Enasidenib in Combination With Cobimetinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia
- Conditions
- Recurrent Acute Myeloid LeukemiaRefractory Acute Myeloid Leukemia
- Interventions
- Registration Number
- NCT05441514
- Lead Sponsor
- City of Hope Medical Center
- Brief Summary
This phase Ib trial tests the safety, side effects, and best dose of a enasidenib in combination with cobimetinib in treating patients with acute myeloid leukemia that has come back (relapsed) or does not respond to treatment (refractory). Enasidenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Cobimetinib is used in patients whose cancer has a mutated (changed) form of a gene called BRAF. It is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving enasidenib and cobimetinib may kill more cancer cells in patients with relapsed or refractory acute myeloid leukemia.
- Detailed Description
PRIMARY OBJECTIVES:
I. Assess the safety and tolerability of cobimetinib in combination with enasidenib.
II. Determine the maximum tolerated dose(s) (MTD) and recommended phase 2 dose (RP2D).
SECONDARY OBJECTIVES:
I. Obtain preliminary estimates of clinical activity as measured by the complete remission (complete response \[CR\], complete response with incomplete hematologic recovery \[CRi\], or complete response with partial hematologic recovery \[CRh\]) rate and minimal residual disease (MRD) rate.
II. Obtain preliminary estimates of clinical activity as measured by overall response rate (CR, CRi, CRh, morphologic leukemia free state \[MLFS\], and partial response \[PR\]).
III. Obtain preliminary estimates of median time to complete remission. IV. Obtain preliminary estimates of median time to first response. V. Obtain preliminary estimates of response duration in all participants and in those attaining CR/CRi/CRh.
VI. Obtain preliminary estimates of median and 1-year event-free survival (EFS).
VII. Obtain preliminary estimates of median and 1-year overall survival (OS).
EXPLORATORY OBJECTIVES:
I. Characterize the effects of the combination on cellular differentiation of leukemic cells as measured by flow cytometry performed at study entry and at serial timepoints throughout the study.
II. Evaluate changes in promotor methylation patterns after treatment with combination therapy.
III. Evaluate changes in gene expression of RAS pathway regulators as a result of the combination therapy.
OUTLINE: This is dose-escalation study of cobimetinib followed by a dose-expansion study.
Patients receive cobimetinib orally (PO) once daily (QD) on days 1-21 and enasidenib mesylate PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, and every 3 months for 1 year at last treatment dose.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 15
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Treatment (cobimetinib, enasidenib mesylate) Enasidenib Mesylate Patients receive cobimetinib PO QD on days 1-21 and enasidenib mesylate PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity. Treatment (cobimetinib, enasidenib mesylate) Cobimetinib Patients receive cobimetinib PO QD on days 1-21 and enasidenib mesylate PO QD on days 1-28 of each cycle. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
- Primary Outcome Measures
Name Time Method Incidence of adverse events Up to 30 days after last dose of study drug Toxicity will be graded according to the NCI- CTCAE version 5.0. Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome.
Dose limiting toxicity Cycle 1 (28 days) Toxicity will be graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
- Secondary Outcome Measures
Name Time Method Response Up to 1 year Response will be determined using European LeukemiaNet (ELN) criteria.
Minimal residual disease (MRD) status Up to 1 year MRD status will be determined by standard of care (SOC) flow cytometry assay.
Complete remission Up to 1 year Time to complete remission is defined as time from first study dose to attainment of complete response(CR), complete response with incomplete hematologic recovery CRi, or complete response with partial hematologic recovery CRh). Will calculate rates and 95% Clopper-Pearson binomial confidence interval (CI).
Time to first response From first study does to first documented complete response, assessed up to 3 years Time to first response is defined as time from first study dose to attainment of first documented CR, CRi, CRh, morphologic leukemia free state (MLFS), or partial response (PR). Will calculate rates and 95% Clopper-Pearson binomial CI.
Response duration From first study does to first documented complete response, assessed up to 1 year Response Duration is defined as the time from the date of first documented response (CR, CRi, CRh, MLFS or PR) to documented disease relapse/progression or death, whichever occurs first. Will be estimated using the product-limit method of Kaplan and Meier.
Event-free survival (EFS) From first study dose to first documented complete response to relapse/progression (> 5% blasts, reappearance of blasts in blood, or development of extramedullary disease) or death, whichever occurs first, assessed up to 1 year Will be estimated using the product-limit method of Kaplan and Meier.
Overall survival (OS) From first study dose to death from any cause, assessed up to 1 year Will be estimated using the product-limit method of Kaplan and Meier.
Trial Locations
- Locations (1)
City of Hope Medical Center
🇺🇸Duarte, California, United States