Phase 1b Study of the Epichaperome Inhibitor PU-H71 Administered Orally with Ruxolitinib Continuation for the Treatment of Patients with Myelofibrosis
Authors: Pemmaraju Naveen , Gundabolu Krishna , Pettit Kristen , Talpaz Moshe , Podoltsev Nikolai A. , Schiller Gary J. , Eisenberg Peter , Youssoufian Hagop , Duggan Susan , Wallner Barbara , Verstovsek Srdan 
Published: November 2019

Background: Myelofibrosis (MF) is a life-threatening disease characterized by splenomegaly, constitutional symptoms, and shortened survival. Although ruxolitinib, a JAK1/2 inhibitor, is approved for Intermediate or High-risk MF and can reduce the spleen size and improve quality of life, many patients discontinue due to loss of efficacy. In preclinical models, the activity of mutated JAK2 is tightly regulated by epichaperomes, a complex network of proteins which forms under cellular stress, such as cancer, and nucleates on heat shock protein 90 (Hsp90), which in turn assumes a specific conformation in its ATP binding domain. PU-H71 is a first-in-class inhibitor of tumor epichaperome-specific Hsp90, which potently kills cancer cells via disruption of the epichaperome and degradation of JAK2 as well as other client proteins. Prior dose-ranging studies of PU-H71 administered intravenously to patients with cancer identified a safe and tolerable dose. In this study, we assess an oral formulation of PU-H71 and evaluate the hypothesis that its cancer-specific mechanism combined with ruxolitinib may result in added clinical benefit as well as a wider therapeutic window.
Methods: This is a multicenter, Phase 1b study with dose escalation and expansion cohorts designed to assess the safety, tolerability, PK, and preliminary efficacy of PU-H71 in patients with PMF, Post-PV MF, Post ET MF. Up to 24 patients who have active disease and receiving ≥3 months of ruxolitinib therapy (and on a stable dose for 8 weeks before starting therapy with PU-H71) will be enrolled. Evidence of persistent or worsening disease consisting of disease-related symptoms and splenomegaly of at least 5 cm below the costal margin as measured by physical examination are required. Additional inclusion criteria include a baseline platelet count of ≥50,000/mL and AST/ALT ≤2 x Upper Limit of Normal. Patients with a QT interval corrected using Fridericia's formula (QTcF) >480 ms (corrected) or left ventricular ejection fraction (LVEF) ≤50% are excluded. The study will employ a standard 3+3 dose escalation design beginning with 50 mg/day to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), with additional patients treated in a dose expansion cohort. Response to treatment will be assessed by the 2013 revised International Working Group-Myeloproliferative Neoplasm Research and Treatment and European Leukemia Net. Additional assessments will include symptom burden assessment using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score, bone marrow histology, JAK2V617F allele burden, serum cytokine profiles, flow cytometry of peripheral blood mononuclear cells for epichaperome status, and pharmacokinetic studies. Enrollment is ongoing. Clinical trial information: NCT03935555.

Disclosures
Pemmaraju: abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding. Gundabolu:Samus Therapeutics: Research Funding; Novartis: Consultancy; Pfizer: Consultancy; Jazz pharmaceuticals: Consultancy. Pettit:Samus Therapeutics: Research Funding. Talpaz:Imago BioSciences: Consultancy, Research Funding; Incyte: Research Funding; Constellation: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Samus Therapeutics: Research Funding. Podoltsev:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Kartos Therapeutics: Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; AI Therapeutics: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Other: Grant funding, Research Funding; Samus Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schiller:Amgen: Other, Research Funding; Biomed Valley Discoveries: Research Funding; Astellas: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding, Speakers Bureau. Eisenberg:Samus Therapeutics: Research Funding. Youssoufian:Samus Therapeutics: Consultancy. Duggan:Samus Therapeutics: Employment. Wallner:Samus Therapeutics: Employment. Verstovsek:Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Gilead: Research Funding; Protaganist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; Incyte: Research Funding; Genetech: Research Funding; CTI BioPharma Corp: Research Funding; Blueprint Medicines Corp: Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Promedior: Research Funding.