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

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

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.

Study Overview

• Status: Terminated
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: Evixapodlin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• New Zealand
  • Auckland, New Zealand, 1023
    • Auckland City Hospital
  • Christchurch, New Zealand, 8011
    • Christchurch Clinical Studies Trust, LLC
  • Grafton, Auckland, New Zealand, 1010
    • Auckland Clinical Studies Ltd
• United States
  • California
    • Encinitas, California, United States, 92024
      • California Care Associates for Research and Excellence Inc
  • Texas
    • San Antonio, Texas, United States, 78229
      • NEXT Oncology
  • Washington
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties, PLLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: Evixapodlin 400 mg (Phase 1); Participants will receive Evixapodlin 400 mg once daily for 21 days of each cycle.	Drug: Evixapodlin; Tablets administered orally.; Other Names: GS-4224
Experimental: Cohort 2: Evixapodlin 700 mg (Phase 1); Participants will receive Evixapodlin 700 mg once daily for 21 days of each cycle.	Drug: Evixapodlin; Tablets administered orally.; Other Names: GS-4224
Experimental: Cohort 3: Evixapodlin 1000 mg (Phase 1); Participants will receive Evixapodlin 1000 mg once daily for 21 days of each cycle.	Drug: Evixapodlin; Tablets administered orally.; Other Names: GS-4224
Experimental: Cohort 4: Evixapodlin 1500 mg (Phase 1); Participants will receive Evixapodlin 1500 mg once daily for 21 days of each cycle.	Drug: Evixapodlin; Tablets administered orally.; Other Names: GS-4224
Experimental: Cohort 5: Evixapodlin 1000 mg (Phase 1); Participants are planned to receive Evixapodlin 1000 mg twice daily (BID) for 21 days of each cycle.	Drug: Evixapodlin; Tablets administered orally.; Other Names: GS-4224
Experimental: Cohort 1 Substudy: Evixapodlin 400 mg (Phase 1); Participants will receive Evixapodlin 400 mg once daily for 21 days of each cycle.	Drug: Evixapodlin; Tablets administered orally.; Other Names: GS-4224
Experimental: Cohort 2 Substudy: Evixapodlin 700 mg (Phase 1); Participants are planned to receive Evixapodlin 700 mg once daily for 21 days of each cycle.	Drug: Evixapodlin; Tablets administered orally.; Other Names: GS-4224
Experimental: Cohort 3 Substudy: Evixapodlin 1000 mg (Phase 1); Participants will receive Evixapodlin 1000 mg once daily for 21 days of each cycle.	Drug: Evixapodlin; Tablets administered orally.; Other Names: GS-4224
Experimental: Dose Expansion (Phase 2); Dose expansion is planned to begin when the recommended Phase 2 dose (RP2D) will be determined.	Drug: Evixapodlin; Tablets administered orally.; Other Names: GS-4224

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Gilead Sciences

Study record dates

Study Major Dates

• Study Start (Actual): August 26, 2019
• Primary Completion (Actual): March 30, 2021
• Study Completion (Actual): March 30, 2021

Study Registration Dates

• First Submitted: July 31, 2019
• First Submitted That Met QC Criteria: August 6, 2019
• First Posted (Actual): August 8, 2019

Study Record Updates

• Last Update Posted (Actual): October 6, 2022
• Last Update Submitted That Met QC Criteria: September 9, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: GS-US-494-5484; 2019-004605-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No