Final results of a phase I/II trial of palbociclib and CPX-351 in patients with Acute Myeloid Leukemia

Abstract

Abstract Introduction Cytarabine resistance limits treatment efficacy in acute myeloid leukemia (AML), due in part to the asynchronous cell cycling of leukemic blasts. Studies have demonstrated that palbociclib, a selective CDK4/6 inhibitor induces G0/G1 arrest and can enhance cytarabine's S-phase-specific cytotoxicity (Aleem et al., 2015; Roberts PJ et al., 2020), providing the rationale for this combination in this study. Here, we report the final results of a prospective phase I/II study of sequential administration of palbociclib followed by a liposomal encapsulation of daunorubicin and cytarabine (CPX-351) in patients with AML (NCT03844997). Methods This was a phase I/II single arm trial of the sequential administration of palbociclib and CPX-351 in patients [pts] with AML [newly diagnosed and primary refractory/relapsed (R/R)]. The trial consisted of two components: a phase I, 3+3 design to evaluate the safety with dose escalation of palbociclib (75 mg, 100 mg, 125 mg) and to determine the recommended phase II dose (RP2D) of palbociclib in combination with CPX-351 and, a phase II to evaluate the overall response rate (ORR) of the combination as per the 2003 International Working Group criteria. Palbociclib was given on day -1 and -2, with a rest on day 0, followed by CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) on day 1, 3, and 5 and additional palbociclib on days 2, 4, and 6. Response assessments with bone marrow evaluation were done no later than day 35. Pts received 1-2 induction courses of the combination and then went on to standard consolidation therapy or allogeneic hematopoietic cell transplantation. Inclusion criteria included age 18-65 years, ECOG performance status (< 2), and adequate organ function. Pts with active infections, concomitant malignancies or cardiac ejection fraction <45 were excluded. Results Thirty-five patients were treated in this study. The median age was 56 years (range, 27-68), 51% were females and majority were Whites (83%) followed by Blacks (11%). Twenty-seven pts (77%) had newly diagnosed AML, and 8 (23%) had R/R AML. Of these, 1 pt (3%) had prior MDS and 3 (9%) had prior MPN. By European LeukemiaNet (ELN) 2017 criteria, 10 pts had favorable-risk (28.6%), 9 pts had intermediate-risk (25.7%), and 16 pts had adverse risk AML (45.7%) [31.4% favorable, 14.3% intermediate, and 54.3% adverse per ELN 2022 criteria]. In the adverse risk group, 2 pts (5.7%) had complex karyotype , 4 pts (11.4%) had monosomy 7and 4 pts (11.4%) had 5q-. Mutational analysis identified FLT3-ITD/TKD in 6 pts (17%), TP53 in 4 pts (11.5%), IDH-2 in 3 pts (8.6%), and IDH-1 in 1 pt (2.8%). No dose-limiting toxicities were observed in phase I, and 125 mg was selected as the RP2D. A total of 6 patients required 2 cycles of induction. The ORR among the 35 pts was 77% (27/35), including complete remission (CR) in 25 pts (71.4%), CR with incomplete hematologic recovery (CRi) in 1 pt and morphologic leukemia-free state in 1 pt. Six pts had stable disease. CR was achieved in 81.4% (22/27) of newly diagnosed AML and 62.5% (5/8) in R/R AML pts including 75% (3/4) of the TP53+ pts. Twenty-one pts (60%) proceeded to allogeneic HCT. At a median follow up of 24 months, 60% were alive. All pts were included in the safety analysis. Most common (> 10 events reported) grade 1-2 adverse events were liver function test (LFT) elevations, hypoalbuminemia, electrolyte abnormalities, cytopenias, gastrointestinal symptoms, headache, and fevers. Grade ≥3 serious adverse events (SAE) were reported in the following proportions of pts: febrile neutropenia in 33 pts (94%), anemia in 30 (86%), thrombocytopenia in 33 (94%), LFT elevations in 11 (31%), lung infections in 5 (14%)—including 1 case (3%) of associated respiratory failure—hypertension in 4 (11%), intracranial hemorrhage in 1 (3%), urinary tract infection in 1 (3%), rash in 2 (6%), cardiac arrest in 1 (3%), and sepsis in 1 (3%).One sepsis related death occurred prior to even starting CPX-351. Toxicities were consistent with those expected from CPX-351 and manageable with supportive care. Conclusions The combination of palbociclib and CPX-351 was safe and showed efficacy as frontline treatment for newly diagnosed AML, including those with R/R AML and adverse risk features. These results support the continued evaluation of CDK4/6 inhibition as a combination strategy in AML.