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.

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