Phase I/II Study of Quizartinib, Venetoclax, and Decitabine Triple Combination in FLT3-ITD Mutated AML

Background: Patients (pts) newly diagnosed with FLT3-ITD mutated (m) acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy (IC) experience poor outcomes with a median overall survival (OS) of 9.9 months with azacitidine+venetoclax (VEN) (Konopleva et al. 2022, Clinical Cancer Research).We aimed to evaluate the safety and efficacy of the triple combination of Quizartinib (Quiz), VEN, and decitabine (DAC) in pts with relapsed/refractory (R/R) or newly diagnosed FLT3-ITD m AML. Aims: The primary objectives were to determine the recommended phase 2 dose (RP2D) and optimal schedule of DAC + VEN + Quiz in R/R or newly diagnosed FLT3m AML. Methods: The study included newly diagnosed pts ineligible for IC and R/R pts who had received ≤ 6 prior treatments for AML. On cycle 1 Day 14, all pts underwent bone marrow (BM) evaluation, and VEN (400 mg/day or equivalent with azole) was discontinued on cycle 1 Day 14 for pts with BM blasts ≤ 5% (or marrow aplasia/hypocellularity). Pts with cycle 1 Day 14 BM blast >5% continued VEN for 21 days. Pts received 10 days of DAC (20 mg/m2) for induction, followed by 5-day DAC in subsequent cycles. Quiz (30 or 40 mg/day) was continuously administered daily. Results: A total of 66 pts were enrolled, including 47 R/R and 19 newly FLT3-ITD mutated AML pts. A detailed demographic data will be reported at the time of presentation. The 47 R/R AML pts were heavily pretreated (median 3 [range 1-5] prior AML therapies), 85% (40/47) had received ≥1 prior FLT3 inhibitors (FLT3i's), with 78% having prior exposure to gilteritinib, and 38% having undergone prior allogeneic stem cell transplantation (ASCT). The rates of CRc, CR+CRi, measurable residual disease (MRD) negativity by multicolor flow cytometry (MFC, sensitivity 10-4), and FLT3-PCR (sensitivity 10-2 - 10-3) negativity among the R/R pts were 60%, 28%, 29% (8/28), and 32% (9/28), respectively). The 60-day mortality in R/R cohort was 13%. With a median follow-up of 29 months, the median OS was 6.3 months, the 1-year OS rate was 20%, and 34% (16 out of 47) underwent ASCT in R/R cohort. Among 40 prior FLT3 inhibitor exposed pts the CRc, CR+CRi, median OS and 1-year OS were 58%, 22%, 6.3 month, and 19%. Among the seven prior FLT3 inhibitor naïve pts the CRc, CR+CRi, median OS and 1-year OS were 71%, 57%, 10.3 months and 28%. We enrolled 19 newly diagnosed AML (median age 70 years, 26% >/= 75 years), 12 with diploid cytogenetics, and 11 ELN adverse. Overall 95% (18/19) achieved CRc (12 CR, 6CRi), with 14/17 (82%) and 11/16 (69%) evaluable responders being FLT3-PCR and MFC negative, respectively. All 18 responders had achieved BM <5% or aplasia/hypocellularity on cycle 1 Day 14. The 60-day mortality was 5%. The median time to ANC>0.5, ANC>1.0, and PLT>50K after cycle 1 were 40 [range 28-56], 40 [range 28-58], and 36 [range 22-56] days. A total of 4 pts have relapsed (all 4 had secondary / therapy related AML, 2 of 4 had RAS/MAPK emergent/expanded mutations at relapse, no TKD emergence detected) and 4 pts died (2 deaths in CR, 2 deaths due to progressive leukemia). 26% (5 out of 19) frontline patients underwent ASCT. With a median follow-up of 17 months, the median OS was not reached with 1-year OS of 78%. No pts experienced dose-limiting toxicity (DLT) with Quiz 30 mg/day; however, with Quiz 40 mg/day, the first 2 pts treated developed hematologic DLT (grade 4 neutropenia with a <5% cellular bone marrow with no residual AML lasting ≥42 days). Consequently, Quiz 30 mg/day was declared the RP2D for this combination. In the R/R cohort, grade ≥3 non-hematologic toxicities regardless of attribution, in >10% of pts, included pneumonia (73%), neutropenic fever (53%), sepsis (18%), other infections involving the skin (18%)bacteremia (15%), and gastrointestinal tract (13%), with 8% experiencing grade 3 QTcF prolongations. Grade ≥3 non-hematologic toxicities was less common in the frontline cohort, with pneumonia (40%), neutropenic fever (50%), sepsis (10%), bacteremia (20%), and no grade 3 QTcF prolongations observed. Conclusion: The combination of DAC + VEN + Quiz demonstrated activity in heavily pretreated and prior FLT3i-exposed (including 78% with prior gilteritinib exposure) R/R FLT3-ITDm pts, with a CRc rate of 60% and a median OS of 6.3 months. In the frontline setting, 95% of pts achieved CRc with a median platelet and ANC recovery of 36 and 40 days, and a median OS not reached. The study continues to accrue, and updated results will be reported at the meeting.