A Study of SR-8541A (ENPPI Inhibitor) in Advanced/Metastatic Solid Tumors

Study Overview
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Brief Summary
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This is an open-label, dose-escalation, multi-center phase 1 study evaluating the safety, tolerability, and pharmacokinetics (PK) of SR-8541A, an ENPP1 inhibitor, administered orally as a monotherapy in subjects with solid tumors.

Detailed Description
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SR-8541A, an ENPP1 inhibitor, will be administered orally as a monotherapy to assess safety, tolerability, and pharmacokinetics (PK) in subjects with advanced/metastatic solid tumors. Subjects eligible for treatment include those whose disease is refractory to standard therapeutic options, or for which there are no standard therapeutic options available. All enrolled patients will orally administer SR-8541A daily. Treatment may continue until the subject's disease worsens or another treatment discontinuation criterion is met.

Official Title
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Phase 1, Dose Escalation, Safety, Tolerability, and Pharmacokinetic Study of SR-8541A (ENPP1 Inhibitor) Administered Orally as Monotherapy in Subjects With Advanced/Metastatic Solid Tumors

Conditions
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Advanced / Metastatic Solid Tumor

Intervention / Treatment
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* Drug: SR-8541A


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Life expectancy of at least 3 months Eastern Cooperative Oncology Group (ECOG) performance status 0 - 1 Histopathologically/cytologically confirmed advanced solid tumor, which is refractory to standard therapeutic options, or for which there are no standard therapeutic options. Measurable disease per RECIST v1.1 Willing to provide archival or fresh tumor tissue during screening (required) and post-treatment (optional) Adequate hematologic, renal and hepatic function Exclusion Criteria: Primary central nervous system (CNS) tumor Prior systemic anti-cancer treatment including other investigational agents, surgery, or radiation within 28 days or 5 half-lives, whichever is less Continuous systemic treatment with either corticosteroids (>10 milligram [mg] daily prednisone equivalents) or other immunosuppressive medications within 28 days Active autoimmune disease that has required systemic treatment in past 2 years History of documented congestive heart failure (New York Heart Association [NYHA] class II - IV); unstable angina; poorly controlled hypertension; clinically significant valvular heart disease; high-risk uncontrolled arrhythmias (including sustained ventricular tachycardia); myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack within the last 6 months, or Canadian Cardiovascular Society angina class > 2 Troponin I > ULN Blood pressure (BP) - Systolic < 95 mmHg or > 160 mmHg or diastolic > 100 mmHg Resting heart rate (HR) > 100 beats per minute (BPM) Corrected QT interval by Fridericia (QTcF) ≥ 470 ms Left Ventricular Ejection Fraction (LVEF) < 50% Symptomatic uncontrolled CNS disease requiring treatment with steroids or anti-seizure medications within 2 months Leptomeningeal disease Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for at least 8 weeks Bleeding diathesis due to underlying medical condition or anticoagulation medication which is unable to be promptly reversed by medical treatment Prior additional malignancy that is progressing or has received treatment the previous 3 years Active infection requiring systemic treatment Positive for human immunodeficiency virus (HIV) (HIV antibodies) or active hepatitis B (e.g., HbsAg reactive) or active hepatitis C (e.g., HCV ribonucleic acid [RNA] qualitative) infection with detectable viral load Major surgery within 28 days prior to Day 1 and/or minor surgery (excluding biopsy) within 7 days

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
Intervention Model: Sequential Assignment
Interventional Model Description: The study will follow an accelerated titration dose (ATD) escalation scheme. Single-subject cohorts will open sequentially when previous cohort milestones are met, e.g. completion of the Dose-Limiting Toxicity (DLT) period. If the single evaluable subject within an ATD cohort experiences a grade ≥ 2 toxicity during the DLT period, the ATD scheme will stop and a traditional 3+3 design will be implemented.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SR-8541A Monotherapy<br>SR-8541A will be orally administered. | Drug: SR-8541A<br>* orally administered ENPP1 inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of Adverse Events | Adverse events will be graded according to CTCAE v5.0. | From first dose of study drug through 30 days following the last dose of study treatment | 
| Recommended Phase 2 Dose (RP2D) of SR-8541A | Based on evaluation of Dose Limiting Toxicities (DLT) | From first dose of study drug through 28 days following the first dose of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum plasma concentration (Cmax) | Cmax measured in ng/mL | From first dose of study drug through 28 days following the first dose of study treatment | 
| Area under the curve from zero up to time t (AUC0-t) | AUC0-t measured in ng.h/mL | From first dose of study drug through 28 days following the first dose of study treatment | 
| Area under the concentration time curve from time 0 extrapolated to infinity (AUC0-inf) | AUC0-inf measured in ng.h/mL | From first dose of study drug through 28 days following the first dose of study treatment | 
| Maximal time for peak concentration (Tmax) | Tmax measured in h | From first dose of study drug through 28 days following the first dose of study treatment | 
| Terminal phase rate constant (λz) | λz measured in 1/h | From first dose of study drug through 28 days following the first dose of study treatment | 
| Half-life (t1/2) | t1/2 measured in h | From first dose of study drug through 28 days following the first dose of study treatment | 
| Overall Response Rate | Defined as the proportion of subjects in the efficacy population who achieve a radiographic investigator-assessed confirmed complete response (CR)/immune CR (iCR) or partial response (PR)/immune PR (iPR) per RECIST v1.1 or immune Response Evaluation Criteria in Solid Tumors (iRECIST) v1.0 | From first dose of study drug through 2 years following first dose | 
| Progression Free Survival | Defined as the time from start of treatment to the first documentation of progressive disease (PD) or death from any cause, whichever occurs first | From first dose of study drug through 2 years following first dose | 
| Duration of Response | Defined as the time from the date a response of PR or better was first recorded to the date on which PD was first noted or the date of death due to any cause | From first dose of study drug through 2 years following first dose | 
| Disease Control Rate | Defined as the proportion of subjects who achieve an investigator-assessed confirmed CR/iCR, PR/iPR, or Stable Disease (SD)/immune SD (iSD) at 16 weeks per RECIST v1.1 or iRECIST v1.0 | From first dose of study drug through 2 years following first dose | 
| Overall Survival | Defined as the time from the start of treatment until death due to any cause | From first dose of study drug through 2 years following first dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory, Relapsing, Solid Tumors