Venetoclax Plus Intensive Chemotherapy in AML and Advanced MDS

Acute Myeloid Leukemia Clinical Trial

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

Status Recruiting

Clinical Trial 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.

Clinical Trial 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)

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

Cohort 2A:

Daunorubicin 90mg/m2 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

Cohort 3A:

Daunorubicin 60mg/m2 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 3-11

Cohort 4A:

Daunorubicin 60mg/m2 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 3-14

Note: No DLTs in induction phase have been observed and Cohort 3A has completed enrollment. However, the daunorubicin dose of 90mg/m2 will not be further studied due to recently reported results of no superiority over the dose of 60mg/m2.

Patients >60 years

Cohort 1B:

Daunorubicin 60mg/m2 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

Cohort 2B:

Daunorubicin 60mg/m2 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 Day 3-11

Cohort 3B:

Daunorubicin 60mg/m2 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 3-14

Expansion Cohort(s):

A maximum of 28 additional patients aged ≤ 60 years and 28 patients >60 years will be randomized (1:1) to the MTD the starting dose (assuming the MTD is not the starting dose), to further evaluate safety and efficacy of the study drug combination and identify the optimal phase 2 dose.

Consolidation Phase:

Patients who achieve CRc post induction will proceed to consolidation therapy with high-dose cytarabine in combination with escalating doses of Venetoclax. The 3+3 algorithm will be applied for dose escalation/de-escalation of Venetoclax in combination with Cytarabine. As of February 2023, there have been 2/6 hematologic DLTs in consolidation cohort 1B, therefore we will no longer give Venetoclax in combination with high-dose cytarabine during the consolidation phase, in pts >60 yrs of age. We will also not explore dose escalation of Venetoclax during consolidation in the 60-year-old or younger age-group before RP2D of induction is determined. All subjects ≤ 60yrs will be treated at the consolidation Cohort 1A dose.

Patients ≤ 60 years

Consolidation cohort 1A:

Cytarabine 1.5gr/m2 every 12 hours on Days 1, 3, 5 Venetoclax 200mg on Days 1-7

Patients >60 years

Consolidation cohort 1B:

Cytarabine 1gr/m2 every 12 hours on days 1, 3, 5

A minimum of 3 patients will be treated in each cohort (dose level) sequentially in a 3+3 design. Additional 3 subjects may be backfilled to lower dose levels so that each cohort will reach a total of 6 subjects. Once the MTD is reached, a maximum of 28 additional patients will be randomized 1:1 to the MTD or a dose level below the MTD the starting dose (assuming the MTD is not the starting dose) for a total of up to 20 patients (6 from Part 1, 20 from Part 2) treated at each of those dose levels. A maximum of 52 patients (including backfill and expansion cohorts) 60 years or younger and 46 patients older than 60 years may be enrolled in this Phase 1b study. ;

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Preleukemia

• NCT number: NCT05342584
• Study type: Interventional
• Source: Montefiore Medical Center
• Status: Recruiting
• Phase: Phase 1
• Start date: May 25, 2022
• Completion date: December 2028