Advanced Solid Tumor Cancer, Metastatic Solid Tumor
Conditions
Keywords
ZE94-0605, Selective CDK2 inhibitor, CCNE1 amplification, Cyclin E1, First-in-human, Dose escalation, Dose optimization, Recommended Phase 2 dose, Project Optimus, Brain-penetrant CDK2 inhibitor
Brief summary
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.
Detailed description
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.
Interventions
DRUGZE94-0605
Oral capsules QD
Sponsors
Eilean Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1a uses sequential 3+3 dose escalation. After completion of dose escalation and selection of the maximally tolerated dose, Phase 1b uses parallel randomized assignment to two expansion doses: the maximally tolerated dose and one dose level below it.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicities | Cycle 1, Day 1 through Day 28 | Number and percentage of participants in Phase 1a who experience a protocol-defined dose-limiting toxicity. Dose-limiting toxicities are specified hematologic or non-hematologic toxicities graded using National Cancer Institute Common Terminology Criteria for Adverse Events, Version 6.0, that are not primarily attributable to the underlying cancer, a known disease complication, or a comorbid condition. |
| Maximally Tolerated Dose of ZE94-0605 | Through completion of the Phase 1a dose-escalation portion, estimated up to approximately 24 months | The maximally tolerated dose is the highest evaluated dose at which no more than 1 of up to 6 participants experiences a dose-limiting toxicity during Cycle 1. Dose-exposure saturation and evidence of an efficacious dose with an acceptable safety margin may also inform termination of dose escalation. |
| Recommended Phase 2 Dose of ZE94-0605 | Through completion of the Phase 1b dose-expansion portion, estimated up to approximately 24 months | The recommended Phase 2 dose will be selected following randomized evaluation of two Phase 1b expansion doses based on integrated safety, tolerability, pharmacokinetic, pharmacodynamic, and preliminary clinical-activity data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events | From first dose through 30 days after the last dose of ZE94-0605 | Number and percentage of participants with treatment-emergent adverse events, serious adverse events, and adverse events leading to dose modification, treatment discontinuation, or death. Severity will be graded using National Cancer Institute Common Terminology Criteria for Adverse Events, Version 6.0. |
| Overall Response Rate | From baseline through Cycle 26 or end of treatment, up to approximately 24 months | The proportion of evaluable participants whose best overall response is complete response or partial response, assessed using Response Evaluation Criteria in Solid Tumors, Version 1.1, or other disease-appropriate response criteria specified for the participant. Results will be summarized by tumor type and CCNE1 amplification status. |
| Duration of Response | From first documented response through study completion, up to approximately 24 months | Among participants with a complete or partial response, duration of response is the time from the first documented response until documented disease progression or death from any cause, whichever occurs first. Results will be summarized by CCNE1 amplification status. |
| Overall Survival | From first dose through long-term follow-up and study completion, up to approximately 24 months | Overall survival is the time from the first dose of ZE94-0605 until death from any cause. |
| Maximum Observed Plasma Concentration of ZE94-0605 | Cycle 1 Day 1 through Cycle 2 Day 2; each cycle is 28 days | Maximum observed plasma concentration (Cmax) of ZE94-0605 derived from serial plasma pharmacokinetic samples. |
| Area Under the Plasma Concentration-Time Curve of ZE94-0605 | Cycle 1 Day 1 through Cycle 2 Day 2; each cycle is 28 days | Area under the plasma concentration-time curve (AUC) of ZE94-0605 derived from serial plasma pharmacokinetic samples. |
| Time to Maximum Observed Plasma Concentration of ZE94-0605 | Cycle 1 Day 1 through Cycle 2 Day 2; each cycle is 28 days | Time to maximum observed plasma concentration (Tmax) of ZE94-0605 derived from serial plasma pharmacokinetic samples. |
| Terminal Elimination Half-Life of ZE94-0605 | Cycle 1 Day 1 through Cycle 2 Day 2; each cycle is 28 days | Apparent terminal elimination half-life of ZE94-0605 derived from serial plasma pharmacokinetic samples. |
| Change From Baseline in Serum Thymidine Kinase 1 | Cycle 1 Day 1 through Cycle 2 Day 2, including additional predose assessments on Cycle 1 Days 8 and 15 | Serum thymidine kinase 1 concentrations and change from baseline will be evaluated as a pharmacodynamic marker of ZE94-0605 activity. |
Countries
Australia, Uzbekistan
Contacts
CONTACTEkaterina Dokukina
Outcome results
None listed