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2746 Phase Ib/2 Study of Oral Decitabine/Cedazuridine (ASTX727) and Venetoclax in Combination with the Targeted Mutant IDH1 Inhibitor Ivosidenib or the Targeted Mutant IDH2 Inhibitor Enasidenib in IDH Mutated Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemias: Commercially Available Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Acute Myeloid Malignancies, AML, Clinical Research, Combination therapy, Diseases, Therapies, Myeloid Malignancies
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Himachandana Atluri, MD1, Abhishek Maiti, MBBS2, Koji Sasaki, MD2, Naval Daver, MD2, Yesid Alvarado, MD2, Md Feroz Hossain, MD, MS3*, Xuemei Wang, MS4*, Naveen Pemmaraju, MD2, Koichi Takahashi, MD, PhD5, Gautam Borthakur, MD2, Alessandra Ferrajoli2, Nicholas Short, MD5, Hussein A Abbas, MD, PhD2, Farhad Ravandi, MD2, Elias Jabbour, MD2, Michael Andreeff, MD, PhD2, Guillermo Garcia-Manero, MD6, Hagop Kantarjian, MD7, Marina Konopleva, MD, PhD2 and Courtney D. DiNardo, MD, MSCE2

1Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
3The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
6Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
7Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Background

Isocitrate Dehydrogenase (IDH) 1 or 2 mutations occur in ~20% of acute myeloid leukemia (AML). Both venetoclax (VEN)-based and targeted IDH-inhibitor (IDHi) therapies are effective treatment options for IDH mutated AML in combination with hypomethylating agents (HMA). ASTX727 is an oral, fixed dose (35 mg/100 mg) combination of decitabine and cedazuridine approved for the treatment of myelodysplastic syndrome (MDS). Herein we report the interim results of the first all-oral triplet regimen of ASTX727 (day 1-5) + VEN (day 1-14) in combination with a targeted mutant IDH1i ivosidenib (IVO) or IDH2i enasidenib (ENA), for IDH mutated AML.

Methods

Eligible patients were > 18 years old with relapsed/refractory (R/R) IDH1 or IDH2 mutated AML, or newly diagnosed (ND) AML not eligible for intensive chemotherapy. For the R/R AML cohort, prior VEN, HMA or IDHi use was not exclusionary. The primary objectives were to determine safety and the recommended phase 2 dose (RP2D) of ASTX727 and VEN with ivosidenib (Arm A) or enasidenib (Arm B) [Phase 1b], and to determine the composite remission rate (CRc; CRh+CRi+CR) for both arms [Phase 2].

Results

A total of 32 patients have enrolled, with 3 screen failures and 2 patients ongoing first cycle of therapy. There are currently 27 evaluable patients (arm A: 10, arm B: 17) with median follow up of 5.7 months. Median age at enrollment was 73 (50 – 81). 44% (n=12) had ND AML and 56% (n=15) had R/R AML. European LeukemiaNet (ELN) risk was intermediate or adverse in 52% and 44%, respectively. Patients received a median of 4 treatment cycles (ND: 5, R/R: 3). The CRc rate in the overall population was 72% (ND: 100%, R/R: 53%). Measurable residual disease (MRD) negative CRc by flow cytometry was achieved in 64% (ND: 83%, R/R: 42%). (Table 1) In the R/R cohort, 78% (n=11) patients had received prior treatment with either an HMA (azacitidine or decitabine), BCL2i and/or IDHi, with a median of 2 prior treatments. (Table 2) 5 patients did not have prior VEN exposure of which 4 (80%) achieved an MRD negative CRc. Four patients transitioned to stem cell transplant (ND: 2, R/R: 2).

The most common non-hematologic grade 3/4 AEs in the overall population included hyperbilirubinemia (n=2, 7%), representing indirect bilirubin in enasidenib-treated patients and mucositis (n=2, 7%) with one considered a residual effect of prior cytoreduction. There were two patients with possible/probable differentiation syndrome which resolved with medical management (dexamethasone and diuresis). Two episodes of reversible grade 1 tumor lysis syndrome were also reported. 60-day mortality within the ND and R/R cohort was 8% (n=1) and 0%, respectively. The ND patient withdrew from the study and went home on hospice after an admission for febrile neutropenia.

Conclusions
The combination of ASTX727 + VEN with IDH1 or IDH2 inhibition appears to be an effective regimen for the treatment of IDH mutated AML with high response rates including MRD-negative CRc, most notably in de novo patients and R/R pts without prior VEN exposure. AEs are anticipated and tolerable. Enrollment to this study is ongoing.

Disclosures: Sasaki: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceuticals: Honoraria. Daver: Agios, Celgene, SOBI and STAR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos and Jazz Pharmaceuticals: Other: Data monitoring committee member; Karyopham Therapeutics and Newave Pharmaceutical: Research Funding; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Novartis, Jazz, Amgen, Servier, Karyopharm, Trovagene, Trillium, Syndax, Gilead, Pfizer, Bristol Myers Squibb, Kite, Actinium, Arog, Immunogen, Arcellx, and Shattuck: Consultancy, Other: Advisory Role; Astellas, AbbVie, Genentech, Daiichi-Sankyo, Gilead, Immunogen, Pfizer, Bristol Myers Squibb, Trovagene, Servier, Novimmune, Incyte, Hanmi, Fate, Amgen, Kite, Novartis, Astex, KAHR, Shattuck, Sobi, Glycomimetics, Trillium: Research Funding. Alvarado: BerGenBio: Research Funding; Daiichi-Sankyo/Lilly: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding. Pemmaraju: Affymetrix: Research Funding; Roche Diagnostics: Honoraria; Plexxikon: Research Funding; LFB Biotechnologies: Honoraria; SagerStrong Foundation: Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Samus Therapeutics: Research Funding; Pacylex Pharmaceuticals: Consultancy; Novartis: Honoraria, Research Funding; Incyte: Research Funding; MustangBio: Honoraria; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding. Takahashi: Ostuka Pharmaceuticals: Honoraria; Agios: Consultancy; GSK: Consultancy; Celgene/BMS: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy; Mission Bio: Honoraria; Illumina: Honoraria. Borthakur: Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy. Ferrajoli: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Research Funding. Short: Takeda Oncology: Consultancy, Research Funding; Stemline Therapeutics: Research Funding; Astellas: Research Funding; AstraZeneca: Consultancy; Amgen: Consultancy, Honoraria; Novartis: Consultancy; Pfizer: Consultancy. Ravandi: Biomea Fusion, Inc.: Research Funding; AstraZeneca: Consultancy; Astex/Taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Xencor: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Syos: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Amgen: Honoraria, Research Funding; Prelude: Research Funding. Jabbour: Genentech: Other: Advisory Role, Research Funding; Takeda: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; Pfizer: Other: Advisory Role, Research Funding; Spectrum: Research Funding; AbbVie: Other: Advisory Role, Research Funding. Andreeff: Chimerix: Current holder of stock options in a privately-held company; Oncolyze: Current holder of stock options in a privately-held company; Daiichi-Sankyo Inc.: Consultancy, Research Funding; Brooklyn ITX: Research Funding; Kintor Pharmaceutical: Research Funding; Breast Cancer Research Foundation: Research Funding; Reata: Current holder of stock options in a privately-held company; Syndax: Consultancy, Research Funding; Senti Bio: Consultancy, Research Funding; Pinot Bio: Research Funding; Oxford Biomedical UK: Research Funding; AstraZeneca: Research Funding; Glycomimetics: Consultancy; Medicxi: Consultancy; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees. Garcia-Manero: Novartis: Honoraria, Research Funding; Gilead Sciences: Research Funding; Aprea: Honoraria; Acceleron Pharma: Consultancy; Curis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding. Kantarjian: KAHR Medical Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Research Funding; Astellas Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; AbbVie: Honoraria, Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ipsen Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. Konopleva: Cellectis: Research Funding; Eli Lilly: Consultancy, Honoraria, Research Funding; Stemline therapuetics: Consultancy, Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Forty Seven: Honoraria, Research Funding; Sanofi: Research Funding; Rafael Pharmaceutical: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Ablynx: Research Funding; Calithera: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. DiNardo: Novartis: Honoraria; Forma: Research Funding; Astellas: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cleave: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Consultancy, Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria; Astex: Research Funding; Foghorn: Honoraria, Research Funding; Gilead: Honoraria; LOXO: Research Funding; Bluebird Bio: Honoraria; Servier: Consultancy, Honoraria, Research Funding.

*signifies non-member of ASH