A First-in-Human Study of ZE94-0605 in Patients With Advanced Solid Tumors

A Phase 1, First-in-Human Study of ZE94-0605 in Patients With Advanced Solid Tumors

ZE94-0605 is an oral, selective cyclin-dependent kinase 2 (CDK2) inhibitor. This multicenter, open-label, first-in-human Phase 1 study will evaluate ZE94-0605 in adults with advanced, unresectable or metastatic solid tumors. Phase 1a will use sequential dose escalation to determine the maximally tolerated dose and biologically effective dose. Phase 1b will randomize participants with CCNE1 amplification, or another prospectively specified molecular feature, between two dose levels to select the recommended Phase 2 dose.

This is a multicenter, open-label, first-in-human Phase 1 study of oral ZE94-0605 in adults with pathologically confirmed advanced, unresectable or metastatic solid tumors that are refractory to, or intolerant of, available therapies known to provide clinical benefit, if available. ZE94-0605 is a selective inhibitor of cyclin-dependent kinase 2 (CDK2).

Phase 1a is a sequential dose-escalation portion using a standard 3+3 design. The planned once-daily dose levels are 100 mg, 200 mg, 350 mg, 500 mg, and 650 mg; an optional 50 mg dose level may be evaluated if 100 mg is not tolerated. Additional approximately 33% dose increments may be explored after 650 mg if a maximally tolerated dose or biologically effective dose has not been identified. Dose-limiting toxicities are evaluated during Cycle 1, which is 28 days.

After dose escalation, Phase 1b will randomize approximately 30 participants with CCNE1 amplification, or another prospectively specified molecular or cellular feature, between two expansion doses: the maximally tolerated dose and one dose level below it. Approximately 15 participants will be assigned to each dose. The recommended Phase 2 dose will be selected based on integrated safety, tolerability, pharmacokinetic, pharmacodynamic, and preliminary clinical-activity data.

ZE94-0605 is administered orally once daily in the fasted state in continuous 28-day cycles. Treatment may continue until disease progression, unacceptable toxicity, withdrawal, or completion of 26 cycles. Response assessments are scheduled before dosing on Day 1 of Cycles 3, 5, 7, 10, 13, 19, and 26. Pharmacokinetic and serum thymidine kinase 1 assessments are performed intensively during Cycles 1 and 2. Plasma circulating tumor DNA is assessed during Cycles 1, 2, 3, and 6, at scheduled response assessments, and at end of treatment, relapse, or progression.

Inclusion Criteria:

Phase 1a Dose-Escalation Cohorts:

1. Age 18 years or older with a pathologically confirmed, advanced, unresectable or metastatic solid tumor that is refractory to, or intolerant of, available existing therapy or therapies known to provide clinical benefit for the condition, if available, and with measurable disease.

   Phase 1b Dose-Expansion Cohorts:

2. Age 18 years or older with a pathologically confirmed, advanced, unresectable or metastatic solid tumor that is refractory to, or intolerant of, available existing therapy or therapies known to provide clinical benefit for the condition, if available, or who has declined such therapy; presence of CCNE1 amplification; and measurable disease.

   Common Eligibility Criteria:

3. Eastern Cooperative Oncology Group performance status of 0 or 1.

4. Adequate end-organ function, defined as creatinine clearance greater than 60 mL/min, aspartate aminotransferase and alanine aminotransferase less than 3 times the upper limit of normal, and total bilirubin less than 1.5 times the upper limit of normal, except for participants with Gilbert's disease.

5. Absolute neutrophil count at least 1.5 × 10^9/L and platelet count at least 100 × 10^9/L.

6. Female participants of childbearing potential must be willing to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from screening throughout study treatment and for 90 days after the last dose of ZE94-0605.

7. Male participants of reproductive potential who have intercourse with females of childbearing potential must be willing to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from the start of study treatment throughout study treatment and for 90 days after the last dose of ZE94-0605. Male participants must also refrain from sperm donation during this period.

8. Willingness to comply with scheduled visits, the drug-administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions.

Exclusion Criteria:

1. History of another malignancy, except 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 another cancer that has been in complete remission without treatment for at least 2 years before enrollment or has a life expectancy of 24 months and does not require therapy that would confound interpretation of this study. Such cases must be discussed with the Medical Monitor before screening.
2. Known active hepatitis C, hepatitis B, or human immunodeficiency virus infection.
3. Pregnancy or breastfeeding.
4. Concurrent participation in an investigational-drug trial with therapeutic intent, defined as receipt of prior study therapy within 14 days before study treatment.
5. Inability to tolerate oral medication, including symptomatic disease that significantly affects gastrointestinal function, such as inflammatory bowel disease or resection of the stomach or small bowel.
6. Receipt of an investigational agent for any indication within 5 half-lives of the agent. If the half-life is unknown, the participant must wait 1 week before the first dose of study treatment. An investigational agent is one for which there is no approved indication from the U.S. Food and Drug Administration.
7. Psychological, familial, social, or geographic factors; another significant medical condition; or a laboratory abnormality that precludes informed consent or protocol compliance, may hamper adherence to study treatment or follow-up, or would confound interpretation of study results.
8. Uncontrolled intercurrent illness, including but not limited to symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, New York Heart Association Class III or IV heart failure, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction-system abnormalities. Participants with medical comorbidities that would preclude safety evaluation of ZE94-0605 must not be enrolled.
9. QT interval corrected using Fridericia's formula (QTcF) greater than or equal to 470 milliseconds, unless the participant has a pacemaker. Participants with an incomplete or complete right or left bundle branch block may participate if cleared for enrollment by a cardiology evaluation.