ZEN003694 and Niraparib for the Treatment of Patients with Metastatic or Recurrent Solid Tumors

Inclusion Criteria

• Patients aged ≥ 18 years (at time of signing informed consent)
• Eastern Cooperative Oncology Group (ECOG) status 0 or 1
• Pathologically documented recurrent or metastatic solid tumor who progressed on standard of care therapy or for whom standard of care does not exist
• Prior PARP inhibitor (i) therapy is allowed
• Have had no more than 5 prior cancer therapy treatment regimens, of which a maximum of 4 were cytotoxic chemotherapy or DNA-damaging agents like PARPi-containing regimens
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Known BRCA1/2 status or willing to be tested
• Hemoglobin ≥ 9.0 gm/dL without transfusions during the 4 weeks prior to screening
• Absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L
• Platelet count ≥ 150,000/mm^3
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.0 x upper limit of normal (ULN) or if liver function abnormalities due to liver metastases AST and ALT ≤ 5.0 x ULN
• Total bilirubin ≤ 1.5 x ULN (≤ 3.0 x ULN for subjects with known Gilbert’s syndrome)
• Normal renal function
• Prothrombin time (PT), international normalized ratio (INR) and partial thromboplastin time (PTT) < 1.5 x ULN
• Female patients may be enrolled if they are not of childbearing potential, permanently sterile or who are post-menopausal, defined as no menses for at least 1 year without an alternative medical cause and follicle stimulating hormone (FSH) levels in the post-menopausal range. Female subjects of childbearing potential may be enrolled if they consistently and correctly use a highly effective form of contraception. Highly effective forms of contraception include combined (estrogen and progestogen) hormonal contraceptives (oral, intravaginal, transdermal) associated with inhibition of ovulation; progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomized partner; sexual abstinence. Female subjects should not donate eggs from the time point of study drug administration until at least 7 months thereafter
• Sexually active male participants and their partners would also be required to use highly effective forms of contraception during intercourse while taking drug and for 7 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner in order to prevent delivery of the drug via semen
• Females of childbearing potential must have a negative serum pregnancy test before the first dose of study drug and must agree to serum or urine pregnancy tests during the study
• Females may not be breast-feeding at the first dose of study drug, during study participation or through 7 months after the last dose of study drug
• Ability to swallow capsules and comply with study procedures
• Ability to understand and willingness to sign informed consent form prior to initiation of any study procedures
• Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to study enrollment, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are neurologically stable with evidence of no disease progression for 6 months

Exclusion Criteria

• Current or anticipated use of medications known to be strong inhibitors or inducers of CYP3A4 or substrates of CYP1A2 with narrow therapeutic windows. Strong inhibitors, inducers or substrates must be discontinued at least 7 days prior to the first administration of study drug
• Current or anticipated use within 7 days prior to the first administration of study drug, or during the study, of strong P-gp inhibitors
• Use of oral Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban, otamixaban, letaxaban, eribaxaban) and Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed
• Radiation to > 25% of the bone marrow
• Treatment with a bone-targeted radionuclide within 6 weeks of first dose of study drug
• Have previously received an investigational BET inhibitor (including previous participation in studies with Zenith drug, ZEN003694)
• Fridericia's corrected QT interval (QTcF) interval > 470 msec
• Insufficient recovery from prior treatment-related toxicities except for alopecia, fatigue and grade 2 neuropathy
• Non-healing wound, ulcer or bone fracture (not including a pathological bone fracture caused by a pre-existing pathological bone lesion)
• Brain metastases not adequately treated and/or clinically stable (at the discretion of the investigator) for at least 6 months prior to the start of study treatment
• Known impaired cardiac function or clinically significant cardiac disease such as uncontrolled supraventricular arrhythmia, ventricular arrhythmia requiring therapy, or congestive heart failure (New York Heart Association functional class III or IV)
• Myocardial infarction or unstable angina within 6 months prior to the first administration of study drug
• Known myelodysplastic syndrome
• Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy, or any other condition that could compromise safety or the patient’s participation in the study
• Impairment of gastrointestinal function that may significantly alter the absorption of ZEN003694 or niraparib
• Other known active cancer requiring therapy at time of study entry or that progressed or required treatment within 3 years prior to starting study drug (except for skin basal cell carcinoma or squamous cell carcinoma or in situ cervical cancer)
• Prior history with posterior reversible encephalopathy syndrome (PRES)
• Hypersensitivity to the active substance of to any of the excipients, including tartrazine (yellow #5) in the capsule formulation
• Patients with not adequately controlled hypertension despite adequate medical treatment
• History of infection with (screening tests not required): human immunodeficiency virus; hepatitis B virus with currently active disease defined as hepatitis B surface antigen (HBsAg) positivity; or hepatitis C virus unless previously treated and viral load is undetectable except following situations: * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of enrollment are eligible for this trial. * Patients with a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) infection are allowed to be included if: participant on a stable dose of antiviral therapy, hepatitis B virus (HBV) viral load below the limit of quantification. HCV viral load below the limit of quantification
• Major surgery other than diagnostic surgery, dental surgery or stenting within 4 weeks prior to the first administration of study drug
• Concurrent participation in another clinical investigational treatment trial
• Any other reason that in the opinion of the Investigator would prevent the patient from completing participation or following the study schedule