Phase II Study of CPX-351 Plus Venetoclax in Patients with Acute Myeloid Leukemia (AML)
Authors: Kadia Tapan M. , Borthakur Gautam , Takahashi Koichi , DiNardo Courtney D. , Daver Naval , Pemmaraju Naveen , Jabbour Elias , Jain Nitin , Short Nicholas J. , Qiao Wei , Adewale Lade , Rausch Caitlin R. , Pierce Sherry A. , Alvarado Yesid , Alousi Amin M. , Popat Uday R. , Khouri Issa F. , Garcia-Manero Guillermo , Konopleva Marina , Cortes Jorge E. , Ravandi Farhad , Kantarjian Hagop M. 
Published: November 2020

Background
CPX-351 is a liposomal formulation of cytarabine (araC) and daunorubicin at a fixed molar ratio that is currently approved for the treatment of patients with therapy-related AML or secondary AML (s-AML) arising from prior myelodysplastic syndrome (MDS). Compared to 7+3, CPX-351 demonstrated higher response rates (ORR), better tolerability, and better survival (OS) in patients with s-AML. The OS benefit was also observed after stem cell transplant (SCT). The dose-finding study of CPX-351 in R/R AML demonstrated an ORR of 23%. Recently, addition of the BCL-2 inhibitor venetoclax (Ven) to hypomethylating agents (HMAs) was shown to improve ORR and OS over HMAs alone. We designed this study to investigate the safety and efficacy of Ven combined with CPX-351 in patients with AML.
Methods
The dose of CPX-351 was constant: (daunorubicin 44 mg/m2 + araC 100 mg/m2) IV on D1,3,5 of induction and (daunorubicin 29 mg/m2 + araC 65 mg/m2) IV on D1,3 during consolidation. The starting effective dose of Ven was 300mg (at the -1 dose level) on D2-21 for the safety lead-in cohort, composed of patients with R/R AML. Interruption of Ven after D14 was allowed if a D14 bone marrow (BM) was hypocellular and without evidence of leukemia. Dose adjustments for Ven were made for concomitant moderate and strong CYP3A inhibitors. Upon encountering 3/6 patients with DLT (cytopenias &gt;43 days), dose level -2 was explored (Ven 300mg on D2-8) and expanded. Once safety was confirmed, two expansions cohorts were opened to confirm safety and efficacy: Cohort A for pts with R/R AML and Cohort B for pts with newly diagnosed AML. Patients with adequate organ function, ECOG PS &lt; 2 were allowed on study and prior Ven exposure was allowed.
Results
18 patients have been treated on study, with a median age of 51 yrs (range, 29-71): 12 (67%) in the lead-in cohort, 5 (28%) in Cohort A and 1 (6%) in cohort B. Overall 17 (94%) had R/R AML with a median of 2 (1-8) prior therapies, and 1 (6%) patient with newly diagnosed treated-secondary AML. Patient characteristics are summarized in Table 1. Nine (50%) pts had adverse karyotype including 6 (33%) with complex karyotype and 6 (33%) with TP53 mutations; 7 (41%) pts with R/R AML had prior Ven. Outcomes are summarized in Table 1. The 1 pt with newly diagnosed AML (who had prior HMA+Ven and SCT for MDS) achieved an MRD (-) CR. Of 16 pts with R/R AML evaluable for response, there was 1 (6%) CR, 5 (31%) CRi, and 1 (6%) MLFS for an ORR of 44%. ORR was 60% (6/10) in pts without prior Ven exposure, compared to just 17% (1/6 evaluable) among those who had prior Ven. 86% of responding pts (6/7) went on for SCT. The median OS overall was 6.4 months with a 6m OS rate of 53% (Figure 1). Among responders, the median OS and RFS were NR and the 6m-OS and RFS were 86% and 86%, respectively (Figure 2). Figure 3 shows the OS of pts who did and did not receive prior Ven. The 4- and 8-week mortality rates were 11% and 22%, respectively. The starting dose level -1 was above the maximum tolerated dose of the combination; DLTs were prolonged neutropenia and thrombocytopenia. Serious adverse events are summarized in Table 2. The most frequent grade 3/4 serious adverse events were infection, nausea, pneumonia, and myelosuppression.
Conclusion
CPX-351 plus 7 days of Ven is tolerable, with acceptable toxicities in patients with R/R AML. Within this high risk AML cohort, CPX + Ven demonstrated encouraging activity, particularly in those who had not received prior Ven. Almost all responders were able to move on to SCT. The study continues to enroll relapsed and frontline cohorts.

Disclosures
Kadia: Astellas: Research Funding; Celgene: Research Funding; Pulmotec: Research Funding; Astra Zeneca: Research Funding; Novartis: Honoraria; Incyte: Research Funding; Cellenkos: Research Funding; Ascentage: Research Funding; Amgen: Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Borthakur:PTC Therapeutics: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Jannsen: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy. DiNardo:Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Takeda: Honoraria; Syros: Honoraria; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Calithera: Research Funding; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pemmaraju:Pacylex Pharmaceuticals: Consultancy; MustangBio: Honoraria; DAVA Oncology: Honoraria; Samus Therapeutics: Research Funding; Cellectis: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Roche Diagnostics: Honoraria; Incyte Corporation: Honoraria; SagerStrong Foundation: Other: Grant Support; AbbVie: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; LFB Biotechnologies: Honoraria; Celgene: Honoraria; Blueprint Medicines: Honoraria; Novartis: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Plexxikon: Research Funding. Jabbour:Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. Jain:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Short:Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria; Astellas: Research Funding. Alvarado:MEI Pharma: Research Funding; BerGenBio ASA: Research Funding; Tolero Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding; Sun Pharma: Research Funding; Jazz Pharmaceuticals: Research Funding. Alousi:Therakos: Research Funding; Alexion: Honoraria; Incyte: Honoraria, Research Funding. Popat:Bayer: Research Funding; Novartis: Research Funding. Khouri:Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Garcia-Manero:Merck: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; Acceleron Pharmaceuticals: Consultancy, Honoraria; Onconova: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding. Konopleva:Agios: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Eli Lilly: Research Funding; Sanofi: Research Funding; AstraZeneca: Research Funding; Amgen: Consultancy; Rafael Pharmaceutical: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Ablynx: Research Funding; Kisoji: Consultancy; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Ascentage: Research Funding; Cellectis: Research Funding; Forty-Seven: Consultancy, Research Funding; Calithera: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Merus: Research Funding; Telios: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Immunogen: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ravandi:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Kantarjian:Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Takeda: Honoraria.

OffLabel Disclosure:
CPX-351 is not indicated in combination with venetoclax nor for patients with relapsed AML. This trials describes and investigational use.