Introduction: Relapsed/refractory acute myeloid leukemia (rAML) remains a significant challenge, with low response to therapy and poor long-term survival. Treatments focusing on achieving a response and, in eligible patients (pts), proceeding with an allogeneic stem cell transplantation (alloSCT) offer the best prospect for improved survival. CPX-351 is a liposomal fixed-ratio formulation of cytarabine and daunorubicin, which has demonstrated higher response rates and reduced early mortality in some subsets of AML and has also been shown to be active in rAML. The BCL2 inhibitor venetoclax (Ven) has demonstrated efficacy in AML in combination with other agents, such as hypomethylating agents, low dose cytarabine, and intensive chemotherapy. We conducted a Phase Ib/II dose-finding study to evaluate the combination of CPX-351 with Ven in AML. Herein we present the results of CPX-351 plus Ven in the cohort of rAML pts treated on study (NCT03629171).
Methods: The study was designed with a safety lead-in phase to establish the safe dose and schedule in R/R AML, followed by 2 expansion cohorts to explore efficacy in (1) R/R AML and (2) frontline AML. Prior Ven use was allowed for pts with R/R AML. The dose of CPX-351 was fixed : daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 IV on days 1, 3 and 5 of induction, and daunorubicin 29 mg/m2 + cytarabine 65 mg/m IV on days 1 and 3 during consolidation. The starting effective dose of Ven was 300mg (at the -1 dose level) on D2-21 for the safety lead-in cohort with appropriate dose adjustment for concomitant CYP3A inhibitors. First, interruption of Ven after D14 was implemented if a D14 bone marrow was hypocellular and without evidence of leukemia. However, a second de-escalation was required (-2 dose level) with Ven given on day 2-8 of each cycle, and daunorubicin dose reduced to 22 mg/m2 during consolidation. This was found to be the recommended phase 2 dose.
Results: Between 11/2018 to 1/2022, 33 pts were enrolled. The median age was 53 yrs (range, 26-72) and 61% were female. Diploid karyotype was present in 7 pts (21%), core binding factor rearrangements in 2 (6%), MECOM rearrangement in 2 (6%) and 13 (39%) had a complex karyotype. The most frequent mutations were DNMT3A (37%), TP53 (21%) and NRAS (21%). 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 Ven.
Pts received a median of 1 cycle (1-4), and the median number of cycles to first response was 1 (1-2). The ORR was 45% (15/33), with 5 patient (15%) achieving CR, 8 (24%) achieving CRi and 2 (6%) achieving MLFS. The ORR was higher in those pts with only one prior line of therapy (59%) compared to those with 2 or more previous therapies (31%). The ORR for pts with prior exposure to Ven was 37% (7/19) vs 57% (8/14) for those not previously exposed to Ven (p=0.4). The 4- and 8-week mortality was 9 and 21%. 9/15 pts (60%) underwent alloSCT including 14 with CR/CRi/MLFS and 1 pt with an aplastic bone marrow insufficient for response assessment.
The most frequent grade 3 or more adverse events were infections (45%, 30% of them pulmonary), febrile neutropenia (24%), and mucositis/stomatitis (6%). Three deaths occurred on study (2 due to sepsis and 1 due to cardiac arrest), all after one cycle of therapy. Other grade 3-4 events registered included rash (6%), cerebrovascular accident (6%), and intracranial hemorrhage (3%).
After a median follow-up time of 20.7 months, the OS at 12 and 24 months was 34% and 25%, respectively. The median OS was 6.4 months. The EFS at 12 and 24 months was 26% and 19%, respectively. The median EFS was 2.8 months. For those who achieved response, the 2-year cumulative incidence of relapse and death without relapse were 41% and 28%, respectively. For those who underwent alloSCT, the median OS after alloSCT was 24 months, with 4 deaths after alloSCT, all following disease relapse.
Conclusion: In this phase Ib dose escalation study, standard dose CPX-351 combined with 7 days of Ven was found to safe and tolerable in pts with rAML. The combination produced encouraging response rates in a poor risk population, including those with prior Ven treatment, allowing a significant proportion to undergo allo-SCT and extended survival. The RP2D is being studied in pts with newly diagnosed and less heavily pretreated AML.
Disclosures
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. Short:AstraZeneca: Consultancy; Novartis: Consultancy; Astellas: Research Funding; Stemline therapeutics: Research Funding; Amgen: Honoraria; Takeda: Consultancy, Research Funding; Pfizer: Consultancy. Jabbour:Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Daver:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Syndax: Consultancy; Shattuck Labs: Consultancy; AbbVie: Consultancy, Research Funding; Agios: Consultancy; AROG: Consultancy; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy; Gilead: Consultancy, Research Funding; Glycomimetics: Research Funding; Trillium: Consultancy, Research Funding; Hanmi: Research Funding; Trovagene: Research Funding; FATE: Research Funding; Novimmune: Research Funding; Servier: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Kite, a Gilead company: Consultancy, Research Funding; Kronos Bio: Research Funding. Issa:Merck: Research Funding; Celgene: Research Funding; Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax: Research Funding; NuProbe: Consultancy. DiNardo:Novartis: Honoraria; ImmuniOnc: Honoraria; AbbVie/Genentech: Honoraria; Servier: Honoraria; Notable Labs: Honoraria; Fogham: Honoraria; Astellas: Honoraria; Takeda: Honoraria; BMS: Honoraria; Schrödinger: Consultancy. Pemmaraju:Karger Publishers: Other: Licenses; PeerView Institute for Medical Education: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Physician Education Resource (PER): Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aplastic Anemia & MDS International Foundation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Pacylex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stemline: Consultancy, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Intellisphere: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Magdalen Medical Publishing: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ASH Committee on Communications: Other: Leadership; Neopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Aptitude Health: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Harborside Press: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Medscape: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Patient Power: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CancerNet: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; OncLive: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Curio Science: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Protagonist Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ASCO Cancer.Net Editorial Board: Other: Leadership; National Institute of Health/National Cancer Institute (NIH/NCI): Research Funding; United States Department of Defense (DOD): Research Funding; Imedex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CareDx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini Group: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ClearView Healthcare Partners: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cimeio Therapeutics AG: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; HemOnc Times/Oncology Times: Other: Uncompensated; Bristol Myers Squibb Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jain:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Adaptive Biotechnologies: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Kite/Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Servier: Research Funding; Pfizer: Research Funding; Dialectic Therapeutics: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Ipsen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; TG Therapeutics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Genentech: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; ADC Therapeutics: Research Funding; MEI Pharma: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; BMS: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; TransThera Sciences: Research Funding; Newave: Research Funding; Incyte: Research Funding; Loxo Oncology: Research Funding; Medisix: Research Funding; Novalgen: Research Funding; CareDX: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Aprea Therapeutics: Research Funding; Cellectis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Beigene: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Precision Biosciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Research Funding; Fate Therapeutics: Research Funding; Mingsight: Research Funding. Montalban-Bravo:Takeda: Research Funding; Rigel: Research Funding. Wierda:NIH P30 CA016672/MDACC Cancer Center Support Grant: Research Funding; National Comprehensive Cancer Network: Other: Nonrelevant Financial Relationship/Chair, CLL). Supported by the NIH/NCI under award number P30 CA016672 and used MDACC Cancer Center Support Grant (CCSG) shared resources; Nurix THerapeutics: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; GlaxoSmithKline: Research Funding; Janssens Biotech: Research Funding; Numab THerapeutics: Research Funding; Janssens Biotech Inc: Research Funding; Accutar Biotechnology: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Cyclacel: Consultancy, Research Funding; Juno Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; AstraZeneca/Acerta Pharma: Consultancy, Research Funding; Gilead Sciences: Research Funding; Bristol Myers Squibb (Juno & Celgene): Consultancy, Research Funding; KITE Pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; GSK/Novartis: Research Funding. Ravandi:Amgen: Honoraria, Research Funding; Xencor: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Biomea fusion: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Astex/taiho: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Daiichih-Sankyo (Inst): Honoraria, Research Funding; AstraZeneca/MedImmune: Honoraria; Amgen: Honoraria; Immunogen (Inst): Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Novartis (Inst): Research Funding; Bristol-Myers Squibb (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; Abbvie (Inst): Research Funding; Amgen (Inst): Research Funding; Jazz Pharmaceuticals (Inst): Honoraria, Research Funding; Ipsen: Honoraria; KAHR Medical: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Precision Biosciences: Honoraria; Shenzhen Target Rx: Honoraria; Taiho Pharmaceutical: Honoraria; Ascentage Pharma Group: Honoraria; Astellas Pharma: Honoraria. Kadia:Novartis: Consultancy; GenFleet Therapeutics: Research Funding; Delta-Fly Pharma, Inc.: Research Funding; Cellenkos Inc.: Research Funding; Cure: Speakers Bureau; Ascentage Pharma Group: Research Funding; Hikma Pharmaceuticals: Speakers Bureau; SELLAS Life Sciences Group: Research Funding; Pulmotect, Inc.: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Research Funding; Biologix, Cure, Hikma Pharmaceuticals: Speakers Bureau; Jazz Pharmaceuticals, Pfizer, Pulmotect, Inc, Regeneron Pharmaceuticals, SELLAS Life Sciences Group: Research Funding; Liberum: Consultancy; Glycomimetics: Research Funding; Amgen, Inc.: Research Funding; AbbVie, Amgen, Inc, Ascentage Pharma Group, Astellas Pharma Global Development, Astex, AstraZeneca, BMS, Celgene, Cellenkos Inc, Cyclacel, Delta-Fly Pharma, Inc, Genentech, Inc., Genfleet, Glycomimetics, Iterion, Janssen Research and Development: Research Funding; Genentech: Consultancy, Research Funding; Astellas Pharma Global Development: Research Funding; Iterion: Research Funding; Janssen Research and Development: Research Funding; Cyclacel: Research Funding; Sanofi-Aventis: Consultancy; AstraZeneca: Research Funding; Regeneron Pharmaceuticals: Research Funding; Genzyme: Honoraria; Daiichi Sankyo, Genentech, Inc., Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Inc, Pulmotect, Inc, Sanofi-Aventis, Servier: Consultancy; Agios: Consultancy; Servier: Consultancy; Pinotb-Bio: Consultancy; BMS: Consultancy, Research Funding; Astex: Honoraria.
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