Study of ZE94-0605 in Patients With Advanced Solid Tumors, With Dose Expansion Cohorts.

This phase 1 study will focus on dose escalation across all solid tumor patients who have no alternative therapies to determine the maximally tolerated dose (MTD) followed by a two dose level expansion (MTD and one dose below) in solid tumors who have amplified CCNE1 (or other molecular/cellular feature determined at a later time) to fulfill the guidelines set forth by project Optimus.

Inclusion criteria

• Phase 1 Escalation cohort:

Patients ≥ 18 with pathologically confirmed, advanced and unresectable or metastatic solid tumor refractory to, or intolerant of existing therapy(ies) known to provide clinical benefit for their condition.

Phase 1 Expansion cohort:

Patients ≥ 18 with pathologically confirmed, advanced and unresectable or metastatic solid tumor refractory to, or intolerant of existing therapy(ies) known to provide clinical benefit for their condition or who have declined it who have CCNE1 amplification.

• ECOG performance status of 0-1.
• Adequate end-organ function as defined by: Creatinine clearance >60 ml/min, AST/ALT <3x upper limit of normal, total bilirubin <1.5x upper limit of normal (except for patients with Gilbert's disease).
• Absolute Neutrophil Count (ANC) must be 1.5 x 109/L or greater, platelets 100 x 109/L or greater.
• For female patients of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from the screening visit throughout the study treatment period and for 30 days following the last dose of either study drug.
• For male patients of childbearing potential having intercourse with females of childbearing potential, the willingness to abstain from heterosexual intercourse or use a protocol recommended method of contraception from the start of study treatment throughout the study treatment period and for 90 days following the last dose of either study drug. Males must also refrain from sperm donation from the start of study treatment throughout the study treatment period and for 90 days following the last dose of either dose of study drug.
• Willingness to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures and study restrictions.

Exclusion criteria

• History of alternative malignancy except for the following: adequately treated local basal cell carcinoma or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease or any other cancer that has been in complete remission without treatment for ≥ 2 years prior to enrollment or that has life expectancy of 24 months and does not require therapy that confounds interpretation of data from this study. Cases where this occurs must be discussed with the medical monitor before screening for enrollment.
• Known active Hepatitis C, Hepatitis B, or HIV.
• Pregnancy or breast feeding.
• Concurrent participation in an investigational drug trial with therapeutic intent defined as prior study therapy within 14 days prior to study treatment.
• Inability to tolerate oral medications including symptomatic disease significantly affecting gastrointestinal function such as inflammatory bowel disease or resection of stomach or small bowel.
• Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent; if the half-life of the agent is unknown, patients must wait 1 week prior to first dose of study treatment. An investigational agent is one for which there is no approved indication by the United States (US) FDA.
• Patients with psychological, familial, social, or geographic factors, other significant medical condition, laboratory abnormality that otherwise preclude them from giving informed consent, following the protocol, potentially hamper compliance with study treatment and follow-up or would confound the interpretation of the results of the trial.
• Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, New York Heart Association (NYHA) Class III or IV heart failure, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled.
• Patients with QTc greater than or equal to 470ms unless patient has a pacemaker. Patients with an incomplete or complete right/left bundle branch block may participate if cleared by a cardiology evaluation for enrollment.