Phase 1 Trial of Navitoclax/Venetoclax/Decitabine Combination in Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Background: Venetoclax (VEN), a first-in-class BCL-2 inhibitor, in combination with hypomethylating agents (HMAs) has significantly improved treatment outcomes for acute myeloid leukemia (AML) patients (pts) who are unfit for intensive induction therapy. However, resistance to this regimen is emerging due to up-regulation of other BCL family members. We hypothesized that the addition of navitoclax (NAV), a BH3 protein inhibitor, may overcome or prevent VEN resistance by targeting BCL_XL.

Methods: This was a single-center phase 1 study to investigate the safety and preliminary efficacy of the addition of NAV to the regimen of VEN and decitabine (DEC) in AML pts. Participants were ≥16 years, relapsed/refractory (R/R) when previously treated with a VEN-containing regimen, and ineligible for other salvage therapies known to be effective in AML (NCT05222984). The tolerability of NAV/VEN was evaluated in cycle 1 for 7 days prior to the addition of DEC, with standard ramp up dosing of VEN, and NAV at dose levels (DL)1 of 25, DL2 of 50 or DL3 of 75 mg starting on study day 1 of cycle 1. NAV/VEN were given orally (PO) once daily (QD) for the entire cycle (cycle 1 was 35 days; cycles 2+ were 28 days). DEC (intravenous (IV); 20 mg/m²) was initiated on day 8 of cycle 1 and continued for a total of 5 days concurrently with NAV/VEN. The observation period for dose-limiting toxicities (DLT) was cycle 1 (35 days). In subsequent cycles (e.g., 2 – 5), DEC was initiated on day 1 for 5 consecutive days concurrently with NAV/VEN. This study employed a utility-based 2-stage Bayesian optimal interval (U-BOIN) design to identify the optimal biological doses (OBD) of NAV in combination with VEN/DEC.

Results: We enrolled 17 pts as of June 7, 2024, to the phase 1 part. These pts were heavily pretreated, with a median of 4 lines of previous treatment (range 1 – 8); 5 pts were in relapse post allogeneic hematopoietic stem cell transplant (allo-HCT). Fifteen pts were evaluable for DLT: 3 on DL1, 6 on DL 2, and 6 on DL3; 2 were pts who became inevaluable due to progressive disease before receiving ≥80% of the planned treatment dose. Among the 15 evaluable pts, the median age was 59 years (range: 27-76 yrs), 47% (n=7) were male, and all of the participants had previously progressed on VEN. All 15 pts completed cycle 1 of treatment (DLT period). Two DLTs were observed, one on DL2 and one on DL3, both with grade 4 thrombocytopenia at least possibly related to the study drug that was not recovered beyond 42 days from C1D1, when C1D35 bone marrow blasts were below 5%. Participants received a median of 2 cycles of treatment (range: 1-5 cycles). Three pts (20%), one from each DL, achieved complete remission (CR) with partial hematologic recovery (1, CRh) or CR with incomplete hematological recovery (2, CRi); 9 (60%) pts had reduction in marrow blast %; 3 pts progressed on treatment. Three pts (20%) proceeded to allo-HCT (1 with stable disease, 1 with CRi, and 1 with CRh). Grade ≥3 adverse events (AEs) at least possibly related to NAV/VEN/DEC regimen that occurred in ≥ 20% of evaluable pts during cycle 1 were thrombocytopenia (93%), leukopenia (87%), anemia (53%) and febrile neutropenia (20%). Thrombocytopenia was anticipated due to NAV targeting of BCL_XL which is required for megakaryocyte and platelet survival, but no major bleeding AEs were observed. The median follow-up for the 15 evaluable pts was 3.5 months (range: 1.2-12.3 months), with 3-month survival rate of 92% (95% C.I.: 79-100%) and 6-month survival rate of 54% (95% C.I.: 31-95%). Of the 3 pts with CRh/CRi, 2 have relapsed (no mortality observed in CR); 8 pts remain alive at last follow-up.

Conclusion: The addition of NAV to VEN/DEC at all 3 DLs was tolerable with an acceptable safety profile in heavily pretreated and VEN regimen R/R AML pts. CRh/CRi were achieved in 20% of patients, 2 of whom proceeded to allo-HCT. BH3 profiling is pending and will be presented at the meeting. OBD determination is expected after completion of stage 2 of the UBOIN design.