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

Introduction: Patients with relapsed/refractory (R/R) Acute Myeloid Leukemia (AML) have a poor prognosis, characterized by modest long-term survival rates and scarcity of effective treatment options. While allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially effective option, its success is often hindered by insufficient response required to achieve a bridge to transplant or other limitations that preclude its use. CPX-351 is a liposomal formulation of cytarabine and daunorubicin in a fixed 5:1 molar ratio that is currently FDA approved for the treatment of newly diagnosed secondary AML. Here we report the results from a completed Phase Ib/II study (NCT03629171) assessing the safety and efficacy of combining CPX-351 with Venetoclax (VEN), with an extended follow-up period of a median of 55.1 months.

Methods: The phase I portion of the study consisted of a safety lead-in phase to establish the optimal dose and schedule for CPX-351 in R/R AML, followed by two phase II expansion cohorts: one for R/R AML and another for frontline AML. Prior use of VEN was permitted for patients with R/R AML. The dose of CPX-351 was standardized: daunorubicin 44 mg/m² and cytarabine 100 mg/m² administered intravenously on days 1, 3, and 5 of the induction phase, and daunorubicin at 29 mg/m² plus cytarabine at 65 mg/m² on days 1 and 3 during consolidation. VEN was initially dosed at 300 mg (at the -1-dose level) from days 2 to 21 in the safety lead-in cohort, with dose adjustments for CYP3A inhibitors as needed. Due to myelosuppression, the protocol implemented a VEN interruption after D14 if a D14 bone marrow showed hypocellularity without leukemia. A 2^nd de-escalation was required (dose level -3) which reduced VEN to days 2 to 8 each cycle and daunorubicin lowered to 22 mg/m² during consolidation. This modified regimen became the recommended phase 2 dose.

Results: Thirty-three patients were enrolled with a median follow up of 55.1 months. The median age of the patients was 58 years (range: 26-72), with 39% being male. Prior malignancies were present in 15% of the patients, and 80% of these had prior radiation therapy for a non-myeloid malignancy. Cytogenetic analysis revealed complex karyotype in 13 (39%), diploid in 7 (21%), CBF in 2 (6%), MECOM rearrangement in 2 (6%) and other in the rest. The most frequent mutations observed were in DNMT3A (24%), NRAS (24%), TP53 (18%), IDH2 (15%), WT (15%), TET2 (15%), RUNX1 (12%), ASXL1 (12%), SF3B1 (9%). 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 Venetoclax.

The median number of treatment cycles was 1 (1-5), and the median cycles to achieve the best response was 1 (1-2). Treatment responses included complete remission in 7 (CR, 21%), CR with incomplete count recovery in 7 (CRi, 21%), morphologic leukemia-free state in 4 (MLFS, 12%), and no response (45%). The overall response rate was 55%. Among 18 responding patients, 4 (22%) achieved minimal residual disease (MRD) negativity. 11 of 18 responding pts (61%) proceeded to allogeneic SCT.

Adverse events included infection (39%), febrile neutropenia (24%), hemorrhage (6%), vascular/neurological events (6%), and pulmonary complications (3%). Dose reductions were required in 27% of patients. The 4- and 8-week mortality rates were 9% and 21.2%, respectively.

The median overall survival (OS) for the R/R cohort was 5.32 months. The median relapse-free survival (RFS) was 23.69 months. Among patients who underwent SCT, the median OS was 19.6 months, with a 1-year and 2-year survival rate of 72.8% and 45.5% respectively.

Conclusion: In this Phase Ib/II study, a combination of CPX-351 with 7 days of Ven for R/R AML demonstrated safety and tolerability, producing an overall response rate of 55% in a very high-risk population of patients and allowing over 60% of responding pts to move to SCT. Despite the myelosuppression observed with the combination, appropriate dose modifications and an optimized phase II dose allowed safe delivery of the combination with promising efficacy in a refractory population.