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 Details
Study Description
Brief Summary
The primary objective of Part A of this study is to define the maximum tolerated dose (MTD) or maximum administered dose of GS-9716 as monotherapy in advanced solid malignancies and to characterize the safety, and tolerability of GS-9716 monotherapy.
The primary objectives of Parts B and C of this study are: To characterize the safety, tolerability, and to define MTD and/or recommended Phase 2 dose (RP2D) of GS-9716 in combination with either docetaxel or sacituzumab govitecan-hziy in adults with metastatic non-squamous non-small cell lung cancer (NSCLC) following treatment for metastatic disease, including an immune checkpoint inhibitor and a single line of platinum containing chemotherapy (for Cohorts B1, B2, C1, and C2) and in adults with metastatic triple-negative breast cancer (TNBC) following a single line of therapy for metastatic disease (for Cohorts B3, B4, C3, and C4); To characterize the safety, tolerability, and to define MTD and/or the RP2D of GS-9716 in combination with gemcitabine and docetaxel in metastatic soft tissue sarcomas (mSTS) with nonspecific histologies previously untreated for metastatic disease (for Cohorts B5 and C5).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Part A: GS-9716 Dose-Escalation Participants will receive escalating doses of GS-9716 to establish MTD. |
Drug: GS-9716
Tablet(s) administered orally
|
| Experimental: Part A: GS-9716 Dose-Expansion Participants will receive the MTD or below MTD of GS-9716. |
Drug: GS-9716
Tablet(s) administered orally
|
| Experimental: Part B (Cohort B1): GS-9716 + Docetaxel Participants with non-squamous metastatic NSCLC will receive combination of GS-9716 and docetaxel. |
Drug: GS-9716
Tablet(s) administered orally
Drug: Docetaxel
Administered intravenously
|
| Experimental: Part B (Cohort B2): GS-9716 + Sacituzumab Govitecan-hziy Participants with non-squamous metastatic NSCLC will receive combination of GS-9716 and sacituzumab govitecan-hziy. |
Drug: GS-9716
Tablet(s) administered orally
Drug: Sacituzumab Govitecan-hziy
Administered intravenously
Other Names:
|
| Experimental: Part B (Cohort B3): GS-9716 + Docetaxel Participants with metastatic TNBC will receive combination of GS-9716 and docetaxel. |
Drug: GS-9716
Tablet(s) administered orally
Drug: Docetaxel
Administered intravenously
|
| Experimental: Part B (Cohort B4): GS-9716 + Sacituzumab Govitecan-hziy Participants with metastatic TNBC will receive combination of GS-9716 and sacituzumab govitecan-hziy. |
Drug: GS-9716
Tablet(s) administered orally
Drug: Sacituzumab Govitecan-hziy
Administered intravenously
Other Names:
|
| Experimental: Part B (Cohort B5): GS-9716 + Docetaxel + Gemcitabine Participants with metastatic STS with nonspecific histologies will receive combination of GS-9716, docetaxel and gemcitabine. |
Drug: GS-9716
Tablet(s) administered orally
Drug: Docetaxel
Administered intravenously
Drug: Gemcitabine
Administered intravenously
|
| Experimental: Part C (Cohort C1): GS-9716 + Docetaxel Participants with non-squamous metastatic NSCLC will receive combination of GS-9716 and docetaxel. |
Drug: GS-9716
Tablet(s) administered orally
Drug: Docetaxel
Administered intravenously
|
| Experimental: Part C (Cohort C2): GS-9716 + Sacituzumab Govitecan-hziy Participants with non-squamous metastatic NSCLC will receive combination of GS-9716 and sacituzumab govitecan-hziy. |
Drug: GS-9716
Tablet(s) administered orally
Drug: Sacituzumab Govitecan-hziy
Administered intravenously
Other Names:
|
| Experimental: Part C (Cohort C3): GS-9716 + Docetaxel Participants with metastatic TNBC will receive combination of GS-9716 and docetaxel. |
Drug: GS-9716
Tablet(s) administered orally
Drug: Docetaxel
Administered intravenously
|
| Experimental: Part C (Cohort C4): GS-9716 + Sacituzumab Govitecan-hziy Participants with metastatic TNBC will receive combination of GS-9716 and sacituzumab govitecan-hziy. |
Drug: GS-9716
Tablet(s) administered orally
Drug: Sacituzumab Govitecan-hziy
Administered intravenously
Other Names:
|
| Experimental: Part C (Cohort C5): GS-9716 + Docetaxel + Gemcitabine Participants with metastatic STS with nonspecific histologies will receive combination of GS-9716, docetaxel and gemcitabine. |
Drug: GS-9716
Tablet(s) administered orally
Drug: Docetaxel
Administered intravenously
Drug: Gemcitabine
Administered intravenously
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants Experiencing Dose-Limiting Toxicities (DLTs) [First dose date up to 21 days]
- Percentage of Participants 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]
- Percentage of Participants Experiencing Laboratory Abnormalities According to NCI CTCAE, Version 5.0 [First dose date up to last dose date (Maximum: 105 weeks) plus 30 days]
Secondary Outcome Measures
- Maximum Observed Concentration (Cmax) for GS-9716 [Approximately 2 years]
- Time to Maximum Observed Concentration (Tmax) for GS-9716 [Approximately 2 years]
- Area Under the Concentration Versus Time Curve From Time 0 to 24 Hours (AUC0-24) for GS-9716 [Approximately 2 years]
- Parts B and C: Objective Response Rate (ORR) [Up to 105 weeks]
ORR is defined as the percentage of participants who achieve a complete response (CR) or partial response (PR) as assessed by response evaluation criteria in solid tumors (RECIST) version 1.1.
- Parts B and C: Confirmed ORR [Up to 105 weeks]
Confirmed ORR is defined as the percentage of participants who achieve a confirmed CR or confirmed PR by RECIST version 1.1.
- Parts B and C: Disease Control Rate (DCR) [Up to 105 weeks]
DCR is defined as the percentage of participants who achieve a CR, PR, or stable disease (SD) as assessed by RECIST version 1.1.
- Parts B and C: Progression-Free Survival (PFS) [First dose date to PD or death, whichever occurs first (up to 39 months)]
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.
- Parts B and C: Time to Response (TTR) [First dose date to the first documentation of CR or PR (up to 105 weeks)]
TTR is defined as the time from first dose of GS-9716 to the first documentation of CR or PR.
- Parts B and C: Duration of Response (DOR) [From first documentation of CR or PR to PD or death, whichever occurs first (up to 37 months)]
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.
- Parts B and C: Overall Survival (OS) [First dose date to death (up to 39 months)]
OS is defined as the time from date of first dose of GS-9716 to death from any cause.
Eligibility Criteria
Criteria
Key Inclusion Criteria:
Part A: GS-9716 Monotherapy
-
Histologically or cytologically confirmed epithelial cancer, stage IV (metastatic) disease or locally advanced and unresectable (mixed histologies not permitted):
-
Breast cancer
-
Castrate-resistant prostate cancer not on hormonal androgen deprivation therapy
-
Cervical cancer
-
Colorectal cancer
-
Endometrial cancer
-
Epithelial ovarian cancer
-
Esophageal cancer
-
Follicular thyroid cancer
-
Gastric or gastroesophageal junction adenocarcinoma
-
Head and neck cancers- squamous cell carcinoma
-
Hepatocellular carcinoma
-
NSCLC
-
Renal cell cancer (clear cell)
-
Small-cell lung cancer
-
Urothelial cancer
-
Progressed after at least 1 prior standard therapeutic regimen, or for whom no standard therapy is available, standard therapy has failed, or for whom standard of care therapy is contraindicated
-
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
-
Measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as described in protocol
-
Adequate hematology, renal and hepatic function as described in the protocol
-
All toxicity at screening ≤ Grade 1, including peripheral neuropathy and excluding alopecia of any grade, well-controlled endocrine toxicities from prior immune checkpoint inhibitor therapy ≤ Grade 2, and chronic electrolyte abnormalities requiring supplementation ≤ Grade 2
-
Left ventricular ejection fraction (LVEF) ≥ 50% acquisition scan (MUGA) may be acceptable per discussion with the medical monitor
-
Tissue criteria: Individuals must have available, sufficient, and adequate formalin-fixed tumor tissue sample or must agree to have a biopsy taken prior to entering the study to provide adequate tissue. Core needle or excisional biopsy or resected tissue is required.
Part B and Part C: GS-9716 in Combination with Anticancer Therapies (All Cohorts)
-
ECOG performance status of 0 or 1
-
Adequate hematology, renal and hepatic function as described in the protocol
-
Otherwise, all toxicity at screening entry ≤ Grade 1, including peripheral neuropathy and excluding alopecia of any grade, well-controlled endocrine toxicities from prior immune checkpoint inhibitor therapy ≤ Grade 2, and chronic electrolyte abnormalities requiring supplementation ≤ Grade 2
-
LVEF ≥ 50%, as well as no clinically significant pericardial effusion
-
Tissue criteria:
-
TNBC cohorts B3, C3, B4, C4: Individuals must have a tumor lesion that a mandatory pretreatment biopsy can be obtained from. Core needle, or excisional biopsy, or resected tissue is required. Fine needle aspirates and bone biopsies are not acceptable
-
Cohorts B1, C1, B2, C2, B5, C5: Individuals must have available, sufficient, and adequate formalin-fixed tumor tissue sample or must agree to have a biopsy taken prior to entering the study to provide adequate tissue. Core needle or excisional biopsy or resected tissue is required.
Cohorts B1, B2, C1, and C2:
-
Histologically or cytologically confirmed unresectable metastatic or locally advanced, non-squamous NSCLC following treatment for metastatic disease including an immune checkpoint inhibitor and a single line of platinum-containing chemotherapy
-
Individuals with bone metastases currently receiving bisphosphonates for palliation will be eligible providing informed consent can be given and that other qualifying sites of measurable disease are present.
Cohorts B3, B4, C3, and C4:
-
Histologically or cytologically confirmed TNBC based on the most recent analyzed biopsy or other pathology specimen. Triple-negative status for TNBC will be defined by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines (US sites) or their equivalent (ex-US sites)
-
Unresectable locally advanced or metastatic disease following only 1 prior standard therapeutic regimen for TNBC. Individuals who have received 2 or more prior systemic therapies are not eligible
-
Individuals with bone metastases currently receiving bisphosphonates for palliation
-
Individuals with stable, treated brain metastases will be eligible.
Cohorts B5 and C5:
- Histologically proven soft tissue sarcoma (except the following histologies: gastrointestinal stromal tumors [GIST], Kaposi's sarcoma, mesotheliomas) which has been previously untreated for metastatic disease.
Key Exclusion Criteria:
-
Prior treatment with any myeloid cell leukemia 1 (MCL1) inhibitor
-
Treatment with any high dose systemic corticosteroids within 2 weeks of the first dose of GS-9716. However, low dose corticosteroids ≤ 10 mg prednisone or equivalent daily is permitted
-
Prior radiotherapy (or other nonsystemic therapy) within 2 weeks prior to dosing with GS-9716
-
Women who are pregnant or lactating
-
Individuals with brain metastases may be enrolled only if treated, nonprogressive, and asymptomatic as well as off high dose steroids (> 10 mg prednisone or equivalent) for at least 4 weeks prior to dosing with GS-9716
-
History of leptomeningeal disease
-
Individuals 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 or HIV positive
-
Known history of unstable angina, myocardial infarction (MI), cardiac angioplasty or stenting, or clinically significant cardiac disease would include QTc interval > 450 ms for males and > 470 ms for females
-
Known history of clinically significant active chronic obstructive pulmonary disease (COPD), or other moderate to severe chronic respiratory illness present within 6 months prior to dosing with GS-9716
-
Known history of clinically significant pulmonary interstitial lung disease, active interstitial lung disease, idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
-
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (more frequently than once monthly)
-
Prior history of clinically significant bleeding, intestinal obstruction, or gastrointestinal (GI) perforation within 6 months of initiation of study treatment
-
Infection requiring intravenous anti-infective use within 2 weeks prior to dosing with GS-9716
-
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.
Cohorts B1, B3, B5, C1, C3, and C5:
- Bilirubin > upper limit of normal (ULN).
Cohorts B1, B2, C1, and C2:
-
More than 1 prior chemotherapy regimen for metastatic non-squamous NSCLC; however, this would not exclude those who received frontline immune checkpoint inhibitor as monotherapy followed by a platinum-containing chemotherapeutic regimen in the second line
-
Non-squamous NSCLC with targetable mutations (e.g., anaplastic lymphoma kinase [ALK], epidermal growth factor receptor [EGFR], proto-oncogene tyrosine-protein kinase ROS [ROS1], v-RAF murine sarcoma viral oncogene homolog B [BRAF]) for which approved therapies are available
-
Cohorts B2 and C2 only: Prior therapy with sacituzumab govitecan-hziy or a topoisomerase 1 inhibitor or agents targeting Trop-2.
Cohorts B3, B4, C3, and C4:
-
More than 1 prior chemotherapy regimen for metastatic TNBC
-
Cohorts B4 and C4 only: Prior treatment with sacituzumab govitecan-hziy or a topoisomerase 1 inhibitor or agents targeting Trop-2.
Cohorts B5 and C5:
-
Any previous treatment for metastatic disease
-
Soft tissue sarcomas with the following histologies: GIST, Kaposi's sarcoma, or mesotheliomas.
Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | START Midwest | Grand Rapids | Michigan | United States | 49546 |
| 2 | START Mountain Region | Grand Rapids | Michigan | United States | 49546 |
| 3 | Oregon Health Oregon Health & Sciences University-Knight Cancer Institute | Portland | Oregon | United States | 97239 |
| 4 | Sarah Cannon Research Institute | Nashville | Tennessee | United States | 37203 |
| 5 | START San Antonio | San Antonio | Texas | United States | 78229 |
Sponsors and Collaborators
- Gilead Sciences
Investigators
- Study Director: Gilead Study Director, Gilead Sciences
Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
None provided.- GS-US-467-5643