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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Solid Tumor; Advanced Solid Tumor Cancer
• Intervention / Treatment: Drug: ZE94-0605

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Ekaterina Dokukina; Phone Number: +1 858 353 4108; Email: kdokukina@eilenther.com

Study Locations

• Australia
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
      • Recruiting
      • St. George Private hospital
      • Contact: Meet Desai; Phone Number: +61285945785; Email: clinicaltrials.sgp@ramsayhealth.com.au
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Recruiting
      • SOCRU - Southern Oncology Clinical Research Unit
      • Contact: Ashlee Hearnden; Phone Number: +61 491 679 039; Email: ashlee.hearnden@socru.org.au
• Uzbekistan
  • Tashkent, Uzbekistan, 100109
    • Recruiting
    • Republican Specialized Scientific and Practical Medical Center of Oncology and Radiology Uzbekistan
    • Contact: Dilshod Rafiev; Phone Number: +998888926569; Email: dilshod.rafiev@cancercenter.uz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1a Dose Level -1: ZE94-0605 50 mg QD; Optional dose-reduction cohort. Participants will receive ZE94-0605 50 mg orally once daily in the fasted state in continuous 28-day cycles. This dose level will be evaluated only if Dose Level 1 is not tolerated.	Drug: ZE94-0605; Oral capsules QD
Experimental: Phase 1a Dose Level 1: ZE94-0605 100 mg QD; Participants will receive ZE94-0605 100 mg orally once daily in the fasted state in continuous 28-day cycles.	Drug: ZE94-0605; Oral capsules QD
Experimental: Phase 1a Dose Level 2: ZE94-0605 200 mg QD; Participants will receive ZE94-0605 200 mg orally once daily in the fasted state in continuous 28-day cycles.	Drug: ZE94-0605; Oral capsules QD
Experimental: Phase 1a Dose Level 3: ZE94-0605 350 mg QD; Participants will receive ZE94-0605 350 mg orally once daily in the fasted state in continuous 28-day cycles.	Drug: ZE94-0605; Oral capsules QD
Experimental: Phase 1a Dose Level 4: ZE94-0605 500 mg QD; Participants will receive ZE94-0605 500 mg orally once daily in the fasted state in continuous 28-day cycles.	Drug: ZE94-0605; Oral capsules QD
Experimental: Phase 1a Dose Level 5: ZE94-0605 650 mg QD; Participants will receive ZE94-0605 650 mg orally once daily in the fasted state in continuous 28-day cycles. If the maximally tolerated dose or biologically effective dose has not been identified, subsequent dose levels may increase by approximately 33% following Safety Review Committee review.	Drug: ZE94-0605; Oral capsules QD
Experimental: Phase 1b Expansion Dose A: ZE94-0605 at the MTD; Approximately 15 participants with CCNE1 amplification, or another prospectively specified molecular or cellular feature, will be randomized to receive ZE94-0605 orally once daily at the maximally tolerated dose in the fasted state in continuous 28-day cycles.	Drug: ZE94-0605; Oral capsules QD
Experimental: Phase 1b Expansion Dose B: ZE94-0605 One Dose Level Below the MTD; Approximately 15 participants with CCNE1 amplification, or another prospectively specified molecular or cellular feature, will be randomized to receive ZE94-0605 orally once daily at one dose level below the maximally tolerated dose in the fasted state in continuous 28-day cycles.	Drug: ZE94-0605; Oral capsules QD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-Limiting Toxicities	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.	Cycle 1, Day 1 through Day 28
Maximally Tolerated Dose of ZE94-0605	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.	Through completion of the Phase 1a dose-escalation portion, estimated up to approximately 24 months
Recommended Phase 2 Dose of ZE94-0605	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.	Through completion of the Phase 1b dose-expansion portion, estimated up to approximately 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events	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.	From first dose through 30 days after the last dose of ZE94-0605
Overall Response Rate	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.	From baseline through Cycle 26 or end of treatment, up to approximately 24 months
Duration of Response	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.	From first documented response through study completion, up to approximately 24 months
Overall Survival	Overall survival is the time from the first dose of ZE94-0605 until death from any cause.	From first dose through long-term follow-up and study completion, up to approximately 24 months
Maximum Observed Plasma Concentration of ZE94-0605	Maximum observed plasma concentration (Cmax) of ZE94-0605 derived from serial plasma pharmacokinetic samples.	Cycle 1 Day 1 through Cycle 2 Day 2; each cycle is 28 days
Area Under the Plasma Concentration-Time Curve of ZE94-0605	Area under the plasma concentration-time curve (AUC) of ZE94-0605 derived from serial plasma pharmacokinetic samples.	Cycle 1 Day 1 through Cycle 2 Day 2; each cycle is 28 days
Time to Maximum Observed Plasma Concentration of ZE94-0605	Time to maximum observed plasma concentration (Tmax) of ZE94-0605 derived from serial plasma pharmacokinetic samples.	Cycle 1 Day 1 through Cycle 2 Day 2; each cycle is 28 days
Terminal Elimination Half-Life of ZE94-0605	Apparent terminal elimination half-life of ZE94-0605 derived from serial plasma pharmacokinetic samples.	Cycle 1 Day 1 through Cycle 2 Day 2; each cycle is 28 days
Change From Baseline in Serum Thymidine Kinase 1	Serum thymidine kinase 1 concentrations and change from baseline will be evaluated as a pharmacodynamic marker of ZE94-0605 activity.	Cycle 1 Day 1 through Cycle 2 Day 2, including additional predose assessments on Cycle 1 Days 8 and 15

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Plasma Circulating Tumor DNA	Plasma circulating tumor DNA will be evaluated by research next-generation sequencing to assess molecular response dynamics and potential mechanisms of resistance.	Predose on Day 1 of Cycles 1, 2, 3, and 6; at scheduled response assessments; and at end of treatment, relapse, or progression
Change From Baseline in Exploratory Biomarkers of CDK2 Inhibition	Alternative exploratory biomarkers of CDK2 pathway inhibition may be evaluated ex vivo using plasma samples to refine and validate surrogate measures of target activity.	Cycle 1 Day 1 predose, 2 hours, 8 hours, and approximately 24 hours postdose
Association of Tumor Molecular Characteristics With Response or Resistance	Archived or newly obtained tumor tissue may be evaluated by next-generation sequencing and other exploratory analyses to assess molecular features associated with response to, or resistance to, ZE94-0605 and to support potential companion-diagnostic development.	From baseline tissue collection through disease progression, up to approximately 24 months

Collaborators and Investigators

• Sponsor: Eilean Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2026
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: March 27, 2026
• First Submitted That Met QC Criteria: April 6, 2026
• First Posted (Actual): April 13, 2026

Study Record Updates

• Last Update Posted (Actual): July 29, 2026
• Last Update Submitted That Met QC Criteria: July 28, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Dose escalation; First-in-human; Recommended Phase 2 dose; Dose optimization; CCNE1 amplification; ZE94-0605; Selective CDK2 inhibitor; Cyclin E1; Project Optimus; Brain-penetrant CDK2 inhibitor
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis
• Other Study ID Numbers: ZE94-0605-0001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No