinct molecular cohort with poor outcomes. Hypomethylating agents (HMA) have emerged as preferred treatment for these patients with CR rate of 20-30% and median OS of 6-12 months. APR-246 is a mutant p53 activator with single agent activity in mTP53 AML. We report preliminary phase 1b results of APR-246 + AZA in mTP53 MDS/AML.

Aims
To evaluate the safety, recommended Phase 2 dose, preliminary activity and minimal residual disease (MRD) status of APR-246 in combination with azacitidine in mTP53 MDS/AML.

Methods
Eligible pts included HMA naïve mTP53 MDS and oligoblastic AML (≤ 30% blasts) ≥ 18 years of age. Pts received APR-246 in a 3+3 dose escalation design (50, 75, 100 mg/kg lean body weight) IV daily over 4 days in a lead-in phase (days -14 to -10) followed by the same dose of APR-246 (days 1-4) + AZA 75 mg/m2 SC/IV over 7 days (days 4-10 or 4-5 and 8-12) in 28 day cycles. Primary objective was safety with AEs graded by CTCAE v4.03 and DLT assessment over 6 weeks. Secondary endpoints included response by IWG 2006 criteria as well as serial next generation sequencing (NGS) and p53 IHC for evaluation of clonal suppression and remission depth. For MRD analysis, a custom target-capture NGS assay was developed using unique molecular Identifiers for error correction with a limit of detection defined as ≥5 mutant reads and ≥1000 read depth.

Results
As of Feb 12th, 2017, 9 pts (33% male; median age 65 years (39-73)) have enrolled with 3 pts per cohort. Three pts had AML-MRC and 6 had MDS; all pts had poor risk cytogenetics (11% poor, 89% very poor) and higher risk disease by IPSS-R (22% high, 78% very high). Median BM blasts were 18% (4-30). Seven pts (78%) remain on study: 2 pts in the 50mg/kg cohort discontinued treatment (Tx), 1 pt due to infection during C2 who later died of sepsis unrelated to Tx, and 1 pt electively discontinued in durable marrow CR (mCR) after 5 cycles of therapy. Median time on study is 133 days (41-248). Tx related AEs during the lead-in phase (all G1) included ataxia (n=1), dizziness (n=1), nausea (n=2) and neuropathy (n=2). AEs occurring in > 1 pt included dizziness (n=3), nausea (n=6), neutropenia (n=6), thrombocytopenia (n=3), infection (n=4), headache (n=2), pain (n=3), weakness (n=2), xerostomia (n=2), mucositis (n=2), falls (n=3), neuropathy (n=4), and ataxia (n=2); all G1/G2 except neutropenia/thrombocytopenia (G4). No Tx-related SAEs or DLTs have occurred to date. Five of six pts were response evaluable with 1 pt discontinuing tx prior to 1st disease assessment. ORR by IWG was 100% with 4 CR (80%, 3/3 in DL2) and 1 mCR. All CR patients achieved complete cytogenetic response. One CR patient achieved a mCR and partial cytogenetic response after APR-246 lead-in prior to combination therapy. All CR pts had high p53 positivity by IHC at baseline (55-70%) which normalized on serial assessment (<5%). Serial NGS with a variant allele frequency (VAF) cutoff of 5% was negative in 80% of patients (4/5). In pts negative on serial NGS, MRD analysis was performed with median TP53 VAF at maximum clearance of 0.8% (not detectable-3.4%) with 1 pt achieving MRD negativity after cycle 6 and 1 pt with VAF of 0.2% after cycle 3. The remaining 3 pts entered the study in Dec 17/Jan 18 with no response data available at data cutoff.

Conclusion
APR-246 + AZA combination is well tolerated in mTP53 MDS/AML. Responses have been achieved in all pts (80% CR) accompanied by deep molecular remissions. The maximum tolerated dose has not been reached and dose escalation is ongoing.

Session topic: 10. Myelodysplastic syndromes – Clinical

Keyword(s): Azacitidine, MDS/AML, Minimal residual disease (MRD), P53

Abstract: S1558

Type: Oral Presentation

Presentation during EHA23: On Sunday, June 17, 2018 from 08:45 - 09:00

Location: Room A4

Background
TP53 mutant (mTP53) MDS and AML represent a distinct molecular cohort with poor outcomes. Hypomethylating agents (HMA) have emerged as preferred treatment for these patients with CR rate of 20-30% and median OS of 6-12 months. APR-246 is a mutant p53 activator with single agent activity in mTP53 AML. We report preliminary phase 1b results of APR-246 + AZA in mTP53 MDS/AML.

Aims
To evaluate the safety, recommended Phase 2 dose, preliminary activity and minimal residual disease (MRD) status of APR-246 in combination with azacitidine in mTP53 MDS/AML.

Methods
Eligible pts included HMA naïve mTP53 MDS and oligoblastic AML (≤ 30% blasts) ≥ 18 years of age. Pts received APR-246 in a 3+3 dose escalation design (50, 75, 100 mg/kg lean body weight) IV daily over 4 days in a lead-in phase (days -14 to -10) followed by the same dose of APR-246 (days 1-4) + AZA 75 mg/m2 SC/IV over 7 days (days 4-10 or 4-5 and 8-12) in 28 day cycles. Primary objective was safety with AEs graded by CTCAE v4.03 and DLT assessment over 6 weeks. Secondary endpoints included response by IWG 2006 criteria as well as serial next generation sequencing (NGS) and p53 IHC for evaluation of clonal suppression and remission depth. For MRD analysis, a custom target-capture NGS assay was developed using unique molecular Identifiers for error correction with a limit of detection defined as ≥5 mutant reads and ≥1000 read depth.

Results
As of Feb 12th, 2017, 9 pts (33% male; median age 65 years (39-73)) have enrolled with 3 pts per cohort. Three pts had AML-MRC and 6 had MDS; all pts had poor risk cytogenetics (11% poor, 89% very poor) and higher risk disease by IPSS-R (22% high, 78% very high). Median BM blasts were 18% (4-30). Seven pts (78%) remain on study: 2 pts in the 50mg/kg cohort discontinued treatment (Tx), 1 pt due to infection during C2 who later died of sepsis unrelated to Tx, and 1 pt electively discontinued in durable marrow CR (mCR) after 5 cycles of therapy. Median time on study is 133 days (41-248). Tx related AEs during the lead-in phase (all G1) included ataxia (n=1), dizziness (n=1), nausea (n=2) and neuropathy (n=2). AEs occurring in > 1 pt included dizziness (n=3), nausea (n=6), neutropenia (n=6), thrombocytopenia (n=3), infection (n=4), headache (n=2), pain (n=3), weakness (n=2), xerostomia (n=2), mucositis (n=2), falls (n=3), neuropathy (n=4), and ataxia (n=2); all G1/G2 except neutropenia/thrombocytopenia (G4). No Tx-related SAEs or DLTs have occurred to date. Five of six pts were response evaluable with 1 pt discontinuing tx prior to 1st disease assessment. ORR by IWG was 100% with 4 CR (80%, 3/3 in DL2) and 1 mCR. All CR patients achieved complete cytogenetic response. One CR patient achieved a mCR and partial cytogenetic response after APR-246 lead-in prior to combination therapy. All CR pts had high p53 positivity by IHC at baseline (55-70%) which normalized on serial assessment (<5%). Serial NGS with a variant allele frequency (VAF) cutoff of 5% was negative in 80% of patients (4/5). In pts negative on serial NGS, MRD analysis was performed with median TP53 VAF at maximum clearance of 0.8% (not detectable-3.4%) with 1 pt achieving MRD negativity after cycle 6 and 1 pt with VAF of 0.2% after cycle 3. The remaining 3 pts entered the study in Dec 17/Jan 18 with no response data available at data cutoff.

Conclusion
APR-246 + AZA combination is well tolerated in mTP53 MDS/AML. Responses have been achieved in all pts (80% CR) accompanied by deep molecular remissions. The maximum tolerated dose has not been reached and dose escalation is ongoing.

Session topic: 10. Myelodysplastic syndromes – Clinical

Keyword(s): Azacitidine, MDS/AML, Minimal residual disease (MRD), P53

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies