Final Analysis of a Phase I Study of Escalating Doses of the BCL-2 Inhibitor Venetoclax in Combination with Daunorubcin/Cytarabine Induction and High Dose Cytarabine Consolidation in Previously Untreated Adults with Acute Myeloid Leukemia

Background: We hypothesized that the addition of the BCL-2 inhibitor venetoclax (VEN) in combination with daunorubicin/cytarabine (3+7) induction (ind) and high dose cytarabine (ara-C) consolidation (consol) in previously untreated adults with acute myeloid leukemia (AML) would be effective and lead to favorable outcomes.

Methods: The primary objective of this trial was to determine the maximum tolerated dose (MTD) of VEN (d 1-11) that could be combined with ind daunorubucin 60 mg/m2 on d 2-4 and ara-C 200 mg/m2/d IVCI (d2-8) as well as the MTD of VEN (d 1-8) with consol ara- C (1.5 or 3 g/m2 over three hours every 12 hours on d 2, 4, and 6). Secondary endpoints included efficacy, including rate of complete remission and flow cytometric negative measurable residual disease (MRD). We enrolled patients with previously untreated AML but excluded those with a FLT3 mutation >5% allelic ratio or core binding factor rearrangement. Strong CYP3A inhibitors were not allowed for seven days prior to starting ind or consol until VEN completion. Hydroxyurea could be used to lower the WBC to <25K/ul, which was required for initiation of therapy. After the first 6 patients were treated on the VEN 200 mg/d ind cohort, due to one patient with grade 4 DIC and another with grade 5 sepsis (in a 73-year old), we amended the protocol to limit enrollment to those less than age 60 and to mandate the use of anti-bacterial gut prophylaxis. VEN ind dose levels were 200, 400, and 600 mg/d with a five-day ramp up; consol dose levels in were 100, 200 and 400 mg/d without ramp up. Phase one dose-escalation followed a 3 + 3 design for both induction and consolidation. Once the MTD for both induction and consolidation were defined, 10 patients are enrolled at the MTDs of VEN (ind and consol, respectively) to ensure safety. Patients were followed for 72 days from ind start and 56 days from consol start or count recovery whichever occurred first. The definition of DLT included any grade 3 or 4 toxicity attributable to VEN, any grade 5 toxicity or failure to recover ANC to 500 by day 42 ind or day 45 consol in the absence of AML. Ancillary studies evaluated the correlation of BH3 profiling and response.

Results: 44 pts have been enrolled to date; 42 received protocol treatment (one was found to have a FLT3 mutation and the other was deemed too ill, each before treatment). 19/42 (45%) were male. Median age 52 years (range 22-73). 22 (55%) had a normal karyotype. 10/42 had an adverse risk karyotype; 10 pts had a mutation considered adverse risk (ELN 2022) (8 had both). 400 mg of VEN was declared the recommended ind dose due to the aforementioned early septic death in a single patient treated at 600 mg. Subsequent pts all received planned doses of 3 + 7 plus VEN at 400 mg/d. Of the 24 pts enrolled during the consol escalation phase, 8 pts did not receive planned protocol consol (1 had persistent disease; of the 7 CRs 2 were deemed too ill to proceed, 3 went to allogeneic transplant, and there were no open consol cohorts for 2). 100 mg/d venetoclax was the MTD for pts treated with consol ara-C at 3 gm/m2; at 200 mg/d 2/4 pts had delayed ANC recovery. At ara-C doses of 1.5g /m², 400 mg/d VEN was declared the recommended dose; none of the 6 pts at that dose during the escalation phase experienced a DLT. We have thus far enrolled 5 of the 10 planned pts in the expansion cohort and expect to report the final analysis. Of 40 patients treated to date who have response data available (2 are still in ind), the CR rate is 92.5% with two failures being due to septic death, and one with no response in an inversion 3 pt. Of the 37 CRs, MRD negativity measured by flow cytometry (0.02% sensitivity) was achieved in 32/35 pts (91.4%). The median time to ANC recovery to 1K/uL was 43 days during ind and 37 days in consol; time to PLT >75K /uL K was 30 and 35 days during induction and consolidation, respectively. Bacteremia occurred in 11 pts. There were no episodes of tumor lysis syndrome.

Conclusions: In AML pts < age 60 with FLT3 WT and without core binding factor disease, VEN 400 mg for 11 days with 3+7 ind and 100 mg/d or 400 mg/d with 1.5 g/m2 or 3 gm/m2 ara-C, respectively, is safe. The 3+7+400mg VEN induction and the 1.5g/m2 ara-C + 400 mg VEN consolidation dosing is being evaluated in an expansion cohort soon to conclude. This regimen has acceptable toxicity and promising efficacy and will be tested in a randomized fashion against standard and other investigational induction therapy in the context of MyeloMatch NCTN trial currently underway.