Phase I Study of Ruxolitinib in Combination with Abemaciclib for Patients with Primary or Post-Polycythemia Vera/Essential Thrombocythemia Myelofibrosis
Authors: Bewersdorf Jan Philipp , Derkach Andriy , Zeidan Amer M. , Stein Eytan M. , Mauro Michael J. , Podoltsev Nikolai A. , Rampal Raajit 
Published: December 2024

Introduction: While the JAK1/2 inhibitor ruxolitinib (RUX) led to significant improvements in symptom burden and spleen volume in patients (pts) with primary and secondary myelofibrosis (MF), it is not a curative therapy and most pts discontinue treatment either due to adverse events or disease progression. With a median overall survival of ~1 year after RUX failure, novel therapeutic approaches for pts with MF and disease progression despite treatment with RUX are needed.
Mutations in the JAK/STAT signaling pathway leading to activation of the cell cycle are a main driver of MF pathophysiology. We and others previously demonstrated in preclinical studies that combined cell cycle inhibition with RUX and CDK4/6 inhibitors has synergistic effects leading to improvements in several disease features including bone marrow fibrosis and spleen volume in MF murine models. Thus, we initiated a multicenter phase I trial to evaluate the safety and efficacy of the combination of RUX and the CDK4/6 inhibitor abemaciclib in pts with MF who were previously treated with RUX.
Methods: This is an ongoing, multicenter, phase I dose-escalation trial (NCT05714072) enrolling adult pts with MF who had an inadequate response to RUX defined as either palpable splenomegaly ≥5 cm below the left costal margin or active MPN symptoms (presence of one symptom score ≥5 or two symptom scores ≥3) at study entry. Inclusion criteria were treatment with RUX for ≥12 weeks with a stable dose of 10mg or 15mg BID for ≥4 weeks at the time of screening, and adequate hematologic (absolute neutrophil count ≥1.5 × 109/L and platelets ≥75 × 109/L), hepatic and renal function. Key exclusion criteria were prior treatment with a CDK 4/6 inhibitor or ≥ 10% circulating or bone marrow blasts.
This study used a traditional “3+3” design of RUX (at fixed doses of 10mg BID or 15mg BID) in combination with three planned dose levels (DL) of abemaciclib (50 mg [DL1], 100 mg [DL2], and 150 mg BID [DL3]). The primary endpoint of this trial was the safety and identification of the recommended phase II dose of the combination therapy. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Dose-limiting toxicities (DLTs) were defined as any of the following AEs during the first cycle of the combination treatment if they were possibly, probably or definitely related to either of the study drugs: (I) non-hematologic AEs ≥ grade 3, (II) ≥ grade 3 thrombocytopenia with clinically significant bleeding, (III) febrile neutropenia, (IV) grade 4 neutropenia with fever that does not clinically resolve within 7 days in the setting of optimal interventions and (V) grade 4 anemia.
Results: As of 7/15/2024, a total of five pts were enrolled (3 patients at DL1 and 2 at DL2). Median age at enrollment was 68 years [range: 54 - 73]. 40% were male. Three and two pts had a JAK2V617F mutation and CALR mutation, respectively. All pts had DIPSS category intermediate-2 (n=4/5 pts) or high (n=1/5) with a median of two lines of prior therapy. Pts were on study treatment for a median of two cycles (range: 1 - 4 cycles) with three patients continuing treatment at time of data cut-off. There were no DLTs among any of the patients enrolled at either DL. The most common AEs of any grade and independent of attribution to therapy were diarrhea (n=3/5 pts), anemia (n=2/5 pts), and thrombocytopenia (n=2/5 pts). The most common treatment-related AEs were diarrhea (n=3/5 pts), anemia (n=1/5 pts), and neutropenia (n=1/5 pts). Grade 3 or higher AEs were limited to grade 3 anemia and neutropenia in a single patient, which resolved with drug interruption. There were no serious adverse events. No patient discontinued treatment due to AEs.
Clinical efficacy data analyses are ongoing and will be reported at the meeting for evaluable patients at DL1 and DL2. Correlative studies are ongoing.
Conclusion: Combination therapy with RUX and the CDK 4/6 inhibitor abemaciclib had an acceptable safety profile among pts with previously RUX-exposed MF. The main treatment-related AEs were diarrhea, anemia, and neutropenia, which were not dose-limiting. Dose escalation, efficacy and biomarker evaluations are ongoing, and updated data will be presented.