First-in Human Phase I Study of ISM3091 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is a first-in-human, multicenter, open-label Phase I study. The study will be comprised of a dose escalation part followed by a dose selection optimization part.

Official Title
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A Phase I, Open-Label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of ISM3091 in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: ISM3091


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient should understand, sign, and date the written informed consent form (ICF) prior to screening Male or female aged 18 years or older Patients with for histologically confirmed locally advanced/metastatic breast cancer, ovarian cancer, prostate cancer who relapsed, progressed, or were intolerant to standard therapy, have no therapy with a known overall survival benefit exists or are not a candidate for these therapies Eastern Cooperative Oncology Group performance status 0, 1, or 2 Life expectancy ≥ 3 months Adequate bone marrow and organ function at study entry Exclusion Criteria: Prior treatment with a ubiquitin specific peptidase 1 (USP1) inhibitor Active infection with human immunodeficiency virus (HIV) or hepatitis B virus or hepatitis C virus Any unresolved toxicities from prior therapy greater than NCI-CTCAE version 5.0 Grade 1 or that have not resolved to baseline at the time of starting study. Exceptions include alopecia, peripheral neuropathy, and, upon discussion with and approval by the medical monitor, other toxicities that are not thought to present a risk to patient safety Other severe, acute, or chronic medical condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of the study results, and in the judgement of the investigator, would make the patient inappropriate for the study Patient inability or unwillingness to comply with requirement for oral drug administration or presence of a gastrointestinal condition

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 - Dose Escalation<br>Patients will receive ISM3091 once daily in sequential cohorts of increasing doses. | Drug: ISM3091<br>* ISM3091 will be administered orally once daily.<br>|
| Experimental: Part 2 - Dose optimization<br>Participants will be randomized to receive one of the two selected dose levels of ISM3091 once daily determined by Study Review Committee. | Drug: ISM3091<br>* ISM3091 will be administered orally once daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-emergent adverse events (TEAEs) and Serious Adverse events (SAEs) | To assess the safety and tolerability of ISM3091. | Approximately 1 year | 
| Number of participants with dose-limiting toxicity (DLTs) | To assess the safety and tolerability of ISM3091. DLTs will be measured only during the dose escalation part. | Cycle 1 (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve from time zero to time t (AUC0-t) | To characterize the PK of ISM3091 following a single dose administration and at a steady state after multiple dosing. | Cycle1 Day 1, 8, 15, 28, Cycle 2 Day 1, Cycle 4 Day 1, and Cycle 6 Day 1 (each cycle is 28 days) | 
| Maximum observed concentration (Cmax) | To characterize the PK of ISM3091 following a single dose administration and at a steady state after multiple dosing. | Cycle1 Day 1, 8, 15, 28, Cycle 2 Day 1, Cycle 4 Day 1, and Cycle 6 Day 1 (each cycle is 28 days) | 
| Time to reach maximum plasma concentration (Tmax) | To characterize the PK of ISM3091 following a single dose administration and at a steady state after multiple dosing. | Cycle1 Day 1, 8, 15, 28, Cycle 2 Day 1, Cycle 4 Day 1, and Cycle 6 Day 1 (each cycle is 28 days) | 
| Apparent terminal elimination half-life (t1/2) | To characterize the PK of ISM3091 following a single dose administration and at a steady state after multiple dosing. | Cycle1 Day 1, 8, 15, 28, Cycle 2 Day 1, Cycle 4 Day 1, and Cycle 6 Day 1 (each cycle is 28 days) | 
| Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUCinf) | To characterize the PK of ISM3091 following a single dose administration and at a steady state after multiple dosing. | Cycle1 Day 1, 8, 15, 28, Cycle 2 Day 1, Cycle 4 Day 1, and Cycle 6 Day 1 (each cycle is 28 days) | 
| AUC from time zero to the time of the dosing interval (AUC0-τ) | To characterize the PK of ISM3091 following a single dose administration and at a steady state after multiple dosing. | Cycle1 Day 1, 8, 15, 28, Cycle 2 Day 1, Cycle 4 Day 1, and Cycle 6 Day 1 (each cycle is 28 days) | 
| Accumulation ratio (AR) | To characterize the PK of ISM3091 following a single dose administration and at a steady state after multiple dosing. | Cycle1 Day 1, 8, 15, 28, Cycle 2 Day 1, Cycle 4 Day 1, and Cycle 6 Day 1 (each cycle is 28 days) | 
| Apparent total body clearance of drug (CL/F) | To characterize the PK of ISM3091 following a single dose administration and at a steady state after multiple dosing. | Cycle1 Day 1, 8, 15, 28, Cycle 2 Day 1, Cycle 4 Day 1, and Cycle 6 Day 1 (each cycle is 28 days) | 
| Apparent volume of distribution associated with the terminal phase (Vz/F) | To characterize the PK of ISM3091 following a single dose administration and at a steady state after multiple dosing. | Cycle1 Day 1, 8, 15, 28, Cycle 2 Day 1, Cycle 4 Day 1, and Cycle 6 Day 1 (each cycle is 28 days) | 
| Overall response rate (ORR) | ORR defined as the proportion of patients with a best overall response of either complete response (CR) or partial response (PR). ORR will be calculated based on disease status evaluated by the investigator according to Prostate Cancer Working Group 3 (PCWG3) for prostate cancer and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for all other tumors. | Approximately 1 year | 
| Duration of response (DoR) | DoR defined as the time between the date of first response and the date of disease progression or death, whichever occurs first, will be computed for patients with a response (CR or PR). | Approximately 1 year | 
| Progression-free survival (PFS) | PFS defined as the time between date of first dose of ISM3091 and date of progression according to Prostate Cancer Working Group 3 (PCWG3) or Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, or death. | Approximately 1 year | 
| Overall survival (OS) | OS defined as length of time from the first dose of ISM3091 to the date of death, regardless of the cause of death, will be computed for all treated patients with measurable disease at baseline. Overall survival will be measured according to PCWG3 for prostate cancer and RECIST version 1.1 for all other tumors. | Approximately 1 year | 
| Number of participants of Prostate specific antigen (PSA) response | To assess the preliminary antitumor activity of ISM3091. | From Screening (Day-28 to Day-1), Day 1, Cycle 1 , Day 1, Cycle 2, end-of-treatment visit (each cycle is 28 days) (approximately 1 year) | 
| Time-to-PSA progression | To assess preliminary antitumor activity of ISM3091. | From Screening (Day-28 to Day-1), Day 1, Cycle 1, Day 1, Cycle 2, end-of-treatment visit (each cycle is 28 days) (approximately 1 year) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancers, ovarian cancer, prostate cancer, recommended Phase II dose, ubiquitin specific peptidase 1 (USP1), Advanced HRD Solid Tumors