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

NCT ID: NCT05441514

Last Updated: 2025-09-16

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-11-03
• Study Completion Date: 2027-05-03

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.

Conditions

Recurrent Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Cobimetinib

Intervention Type: DRUG

Given PO

Enasidenib Mesylate

Intervention Type: DRUG

Given PO

Interventions

Cobimetinib

Given PO

Intervention Type: DRUG

Enasidenib Mesylate

Given PO

Intervention Type: DRUG

Other Intervention Names

Cotellic; GDC-0973; MEK Inhibitor GDC-0973; XL518; 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

Eligibility Criteria

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.

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

City of Hope Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Brian Ball

Role: PRINCIPAL_INVESTIGATOR

City of Hope Medical Center

Locations

City of Hope Medical Center

Duarte, California, United States

Countries

United States

Other Identifiers

NCI-2022-04926

Identifier Type: REGISTRY

Identifier Source: secondary_id

21751

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA033572

Identifier Type: NIH

Identifier Source: secondary_id

View Link

21751

Identifier Type: -

Identifier Source: org_study_id