Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Evixapodlin (Formerly GS-4224) in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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The primary objectives of this study are to characterize the safety and tolerability of evixapodlin (formerly GS-4224) and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of evixapodlin in participants with advanced solid tumors.

Detailed Description
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This was a planned Phase 1/2 study. However, Phase 2 was not conducted because the study was closed due to sponsor decision prior to opening the dose expansion cohort and hence, RP2D analysis was not performed.

Official Title
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A Phase 1b/2 Dose Escalation/Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of GS-4224 in Subjects With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: Evixapodlin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Dose Escalation Cohorts: Histologically or cytologically confirmed advanced malignant solid tumor that is refractory to or intolerant of all standard therapy or for which no standard therapy is available. Dose Expansion and 1000 mg twice a day (BID) Dose Escalation Cohorts: Individuals must have available sufficient and adequate formalin fixed tumor sample preferably from a biopsy of a tumor lesion obtained either at the time of or after the diagnosis of advanced disease has been made and from a site not previously irradiated. Alternatively, individuals must agree to have a biopsy taken prior to entering the study to provide adequate tissue. For the 1000 mg BID dose escalation cohort, individuals with melanoma, Merkel cell, microsatellite instability-high (MSI-H) cancers, and classical Hodgkin lymphoma (cHL) are not required to have archival or fresh biopsy tissue. Dose Escalation Biopsy Substudy and 1000 mg BID Dose Escalation Cohorts: Documented ligand 1 of programmed cell death protein 1 (PD-L1) expression in the tumor (tumor proportion score (TPS) ≥ 10% or combined positive score (CPS) ≥ 10). In the 1000 mg BID Cohort, PD-L1 expression will not be required for Merkel cell, melanoma, MSI-H cancers, and cHL. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2. Adequate organ function. Key Exclusion Criteria: History or evidence of clinically significant disorder, condition, or disease that, in the opinion of the Investigator or Medical Monitor would pose a risk to individual safety or interfere with the study evaluations, procedures, or completion. Dose Escalation Cohorts: History of ≥ Grade 3 Adverse Events (AEs) during prior treatment with an immune checkpoint inhibitor, or history of discontinuation of treatment with an immune checkpoint inhibitor due to AEs. Dose Escalation 1000 mg BID and Dose Expansion Cohort: Prior treatment with an immune checkpoint inhibitor (anti-PD-1, anti-PD-L1, or anti- ligand 2 of programmed cell death protein 1 (PD-L2) antibodies). History of autoimmune disease (for example, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis). 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: Cohort 1: Evixapodlin 400 mg (Phase 1)<br>Participants will receive Evixapodlin 400 mg once daily for 21 days of each cycle. | Drug: Evixapodlin<br>* Tablets administered orally.<br>* Other names: GS-4224;|
| Experimental: Cohort 2: Evixapodlin 700 mg (Phase 1)<br>Participants will receive Evixapodlin 700 mg once daily for 21 days of each cycle. | Drug: Evixapodlin<br>* Tablets administered orally.<br>* Other names: GS-4224;|
| Experimental: Cohort 3: Evixapodlin 1000 mg (Phase 1)<br>Participants will receive Evixapodlin 1000 mg once daily for 21 days of each cycle. | Drug: Evixapodlin<br>* Tablets administered orally.<br>* Other names: GS-4224;|
| Experimental: Cohort 4: Evixapodlin 1500 mg (Phase 1)<br>Participants will receive Evixapodlin 1500 mg once daily for 21 days of each cycle. | Drug: Evixapodlin<br>* Tablets administered orally.<br>* Other names: GS-4224;|
| Experimental: Cohort 5: Evixapodlin 1000 mg (Phase 1)<br>Participants are planned to receive Evixapodlin 1000 mg twice daily (BID) for 21 days of each cycle. | Drug: Evixapodlin<br>* Tablets administered orally.<br>* Other names: GS-4224;|
| Experimental: Cohort 1 Substudy: Evixapodlin 400 mg (Phase 1)<br>Participants will receive Evixapodlin 400 mg once daily for 21 days of each cycle. | Drug: Evixapodlin<br>* Tablets administered orally.<br>* Other names: GS-4224;|
| Experimental: Cohort 2 Substudy: Evixapodlin 700 mg (Phase 1)<br>Participants are planned to receive Evixapodlin 700 mg once daily for 21 days of each cycle. | Drug: Evixapodlin<br>* Tablets administered orally.<br>* Other names: GS-4224;|
| Experimental: Cohort 3 Substudy: Evixapodlin 1000 mg (Phase 1)<br>Participants will receive Evixapodlin 1000 mg once daily for 21 days of each cycle. | Drug: Evixapodlin<br>* Tablets administered orally.<br>* Other names: GS-4224;|
| Experimental: Dose Expansion (Phase 2)<br>Dose expansion is planned to begin when the recommended Phase 2 dose (RP2D) will be determined. | Drug: Evixapodlin<br>* Tablets administered orally.<br>* Other names: GS-4224;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase | A DLT was any toxicity defined as follows excluding toxicities clearly related to disease progression or disease-related processes occurring during the DLT assessment window (Day 1 through Day 21): Grade ≥ 4 neutropenia Grade ≥ 3 neutropenia with fever Grade ≥ 3 thrombocytopenia Grade ≥ 2 bleeding Grade ≥ 3 anemia Grade ≥ 3 or higher non-hematologic toxicity (excluding Grade 3 nausea or emesis or Grade 3 diarrhea) Grade ≥ 2 non-hematologic treatment-emergent adverse event that in the opinion of the investigator is of potential clinical significance Treatment interruption of ≥ 7 days due to unresolved toxicity Any toxicity event that precludes further administration of evixapodlin Any Grade 3 or Grade 4 elevation in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) associated with a Grade 2 elevation in bilirubin lasting ≥ 7 days An immune-related adverse event (irAE) for which immunotherapy should be permanently discontinued | Day 1 through Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter: AUCtau of Evixapodlin During the Dose Escalation Phase | AUCtau was defined as area under the concentration-time curve from time zero to the end of the dosing interval. | Intensive PK: Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 hours (h) postdose (400-1500 once daily [QD] mg cohorts) on Cycle (C) 1 Day (D) 1 & D15 | 
| PK Parameter: Cmax of Evixapodlin During the Dose Escalation Phase | Cmax was defined as the maximum observed drug concentration. | Intensive PK: Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose (400-1500 QD mg cohorts) on C1D1 & D15 | 
| PK Parameter: Ctrough of Evixapodlin During the Dose Escalation Phase | Ctrough is defined as the observed concentration at the end of the dosing interval. | Intensive PK: Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose (400-1500 QD mg cohorts) on C1D1 & D15 | 
| PK Parameter: Tmax of Evixapodlin During the Dose Escalation Phase | Tmax is defined as the time to maximum observed concentration. | Intensive PK: Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose (400-1500 QD mg cohorts) on C1D1 & D15 | 
| Percentage of Participants Experiencing ≥ Grade 3 Treatment-Emergent Adverse Events During the Dose Expansion Phase |  | First dose date through end of treatment plus 30 days, approximately 5 years | 
| Percentage of Participants Experiencing ≥ Grade 3 Treatment-Emergent Laboratory Abnormalities During the Dose Expansion Phase |  | First dose date through end of treatment plus 30 days, approximately 5 years |