Recurrent Acute Myeloid Leukemia, Refractory Acute Myeloid Leukemia
Conditions
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.
Interventions
DRUGCobimetinib
Given PO
Given PO
Sponsors
National Cancer Institute (NCI)
City of Hope Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Up to 1 year | Response will be determined using European LeukemiaNet (ELN) criteria. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Level of myeloid differentiation | Up to 1 year | Level of myeloid differentiation on pre and post-treatment peripheral blood (PB) and bone marrow (BM) samples by flow cytometry. |
| Promotor methylation status of RAS pathway regulator | Up to 1 year | Promotor methylation status of RAS pathway regulators by enhanced reduced representation bisulfite sequencing. |
| Changes in RAS pathway regulatory gene expression levels | Pre and post- treatment, assessed up to 1 year | 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). |
Countries
United States
Outcome results
None listed