dual bet and cbp/p300 inhibitor in patients with targeted advanced solid tumors and hematological malignancies

Conditions: Castrate Resistant Prostate Cancer; NUT Carcinoma; Chronic Myelomonocytic Leukemia; Myelofibrosis

Summary: a phase 1, first-in-human study of ep31670, a dual bet and cbp/p300 inhibitor in patients with targeted advanced solid tumors and hematological malignancies

ep31670 (also known as neo2734) is a first-in-class dual bet and cbp/p300 inhibitor which has demonstrated antitumor activity in in vitro and in vivo models of human cancer. this phase i open-label, multi-center, dose-escalation study will assess the safety and determine the maximum tolerated dose of ep31670 administered orally in patients with castration-resistant prostate cancer, nut midline carcinoma and other targeted advanced solid tumors as well as chronic myelomonocytic leukemia (cmml), myelofibrosis (mf) and other targeted hematological malignancies.

Eligibility criteria:
inclusion criteria: part 1 * relapse or refractory castration-resistant prostate cancer (crpc) following at least one anti-androgen regimen and a docetaxel-containing regimen or * metastatic or unresectable nut midline carcinoma for which standard curative or palliative measures do not exist; or part 2 * relapsed or refractory cmml following at least 4 cycles of hypomethylating agent-containing regimen or hydroxyurea unless demonstration of progression or intolerance; * advanced mf (intermediate or high-risk) following at least one jak inhibitor-containing regimen or unsuitable candidates for jak inhibitor treatments. part 3: advanced mf (intermediate or high-risk) with ≤10% blasts in peripheral blood who have not achieved an adequate response or have lost the response to a jak inhibitor-containing regimen after being on treatment for at least 3 months. patients who have other types of relapsed or refractory solid tumors (part 1) or hematological malignancies (part 2) with pathological and/or biological features suggesting a potential benefit from dual bet and cbp/p300 inhibition may be enrolled after discussion with and approval from medical monitor and sponsor. eastern cooperative oncology group (ecog) performance status 0-1 life expectancy ≥ 3 months evaluable disease adequate bone marrow function: * hemoglobin ≥ 9.0 g/dl (part 1) * absolute neutrophil count (anc) ≥ 1,500/dl (part 1) * platelet count ≥100,000/μl (part 1) or ≥75,000/μl (part 3) adequate renal function: creatinine clearance (clcr) ≥ 60 ml/min adequate liver function: total bilirubin ≤ 1.5 x uln; alanine aminotransferase (alt) or aspartate aminotransferase (ast) ≤ 2.5 x uln or ≤ 5 x uln in patients with liver metastases internal normalized ratio for prothrombin time (inr) ≤ 1.2 in patients not receiving chronic anticoagulation four weeks from prior anti-cancer therapy including chemotherapy, immunotherapy, investigational anti-cancer therapy or 5 half-lives from targeted agents, radiation and have recovered from prior treatment toxicities to grade 1 or less. four weeks from major surgery. for fertile men and women, agreement to use effective contraceptive methods duration of study participation and 4 weeks after the last dose of study drug. ability to understand and willingness to sign the informed consent form. exclusion criteria: * new and progressive central nervous system (cns) metastasis; patients with treated brain metastases are eligible if follow-up brain imaging at least 4 weeks after cns-directed therapy shows no evidence of progression and the patient is neurologically stable * corrected qt interval ≥470 msec * uncontrolled concurrent illnesses including, but not limited to, ongoing active infection requiring intravenous antibiotics or antifungal agents, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social situations that would affect compliance with study requirements; patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of ep31670 are eligible for this trial * pregnant or lactating women * known history of hepatitis b, hepatitis c requiring antiviral treatment * human immunodeficiency virus (hiv)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial