A Phase 1 Dose-Escalation Study of the Oral Epichaperome Inhibitor, Zelavespib (ZEL) in Combination with Ruxolitinib (RUX), in Patients with Relapsed Myelofibrosis: Results of the Dose Escalation Stage

Background: ZEL (PU-H71) is an oral synthetic purine-scaffold epichaperome inhibitor that selectively binds to epichaperome complexes found in cancer cells via the altered ATP binding site of disease-associated heat shock protein (HSP90). ZEL has shown efficacy in cell line and mouse models of myeloproliferative neoplasm (MPN) and specifically myelofibrosis (MF) by disrupting JAK2 protein stability, resulting in dose-dependent inhibition of cell growth and signaling. JAK2 inhibitors are the only currently approved class of therapies for intermediate/higher risk MF, but there is still an urgent unmet medical need for 2^nd line and beyond therapies. An emerging approach is the add-on/add-back strategy, with the addition of the second/novel agent in the setting of suboptimal response to JAKi monotherapy. In a prior trial of ZEL as IV monotherapy in an advanced malignancy study (including both solid and hematologic malignancies), ZEL demonstrated clinical activity in patients with lymphoma and MF. Based on this efficacy signal, the tolerability profile of ZEL in hematological malignancies, and the potential for synergy between mechanisms of action, a study with ZEL in combination with RUX was initiated.

The present phase 1 study is the first to establish the safety, MTD, and preliminary efficacy of oral ZEL when added to RUX in MF (NCT03935555).

Methods: Patients with primary, post-polycythemia vera or post-essential thrombocythemia MF were eligible if age ≥18 years, ECOG performance status ≤2, treatment with RUX >3 months prior to start with persistent or worsening splenomegaly and disease-related symptoms (by MPN-SAF TSS), adequate cardiac, hepatic and renal function, platelets ≥ 25,000/uL, ANC ≥500/uL, and no active ocular pathology. Oral solution of ZEL was administered daily in continuous 21-day cycles in combination with each patient's stable baseline RUX dose. The initial dose of ZEL was 50 mg with each subsequent cohort dose-escalating by 50 mg QD increments. DLTs were assessed in Cycle 1 (21 days). Response was assessed by IWG-MRT and ELN criteria.

Results: Eleven patients have been enrolled: 3 patients each in the 50 and 100 mg cohorts, and 5 in the 150 mg cohort following DLT-driven cohort expansion. Median age was 69 years (range 59-78). Baseline RUX dose ranged from 5-25 mg bid, with a median of 15 mg. Median number of ZEL cycles administered was 4 (range 1-25). Most AEs were Gr 1 and 2 and the most frequent were abdominal pain, diarrhea and fatigue. Gr 4 thrombocytopenia in 2 patients (150 mg) met DLT criteria with platelet nadirs of 7K and 22K during cycle 1. One patient (150 mg with symptomatic improvement) developed Grade 3 bone marrow hypoplasia after 22 cycles of treatment, an SAE judged by the Investigator to be related to treatment. To date, 2 patients (1 each at 100 and 150 mg) demonstrated symptom improvement without significant reduction in spleen size. One patient (50 mg) had stable disease maintained for 20 cycles and successfully bridged to allogeneic stem cell transplant. Allele burden, cytokine profiles, flow cytometry for biomarkers, and PK analyses are in progress and will be presented.

Conclusions: The ZEL dose 100 mg QD was well tolerated and was selected as the RP2D in combination with RUX. Although ZEL has not been shown to cause myelosuppression as monotherapy, further evaluation is necessary to understand possible effects on bone marrow and megakaryocyte function when used in combination with RUX. Further exploration of the therapeutic potential of oral ZEL in the treatment of MF and other MPNs, as monotherapy and with RUX, is warranted.

Pemmaraju:stemline: Consultancy; abbvie: Consultancy; immunogen: Consultancy; mustangbio: Research Funding; incyte: Consultancy; novartis: Research Funding; pacylex: Consultancy, Research Funding; samus: Research Funding; daiichi sankyo: Research Funding; cellectis: Research Funding; cellularity: Research Funding. Gundabolu:Blueprint Medicines: Honoraria; Pfizer: Honoraria, Research Funding; Jazz: Honoraria; BioMarin Pharmaceuticals: Honoraria; Novartis: Honoraria; BMS: Honoraria; Samus: Research Funding. Snyder:Allucent: Current Employment. Silverman:Samus Therapeutics Inc.: Consultancy. Bardelli:Samus Therapeutics Inc.: Current Employment; Ziopharm Oncology: Ended employment in the past 24 months. Verstovsek:Roche: Research Funding; Protagonist Therapeutics: Research Funding; Promedior: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; Novartis: Consultancy, Research Funding; ItalPharma: Research Funding; Incyte: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; CTI BioPharma Corp.: Research Funding; Celgene: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Blueprints Medicines Corp.: Research Funding; AstraZeneca: Research Funding; Constellation Pharmaceuticals: Consultancy; Pragmatist: Consultancy. Schiller:Sellas: Research Funding; Cellectis: Research Funding; Janssen: Research Funding; Incyte: Other: speaker fees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Actinium: Research Funding; Deltafly: Research Funding; FujiFilm: Research Funding; PreCOG LLC: Research Funding; AltruBio: Research Funding; Geron: Research Funding; Stemline: Research Funding; Medimmune: Research Funding; Stemline: Speakers Bureau; Novartis: Honoraria, Other: Speaker fees, Research Funding; Arog: Research Funding; Ono Pharma: Honoraria; Trovagen: Research Funding; Jazz: Consultancy; CTI: Research Funding; Constellation: Research Funding; Cellerant: Research Funding; Forma: Research Funding; Genentech-Roche: Research Funding; Deciphera: Research Funding; AVM Biopharma: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Glycomimetics: Research Funding; Bristol Myers Squibb: Current equity holder in publicly-traded company, Speakers Bureau; Gamida: Research Funding; Amgen: Current equity holder in publicly-traded company, Honoraria; Kite, a Gilead Company: Research Funding, Speakers Bureau; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Actuate: Research Funding; AstraZeneca: Honoraria; Samus: Research Funding; Astellas: Research Funding, Speakers Bureau; Pfizer: Research Funding; Gilead: Research Funding; Karyopharm: Research Funding, Speakers Bureau; Regimmune: Research Funding; Mateon: Research Funding; Agios: Consultancy, Honoraria; AbbVie: Research Funding, Speakers Bureau; Millennium: Research Funding; Onconova: Research Funding; Sangamo: Research Funding; Takeda: Research Funding; Tolero: Research Funding.