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
Authors: Ball Brian J. , Zhang Jianying , Afkhami Michelle , Robbins Marjorie , Chang Lauren , Humpal Samantha , Porras Vania , Liu Yilun , Synold Tim W , Farzinkhou Sarah , Borogovac Azra , Koller Paul B. , Pourhassan Hoda , Agrawal Vaibhav , Stein Anthony S. , Percival Mary-Elizabeth M. , Danilov Alexey V. , Marcucci Guido 
Published: December 2024

Background:
Targeting of methylation by mutant isocitrate dehydrogenase (IDH) has changed the therapeutic landscape of relapsed or refractory (R/R) AML, culminating in the approval of IDH inhibitors, enasidenib, ivosidenib, and olutasidenib. Concurrent RAS-signaling mutations represent a growing problem in the management of R/R IDH mutant AML, since they are associated with resistance to IDH inhibitors and other approved therapies such as venetoclax-based regimens. In preclinical studies, co-occurring TET2 or IDH2 mutations cooperate with RAS mutations to enhance RAS signaling and increase susceptibility to MEK inhibition. In mice with co-occurring IDH2 and NRAS mutations, combined IDH2 and MEK inhibition led to a greater improvement in blood counts, decreased spleen weight and a greater reduction in leukemic stem and progenitor cells. We thus hypothesize that combined MEK inhibition with cobimetinib and IDH2 inhibition with enasidenib will be safe and overcome these mechanisms of resistance, resulting in enhanced responses.
Study Design and Methods:
This is a multi-center, open label, single arm, phase 1b study to investigate the safety and preliminary efficacy of the combination of cobimetinib and enasidenib in patients with R/R AML with co-occurring IDH2 and RAS-pathway mutations. The study consists of 1) a dose escalation cohort to determine the maximum tolerated dose and the recommended phase 2 dose (RP2D) and 2) a dose expansion cohort to better characterize safety of the combination as well as preliminary efficacy. Key eligibility criteria include age ≥ 18 years, R/R AML, and the presence of co-occurring IDH2 and RAS-pathway mutations. Previous treatment with enasidenib is allowed. Enasidenib (100 mg) is given orally (PO) once daily (QD) for the entire cycle (28 days). Cobimetinib is given PO QD for days 1-21 of each cycle at one of 2 dose levels (DLs), DL 1 = 40 mg and DL 2 = 60 mg. The study primary endpoint is safety. In order to determine the maximum tolerated dose (MTD) for cobimetinib in combination with enasidenib, a standard 3+3 design governs enrollment and dose escalation and de-escalation in the two potential dosing cohorts. Toxicity severity is graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Secondary endpoints include overall response (CR, CRi, MLFS, and PR) by ELN 2022 response criteria, median to first response, response duration, median and 1-year OS and EFS, pharmacokinetics, and pharmacodynamics (phospho-ERK by CYTOF). Correlative objectives include determining the expression of RAS negative regulators by RNA sequencing and epigenetic regulation of RAS regulators by bisulfite sequencing and H3K4me3 and H3K27Ac ChIP-Seq.
The protocol was amended to expand eligibility to include RAS mutations involving NRAS, KRAS, PTPN11, NF1, CBL, BRAF, KIT, and RIT1. As enasidenib is a moderate CYP3A inducer, the protocol was amended to also allow concomitant use of the moderate CYP3A4 inhibiting antifungal, isavuconazonium sulfate (cresemba). Two innovative changes were made to enhance rapid identification of this very rare IDH2 and RAS-mutant AML patient population. First, a central next-generation sequencing assay with a customized Rapid Panel was developed to identify and confirm patients with IDH2 and RAS-pathway mutations within 7 days. Additionally, potential clinical trial participants have recently been identified through POSEIDON (Precision Oncology Software Environment Interoperable Data Ontologies Network), which is a secure, cloud-based Oncology Insights Engine that enables investigators to visualize clinical and comprehensive genomic profiling data. To date, four patients have enrolled with three patients completing at least 1 cycle of treatment. Enrollment is open at City of Hope and the Fred Hutchinson Cancer Center (NCT05441514).