Venetoclax Plus Intensive Chemotherapy in AML and Advanced MDS
brief summary
This is a Phase 1b, open-label study evaluating Venetoclax in combination with intensive induction and consolidation chemotherapy in previously untreated, adult patients with acute myeloid leukemia. In Part 1, the dose escalation phase, the safety and tolerability of the combination with Venetoclax at different doses and duration will inform the appropriate dose(s) and regimen(s) for Part 2. In Part 2, the dose expansion phase, a maximum of 28 additional patients will be randomized 1:1 to the MTD determined in Part 1 and the starting dose (assuming the MTD is not the starting dose), to further evaluate the safety and efficacy of the study drug combination.
detailed description
PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability and determine the dose-limiting toxicity and the maximum tolerated dose (MTD) of the combination of daunorubicin \& cytarabine chemotherapy plus Venetoclax for patients with AML
SECONDARY OBJECTIVES:
I. To assess efficacy by response per 2022 ELN and revised International Working Group (IWG) criteria.
II. To determine additional response parameters: CR/CRi and CR/CRh rates.
III. To determine time to response variables including overall survival (OS), event-free survival (EFS) and duration of response (DOR)
EXPLORATORY OBJECTIVES:
I. To assess MRD eradication by targeted duplex sequencing
II. To assess rates of LSC eradication by means of MFC and single cell sequencing, as well as a novel assay that uses an extended leukemia-specific NGS panel for measuring MRD in cfDNA and BM ("high resolution MRD assay")
III. To comprehensively analyze the clonal architectural and transcriptomic shifts in residual LSC under therapy
IV. To determine the protein expression of BCL-2 family members and the reliance of leukemic cells on differing members of the BH3 family at the time of diagnosis and relapse and explore association of such observations with response to Venetoclax when combined with chemotherapy
Induction Phase
Dose Escalation Cohorts:
A minimum of 3 patients will be treated in each cohort (dose level) sequentially in a 3+3 design. Patients will receive the Venetoclax plus daunorubicin/cytarabine combination as shown below
Patients aged ≤ 60 years
Cohort 1A:
Daunorubicin 60mg/m2 intravenously (IV) daily on Days 2-4; Cytarabine 100mg/m2 IV daily on Days 2-8; Venetoclax 100mg orally on Day 1, 200mg on Day 2, 400mg on Days 3-8
official title
Phase 1B Study of Venetoclax in Combination With Standard Intensive Chemotherapy With Daunorubicin Plus Cytarabine Followed by High-Dose Cytarabine in Adult Patients With Newly Diagnosed Acute Myeloid Leukemia and Advanced Myelodysplastic Syndrome