Enasidenib in Combination With Cobimetinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

Phase 1b Study of IDH Inhibition With Enasidenib and MEK Inhibition With Cobimetinib in Patients With Relapsed or Refractory Acute Myeloid Leukemia Who Have Co-Occurring IDH2 and RAS Signaling Gene Mutations

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Enasidenib Mesylate; Drug: Cobimetinib

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Main Inclusion Criteria

• Patients with histologically confirmed AML, according to WHO criteria, with refractory/relapsed (R/R) disease who are ineligible for therapies known to be effective for treatment of their AML.

  • Patients with non-central nervous system (CNS) extramedullary disease may be included if they also have marrow involvement
  • Patients with acute promyelocytic leukemia (APL) will not be eligible
  • Patients with IDH2 mutations, who were previously treated with enasidenib are allowed
• Have a documented IDH2 gene mutation (≥ 2% allele frequency) and a concomitant detectable RAS-pathway mutation (as determined by local testing), involving NRAS, KRAS, HRAS, BRAF, KIT, RIT1, PTPN11, CBL or NF1 genes.
• Adults aged ≥ 18 years
• ECOG ≤ 2
• WBC ≤25 x 10^9/L prior to initiation of enasidenib.

Main Exclusion Criteria

• Current or planned use of other investigational agents, antineoplastic, chemotherapy, radiation therapy, biological therapy, immunotherapy or major surgery within 2 weeks or 5 half-lives, whichever is shorter, prior to Day 1 of protocol therapy (exception: hydroxyurea is allowed in cycles 1 and 2 for control of rapidly progressing leukemia or for treatment of enasidenib-related leukocytosis)
• Systemic steroid therapy > 10 mg/day (≤ 10mg/day prednisone equivalent ok) or any other form of immunosuppressive medication within 28 days, except as required for treatment of differentiation syndrome
• Strong and moderate CYP3A4 inducers/inhibitors (moderate CYP3A4 inhibitors only allowed on Principal Investigator approval) within 14 days or 5 half-lives, whichever is shorter, prior to Day 1 of protocol therapy
• Foods/supplements that are strong or moderate inhibitors or inducers of CYP3A (such as grapefruit, Seville oranges, starfruit and St. John's wort) within 7 days prior to initiation of and during study treatment
• Gastrointestinal disorder such as maladsorption syndrome or any other disorder that may interfere with oral drug absorption
• Clinically significant cardiac morbidities (Class III/IV cardiovascular disability according to the New York Heart Association Classification, arrhythmia not stable on medical management, acute cardiovascular ischemic event within 6 months of enrollment, etc)
• Active CNS disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (cobimetinib, 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.

Drug: Enasidenib Mesylate; Given PO; Other Names: 2-Methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol Methanesulfonate; 2-Propanol, 2-Methyl-1-((4-(6-(trifluoromethyl)-2-pyridinyl)-6-((2-(trifluoromethyl)-4-pyridinyl)amino)-1,3,5-triazin-2-yl)amino)-, Methanesulfonate (1:1); AG-221 Mesylate; CC-90007; Enasidenib Methanesulfonate; Idhifa; Drug: Cobimetinib; Given PO; Other Names: Cotellic; GDC-0973; MEK Inhibitor GDC-0973; XL518

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicity	Toxicity will be graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.	Cycle 1 (28 days)
Incidence of adverse events	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.	Up to 30 days after last dose of study drug

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response	Response will be determined using European LeukemiaNet (ELN) criteria.	Up to 1 year
Minimal residual disease (MRD) status	MRD status will be determined by standard of care (SOC) flow cytometry assay.	Up to 1 year
Complete remission	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).	Up to 1 year
Time to first response	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.	From first study does to first documented complete response, assessed up to 3 years
Response duration	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.	From first study does to first documented complete response, assessed up to 1 year
Event-free survival (EFS)	Will be estimated using the product-limit method of Kaplan and Meier.	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
Overall survival (OS)	Will be estimated using the product-limit method of Kaplan and Meier.	From first study dose to death from any cause, assessed up to 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of myeloid differentiation	Level of myeloid differentiation on pre and post-treatment peripheral blood (PB) and bone marrow (BM) samples by flow cytometry.	Up to 1 year
Promotor methylation status of RAS pathway regulator	Promotor methylation status of RAS pathway regulators by enhanced reduced representation bisulfite sequencing.	Up to 1 year
Changes in RAS pathway regulatory gene expression levels	Changes in RAS pathway regulatory gene expression levels by ribonucleic acid (RNA) sequencing pre- and post-treatment. Will use Next generation sequencing (HopeSeq) and/or rapid sequencing assays (Rapid AML Panel).	Pre and post- treatment, assessed up to 1 year

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Brian Ball, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2023
• Primary Completion (Actual): March 19, 2026
• Study Completion (Actual): March 19, 2026

Study Registration Dates

• First Submitted: June 28, 2022
• First Submitted That Met QC Criteria: June 28, 2022
• First Posted (Actual): July 1, 2022

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 30, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Organic Chemicals; Alcohols; Propanols; cobimetinib; enasidenib; 2-Propanol; methanesulfonic acid
• Other Study ID Numbers: 21751 (Other Identifier: City of Hope Medical Center); P30CA033572 (U.S. NIH Grant/Contract); NCI-2022-04926 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No