Trial in progress – a phase 1b trial of ivosidenib combined with ruxolitinib in IDH1-mutated advanced myeloproliferative neoplasms

Abstract Introduction and Rationale Philadelphia-chromosome negative (Ph-) myeloproliferative neoplasms (MPNs) are hematopoietic stem cell disorders typified by activation of the JAK/STAT pathway along with single or multi-lineage cellular hyperplasia. Ph- MPNs also have a variable propensity to evolve into acute leukemia; a blast percentage of ≥5% in the blood or bone marrow is associated with a high risk of progression to blast phase (≥20% blasts) and poor long-term outcomes (Patel et al, CLML 2023). Standard acute myeloid leukemia (AML)-based therapies have limited efficacy, with a median overall survival of less than 1 year (Patel et al, Blood Adv 2024). Mutations in IDH1 and IDH2 are enriched in accelerated/blast-phase MPNs (MPN-AP/BP), with the incidence of IDH1 mutations being 12-13%. Ivosidenib, a small-molecule inhibitor of the IDH1 mutant enzyme, has provided a new treatment paradigm for IDH1-mutated AML and myelodysplastic syndrome (MDS). While there are limited prospective clinical trial data of IDH inhibition in advanced-phase MPNs, several retrospective studies have highlighted the efficacy of IDH inhibition including patients with responses of ≥ 1 year (Patel et al, BJH 2020; Chifotides et al, Blood Adv 2020; Gangat et al, BJH 2023). Of note, IDH inhibition addresses the blast component of the disease but the chronic-phase MPN typically persists (Patel et al, SOHO 2020). Ruxolitinib, a selective oral inhibitor of JAK1 and JAK2, is approved for use in both polycythemia vera (PV) and myelofibrosis (MF). It has also been investigated in a variety of combinatorial approaches for both chronic-phase MPNs and accelerated/blast-phase MPNs. Work in murine models has demonstrated that concurrent JAK2 and IDH1/2 mutations initiate and propagate the proliferative process within long-term hematopoietic stem cells. In addition, there is expansion of a blast population and impaired differentiation of these cells, allowing for leukemic transformation. Of note, synergism was demonstrated with combined JAK2/IDH inhibition in these models with resultant reduction in spleen size, reduction in leukemic blasts, and reduction in the mutant variant allele frequency (McKenney et al, JCI 2018). We therefore, seek to determine the safety and preliminary efficacy of ruxolitinib in combination with ivosidenib in IDH1-mutated advanced phase MPNs, based on the hypothesized synergism in this context. (NCT06291987). Study Design and Methods This study is an investigator-initiated, Phase 1b study to establish the maximum tolerated dose (MTD) of ivosidenib in combination with ruxolitinib. Eligible patients must have a IDH1-mutated Ph- MPN or MDS/MPN overlap syndrome with ≥5% blasts. Patients with IDH1-mutated chronic-phase MF and ≤5% blasts with an inadequate response to JAK inhibitor therapy are also eligible. Other pertinent inclusion criteria include age ≥18 years, ECOG ≤2, and a platelet count ≥50 x 109/L for patients with MF and ≤5% blasts. Relevant exclusion criteria include prior treatment with ivosidenib. This study will follow a Rolling 6 design. Cycles are 28 days. Enrollment will begin at dose level (DL) 1 (ivosidenib 500mg daily, ruxolitinib 10mg twice daily), with a planned escalation to DL2 (ivosidenib 500mg daily, ruxolitinib 20mg twice daily) or de-escalation to DL-1 (ivosidenib 500mg daily, ruxolitinib 5mg twice daily) based on an assessment of DLTs. The primary endpoint is to establish the MTD of the combination. At the DL designated to be the MTD, defined as a DL where <2/6 DLTs are observed, we will plan to expand enrollment to have 12 patients in total treated at that dose to better characterize safety and efficacy. Total accrual is anticipated to be 18 patients. Secondary endpoints include overall survival, overall response rate, and time to response. For patients with ≥5% blasts the response will be characterized using 2012 MPN-BP criteria (Mascarenhas et al, Leuk Res 2012); for patients with MF and ≤5% blasts the response will be characterized using 2013 International Working Group-Myelofibrosis Research Treatment/European LeukemiaNet revised response criteria. Exploratory endpoints include characterization of co-occurring pathogenic mutations, evaluation of measurable residual disease (MRD status) via error-corrected next generation sequencing, assessment of the proportion of patients going onto allogeneic stem cell transplant, and assessment of clonal dynamics under combined IDH1/JAK2 inhibition.