A Phase II Study of CPX-351 Plus Venetoclax in Patients with Relapsed/Refractory (R/R) or Newly Diagnosed Acute Myeloid Leukemia (AML)
Authors: Kim Kunhwa , Kantarjian Hagop , Borthakur Gautam , Takahashi Koichi , Short Nicholas J. , DiNardo Courtney D. , Jabbour Elias J. , Chien Kelly S. , Daver Naval , Pemmaraju Naveen , Jain Nitin , Adewale Lade , Montalban-Bravo Guillermo , Wierda William G. , Verstovsek Srdan , Konopleva Marina , Ravandi Farhad , Kadia Tapan M. 
Published: November 2021

Abstract
Background : CPX-351 is a dual-drug liposomal encapsulation of cytarabine(araC) and daunorubicin at a 5:1 molar ratio that is approved for treatment of newly diagnosed therapy-related AML or AML-MRC. Compared to 7+3, CPX-351 was associated with higher response rates (47.7% vs 33.3%) and improved overall survival (OS) in these patients. In an earlier phase I study, CPX-351 produced a CR/CRi rate of 23% in patients with R/R AML. Based on the activity of venetoclax (VEN) with lower intensity therapy in newly diagnosed AML, we investigated safety and efficacy of VEN combined with CPX-351 in pts with newly diagnosed (frontline) and R/R AML who are considered fit for intensive chemotherapy.
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 R/R AML (Cohort A) and frontline AML (Cohort B). Patients aged ≥ 18 years with adequate organ function, and ECOG PS ≤2 were eligible. 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 D1,3,5 of induction, and daunorubicin 29 mg/m2 + cytarabine 65 mg/m 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. with appropriate dose adjustment for concomitant CYP3A inhibitors. Interruption of VEN after D14 was implemented if a D14 bone marrow (BM) was hypocellular and without evidence of leukemia.
Results : A total of 31 patients were treated on the trial. 26 (84%) patients with R/R AML were treated on study: 12(46%) in the lead-in phase, and 14 (54%) in the expansion cohort (A). 5 (16%) patients with frontline AML were treated on expansion cohort B. Patient characteristics are summarized in Table 1. Median number of prior treatments in R/R AML was 1 (range 1-7). Notably, 3 (60%) pts with frontline AML and 10 (42%) with R/R AML had a complex karyotype; 3 (60%) frontline AML patients and 6 (23%) R/R AML patients had TP53-mutated AML. 4 of the 5 (80%) patients in the frontline cohort had treatment for a prior myeloid neoplasm before transforming to AML (treated secondary-AML). Among the 5 frontline AML patients, 4 (80%) achieved CR/CRi including 1 (20%) CR and 3 (60%) CRi. Of 26 R/R AML patients, there were 12 (46%) CR/CRi including 4(15%) CR and 8(31%) CRi. Rates of MRD negativity by flow cytometry were 75% and 78% in frontline and R/R AML, respectively. 4 out of 4 (100%) responding pts in the frontline AML cohort transitioned to SCT, and all are alive to date. 10 out of 12 responding patients in the R/R cohort (83%) underwent SCT. The 4- and 8-week mortality was 12% and 19% for the R/R cohort - all were patients with persistent AML; there were no early deaths in the frontline cohort (Table2). The median OS in frontline AML was not reached, compared to 7.1 months in R/R AML patients (Figure 1a). 1-year estimated OS was 75% (95% CI 13-96%) and 39% (95% CI 18-60%) in frontline and R/R AML, respectively. The median RFS was 6.7 months and 10.9 months in frontline and R/R AML, respectively (P=0.71; Figure 1b). Among R/R AML, the median OS in responding pts was 26.9 months (Figure 1d). Achieving MRD negativity was associated with better OS in R/R AML, with median OS of 26.9 months compared to 2.6 months in responders with detectable MRD (P=.061)(Figure 1c). Serious adverse events (SAEs) are summarized in Table 3. The most common grade 3/4 SAEs were infection NOS (19), pneumonia (7) and febrile neutropenia without source (4). Myelosuppression was universal. Grade 5 SAEs included 1 each of sepsis, pneumonia, intracranial bleed, and respiratory failure.
Conclusion
The combination of CPX-351 + 7 days of VEN was safe and tolerable, demonstrating encouraging rates of CR/CRi in adverse-risk frontline AML (80%) and R/R AML (52%), respectively. Median OS was not reached in frontline AML, and 7.1 months in R/R AML patients. 80% of frontline AML patients and 42% R/R AML patients overall successfully transitioned to SCT. Further investigation into efficacy in frontline AML and confirmation in R/R AML is planned.
Figure 1 Figure 1.

Disclosures
Kantarjian: Jazz: Research Funding; Ascentage: Research Funding; Astra Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; BMS: Research Funding; Aptitude Health: Honoraria; Astellas Health: Honoraria; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Taiho Pharmaceutical Canada: Honoraria. Borthakur: Ryvu: Research Funding; Astex: Research Funding; Protagonist: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Takahashi: Celgene/BMS: Consultancy; GSK: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Short: Novartis: Honoraria; NGMBio: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas: Research Funding; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Daver: Genentech: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Sevier: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Astellas: Consultancy, Research Funding; Hanmi: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Pemmaraju: Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; LFB Biotechnologies: Consultancy; Celgene Corporation: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; DAVA Oncology: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Incyte: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; Roche Diagnostics: Consultancy; Springer Science + Business Media: Other; Sager Strong Foundation: Other; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Jain: Adaptive Biotechnologies: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; Cellectis: Honoraria, Research Funding; Servier: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Janssen: Honoraria; Beigene: Honoraria; TG Therapeutics: Honoraria; Precision Biosciences: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Incyte: Research Funding. Wierda: Loxo Oncology, Inc.: Research Funding; Cyclacel: Research Funding; Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AstraZeneca: Research Funding; KITE Pharma: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Juno Therapeutics: Research Funding; Xencor: Research Funding; GSK/Novartis: Research Funding; Miragen: Research Funding; Janssen: Research Funding; Sunesis: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; Karyopharm: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Verstovsek: PharmaEssentia: Research Funding; Ital Pharma: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Konopleva: Cellectis: Other: grant support; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Agios: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Ablynx: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; KisoJi: Research Funding; Stemline Therapeutics: Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding. Ravandi: Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Prelude: Research Funding; Novartis: Honoraria; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Taiho: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Kadia: Astellas: Other; Ascentage: Other; Genfleet: Other; AstraZeneca: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support.

OffLabel Disclosure:
currently FDA approved CPX-351 for t-AML or AML with myelodysplastic changes, we are conducting trial including frontline AML patients or relapsed/refractory AML patients.