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

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 >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 < 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.