Phase Ib/II Study of CPX-351 Plus Venetoclax in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML)

Introduction: Patients with relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) have a poor prognosis, characterized by modest long-term survival rates and scarcity of effective treatment options. While allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially effective option, its success is often hindered by insufficient response required to achieve a bridge to transplant or other limitations that preclude its use. CPX-351 is a liposomal formulation of cytarabine and daunorubicin in a fixed 5:1 molar ratio that is currently FDA approved for the treatment of newly diagnosed secondary AML. Here we report the results from a completed Phase Ib/II study (NCT03629171) assessing the safety and efficacy of combining CPX-351 with Venetoclax (VEN), with an extended follow-up period of a median of 55.1 months.

Methods: The phase I portion of the study consisted of a safety lead-in phase to establish the optimal dose and schedule for CPX-351 in R/R AML, followed by two phase II expansion cohorts: one for R/R AML and another for frontline AML. Prior use of VEN was permitted for patients with R/R AML. The dose of CPX-351 was standardized: daunorubicin 44 mg/m² and cytarabine 100 mg/m² administered intravenously on days 1, 3, and 5 of the induction phase, and daunorubicin at 29 mg/m² plus cytarabine at 65 mg/m² on days 1 and 3 during consolidation. VEN was initially dosed at 300 mg (at the -1-dose level) from days 2 to 21 in the safety lead-in cohort, with dose adjustments for CYP3A inhibitors as needed. Due to myelosuppression, the protocol implemented a VEN interruption after D14 if a D14 bone marrow showed hypocellularity without leukemia. A 2^nd de-escalation was required (dose level -3) which reduced VEN to days 2 to 8 each cycle and daunorubicin lowered to 22 mg/m² during consolidation. This modified regimen became the recommended phase 2 dose.

Results: Thirty-three patients were enrolled with a median follow up of 55.1 months. The median age of the patients was 58 years (range: 26-72), with 39% being male. Prior malignancies were present in 15% of the patients, and 80% of these had prior radiation therapy for a non-myeloid malignancy. Cytogenetic analysis revealed complex karyotype in 13 (39%), diploid in 7 (21%), CBF in 2 (6%), MECOM rearrangement in 2 (6%) and other in the rest. The most frequent mutations observed were in DNMT3A (24%), NRAS (24%), TP53 (18%), IDH2 (15%), WT (15%), TET2 (15%), RUNX1 (12%), ASXL1 (12%), SF3B1 (9%). 8 (24%) pts had secondary AML including 4 (12%) with prior HMA exposure; the median number of prior lines of myeloid-directed therapies was 1 (1-7), including 58% of them with a previous exposure to Venetoclax.

The median number of treatment cycles was 1 (1-5), and the median cycles to achieve the best response was 1 (1-2). Treatment responses included complete remission in 7 (CR, 21%), CR with incomplete count recovery in 7 (CRi, 21%), morphologic leukemia-free state in 4 (MLFS, 12%), and no response (45%). The overall response rate was 55%. Among 18 responding patients, 4 (22%) achieved minimal residual disease (MRD) negativity. 11 of 18 responding pts (61%) proceeded to allogeneic SCT.

Adverse events included infection (39%), febrile neutropenia (24%), hemorrhage (6%), vascular/neurological events (6%), and pulmonary complications (3%). Dose reductions were required in 27% of patients. The 4- and 8-week mortality rates were 9% and 21.2%, respectively.

The median overall survival (OS) for the R/R cohort was 5.32 months. The median relapse-free survival (RFS) was 23.69 months. Among patients who underwent SCT, the median OS was 19.6 months, with a 1-year and 2-year survival rate of 72.8% and 45.5% respectively.

Conclusion: In this Phase Ib/II study, a combination of CPX-351 with 7 days of Ven for R/R AML demonstrated safety and tolerability, producing an overall response rate of 55% in a very high-risk population of patients and allowing over 60% of responding pts to move to SCT. Despite the myelosuppression observed with the combination, appropriate dose modifications and an optimized phase II dose allowed safe delivery of the combination with promising efficacy in a refractory population.

Borthakur:Catamaran Bio, AbbVie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy; Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding. Jabbour:AbbVie, Adaptive Biotechnologies, Amgen, Astellas Pharma, BMS, Genentech, Incyte, Pfizer, Takeda: Consultancy; AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Pfizer, Takeda: Research Funding. Daver:Novartis: Consultancy; KITE: Research Funding; Shattuck Labs: Consultancy; Jazz: Consultancy; Novimmune: Research Funding; Menarini Group: Consultancy; Hanmi: Research Funding; Glycomimetics: Research Funding; Astellas: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Servier: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Trovagene: Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Agios: Consultancy; Trillium: Consultancy, Research Funding; Celgene: Consultancy; Syndax: Consultancy; Arog: Consultancy. Short:Takeda Oncology: Honoraria, Research Funding; Amgen: Honoraria; Stemline Therapeutics: Research Funding; Astellas Pharma, Inc.: Honoraria, Research Funding; Autolus: Honoraria; Xencor: Research Funding; GSK: Consultancy, Research Funding; NextCure: Research Funding; Novartis: Honoraria; Sanofi: Honoraria; Adaptive Biotechnologies: Honoraria; BeiGene: Honoraria; Pfizer Inc.: Honoraria. Issa:Kura Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Astex: Research Funding; Merck: Research Funding; Syndax Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Celgene: Research Funding; NuProbe: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: consultancy/ad board fees. DiNardo:Foghorn: Research Funding; Jazz: Consultancy, Honoraria; Loxo: Research Funding; Cleave: Research Funding; Rigel: Research Funding; Amgen: Consultancy; Servier: Consultancy, Honoraria, Other: meetingsupport, Research Funding; GenMab: Consultancy, Honoraria, Other: data safety board; Schrodinger: Consultancy, Honoraria; Astex: Research Funding; ImmuneOnc: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Riegel: Honoraria; BMS: Consultancy, Honoraria, Research Funding; Genetech: Honoraria; Immunogen: Honoraria; AstraZeneca: Honoraria; GSK: Consultancy, Honoraria; Notable Labs: Honoraria; Astellas: Consultancy, Honoraria; Gilead: Consultancy; Stemline: Consultancy. Pemmaraju:Mustang Bio: Honoraria, Other: Travel Expenses, Research Funding; Roche Molecular Diagnostics: Honoraria; Celgene: Honoraria, Other: Travel Expenses; Protagonist Therapeutics: Consultancy; Incyte: Honoraria; LFB Biotechnologies: Honoraria; CareDx: Honoraria; Pacylex: Consultancy; DAVA Oncology: Honoraria, Other: Travel Expenses; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; Bristol-Myers Squibb: Consultancy; Affymetrix/Thermo Fisher Scientific: Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Samus Therapeutics: Research Funding; Triptych Health Partners: Consultancy; Stemline Therapeutics: Honoraria, Other: Travel Expenses, Research Funding; Springer Science + Business Media: Honoraria; Blueprint Medicines: Consultancy, Honoraria; Plexxikon: Research Funding; Immunogen: Consultancy; Neopharm: Honoraria; ClearView Healthcare Partners: Consultancy; Blueprint Medicines OncLive PeerView Institute for Medical Education: Consultancy, Other: advisory board; CTI BioPharma: Consultancy; Astellas: Consultancy; AbbVie: Honoraria, Other: Travel Expenses, Research Funding; ASH Committee on Communications ASCO Cancer.NET Editorial Board: Other: Leadership; Karger Publishers: Other: Licenses; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; HemOnc Times/Oncology Times: Other: uncompensated. Jain:Genentech: Consultancy, Honoraria, Other: Travel Support, Research Funding; Newave: Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel Support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; MEI Pharma: Consultancy, Honoraria, Other: Travel Support; Incyte: Research Funding; Precision Biosciences: Consultancy, Honoraria, Other: Travel Support, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Travel Support; ADC Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Dialectic Therapeutics: Research Funding; Janssen: Consultancy, Honoraria, Other: Travel Support; MingSight: Honoraria, Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel Support, Research Funding; CareDx: Consultancy, Honoraria, Other: Travel Support; Fate Therapeutics: Research Funding; Loxo Oncology: Research Funding; Ipsen: Consultancy, Honoraria, Other: Travel Support; BeiGene: Consultancy, Honoraria, Other: Travel Support; Medisix: Research Funding; NovalGen: Research Funding; Pfizer: Research Funding; Servier: Research Funding; Takeda: Research Funding; TransThera Sciences: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Other: Travel Support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel Support, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel Support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel Support, Research Funding. Montalban-Bravo:Takeda: Research Funding; Rigel: Research Funding. Wierda:National Comprehensive Care Center (NCCN): Other: Financial relationship (Chair, CLL); Kite: Research Funding; Gilead Sciences: Research Funding; Novartis: Research Funding; GSK: Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd.: Research Funding; Loxo Oncology: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AbbVie: Research Funding; Cyclacel Pharmaceuticals Inc: Research Funding; Oncternal Therapeutics: Research Funding; Accutar Biotechnology: Research Funding; Oncternal Therapeutics: Research Funding; Numab Therapeutics: Research Funding; Eli Lilly: Research Funding; Nurix Therapeutics: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Janssen: Research Funding. Ravandi:Prelude: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen: Research Funding; BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Xencor: Research Funding; Astyex/Taiho: Research Funding. Kantarjian:AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda: Consultancy, Honoraria. Kadia:AstraZeneca: Research Funding; Incyte: Research Funding; Novartis: Honoraria; Amgen: Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; ASTEX: Research Funding; Genentech: Consultancy, Research Funding; Regeneron: Research Funding; JAZZ: Research Funding; DrenBio: Consultancy, Research Funding; Sellas: Consultancy, Research Funding; Rigel: Honoraria; Pfizer: Research Funding; Servier: Consultancy; Ascentage: Research Funding; Cellenkos: Research Funding.

CPX-351 and Venetoclax are not approved in patients with R/R AML