Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of GS-9716 as Monotherapy and in Combination With Anticancer Therapies in Adults With Solid Malignancies

Study Overview
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Brief Summary
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This is a Phase I open-label, multi-center study of GS-9716 tested either as monotherapy or in combination with other anti-cancer agents in patients with advanced solid malignancies. Primary objectives are to define the maximum tolerated dose (MTD) or maximum administered dose of GS-9716, and characterize the safety and tolerability of GS-9716 as monotherapy and in combination with anti-cancer therapies.

Official Title
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A Phase 1a/b Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of GS-9716 as Monotherapy and in Combination With Anticancer Therapies in Subjects With Solid Malignancies

Conditions
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Solid Malignancies

Intervention / Treatment
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* Drug: GS-9716
* Drug: Docetaxel
* Drug: sacituzumab govitecan-hziy


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: General Inclusion Criteria (all cohorts): Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Measurable disease per RECIST version 1.1 Adequate hematology, renal and hepatic function Left ventricular ejection fraction (LVEF) ≥ 50% Patients with brain metastases may be enrolled only if treated, nonprogressive, asymptomatic and not taking high dose steroids for at least 4 weeks prior to Cycle 1 Day 1 (C1D1) Individuals of childbearing potential who engage in heterosexual intercourse must agree to use method(s) of contraception, per protocol. Tissue criteria: must provide sufficient, and adequate tumor tissue sample or agree to have a biopsy taken. Part A Specific Inclusion Criteria: GS-9716 as monotherapy Histologically or cytologically confirmed locally advanced or metastatic malignant solid tumor for which no standard therapy is available, standard therapy has failed, or for whom standard-of-care therapy is contraindicated. Cohorts B1 and C1 Specific Inclusion Criteria: Histologically or cytologically confirmed unresectable metastatic or locally advanced disease following treatment for metastatic disease including an immune checkpoint inhibitor and a platinum-containing chemotherapy Patients with actionable genomic alterations must have also received treatment with at least 1 approved therapy appropriate to the genomic alteration unless unavailable or contraindicated Cohorts B4 and C4 Specific Inclusion Criteria: Histologically or cytologically confirmed disease based on the most recent analyzed biopsy metastatic disease that is refractory to or relapsed after at least 2 prior standard-of-care chemotherapy regimens, one of which was a taxane (unless contraindicated). Key Exclusion Criteria: Prior systemic anti-cancer therapy must meet wash-out criteria outlined in protocol Treatment with any high dose systemic corticosteroids or nonsystemic radiotherapy within 2 weeks of the first dose of GS-9716 (low dose corticosteroids permitted). Women who are pregnant or lactating Patients with active ≥ Grade 2 nausea or vomiting, and/or signs of intestinal obstruction Known active or chronic hepatitis B or C infection or HIV infection/ HIV positive Known history of clinically significant cardiovascular disease or heart failure. Known history of clinically significant active chronic obstructive pulmonary disease or other moderate to severe chronic respiratory illness present within 6 months prior to C1D1 Known history of other clinically significant pulmonary disease or evidence of active pneumonitis Uncontrolled pleural effusion, pericardial effusion, or ascites History of clinically significant bleeding, intestinal obstruction, or gastrointestinal (GI) perforation within 6 months prior to C1D1 Infection requiring intravenous anti-infective use within 2 weeks prior to C1D1 Active or history of autoimmune disease or immune deficiency History of uncured coexisting cancer, not including uncured basal cell carcinoma, cervical cancer in situ, or superficial bladder cancer. Cohort A Specific Exclusion Criteria: GS-9716 as monotherapy: Known heart failure or elevated cardiac biomarkers Cohorts B1 and C1 Specific Exclusion Criteria: Known hypersensitivity to excipients in study treatments. Cohorts B4 and C4 Specific Exclusion Criteria: Prior treatment with sacituzumab govitecan-hziy or a topoisomerase 1 inhibitor or agents targeting Trop-2. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

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 A: GS-9716 Dose-Escalation<br>Patients will receive escalating doses of GS-9716 to estimate MTD. | Drug: GS-9716<br>* Tablet(s) administered orally<br>|
| Experimental: Part A: GS-9716 Dose-Expansion<br>Patients will receive ≤ MTD of GS-9716. | Drug: GS-9716<br>* Tablet(s) administered orally<br>|
| Experimental: Part B (Cohort B1): GS-9716 + docetaxel<br>Patients will receive escalating doses of GS-9716 in combination with docetaxel. | Drug: GS-9716<br>* Tablet(s) administered orally<br>Drug: Docetaxel<br>* Administered intravenously<br>|
| Experimental: Part B (Cohort B4): GS-9716 + sacituzumab govitecan-hziy<br>Patients will receive escalating doses of GS-9716 in combination with sacituzumab govitecan-hziy. | Drug: GS-9716<br>* Tablet(s) administered orally<br>Drug: sacituzumab govitecan-hziy<br>* Administered intravenously<br>|
| Experimental: Part C (Cohort C1): GS-9716 + docetaxel<br>Patients will receive ≤ MTD GS-9716 in combination with docetaxel. | Drug: GS-9716<br>* Tablet(s) administered orally<br>Drug: Docetaxel<br>* Administered intravenously<br>|
| Experimental: Part C (Cohort C4): GS-9716 + sacituzumab govitecan-hziy<br>Patients will receive ≤ MTD GS-9716 in combination with sacituzumab govitecan-hziy. | Drug: GS-9716<br>* Tablet(s) administered orally<br>Drug: sacituzumab govitecan-hziy<br>* Administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Experiencing Dose-Limiting Toxicities (DLTs) |  | First dose date up to 21 days | 
| Percentage of Patients Experiencing Adverse Events (AEs) According to National Cancer Institute (NCI) Common Terminology Criteria for AEs (CTCAE), Version 5.0 |  | First dose date up to last dose date (Maximum: 105 weeks) plus 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Observed Concentration (Cmax) for GS-9716 |  | Approximately 105 Weeks | 
| Time to Maximum Observed Concentration (Tmax) for GS-9716 |  | Approximately 105 Weeks | 
| Area Under the Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24) for GS-9716 |  | Approximately 105 Weeks | 
| Parts B and C: Objective Response Rate (ORR) | ORR is defined as the percentage of patients who achieve a confirmed complete response (CR) or confirmed partial response (PR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. | Up to 105 weeks | 
| Parts B and C: Disease Control Rate (DCR) | DCR is defined as the percentage of patients who achieve a CR, PR, or stable disease (SD) as assessed by RECIST version 1.1. | Up to 105 weeks | 
| Parts B and C: Progression-Free Survival (PFS) | PFS is defined as the interval from the first dose of GS-9716 to the earlier of the first documentation of definitive progressive disease (PD) or death from any cause. | First dose date to PD or death, whichever occurs first (up to 39 months) | 
| Parts B and C: Time to Response (TTR) | TTR is defined as the time from first dose of GS-9716 to the first documentation of CR or PR. | First dose date to the first documentation of CR or PR (up to 105 weeks) | 
| Parts B and C: Duration of Response (DOR) | DOR is defined as the time from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause. | From first documentation of CR or PR to PD or death, whichever occurs first (up to 37 months) |