The purpose of this study is to evaluate the effects of GS-4224 in patients with advanced solid tumors who have failed other therapies that are commonly used for this type of cancer.

Phase 1

Active, not recruiting

• Conditions: Advanced Solid Tumors; MedDRA version: 21.0Level: LLTClassification code 10049280Term: Solid tumourSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2019-004605-27-PL
• Lead Sponsor: Gilead Sciences, Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2020-07-07
• Study Completion: 2021-03-30
• Last Update Posted: 19 April 2022

Recruitment & Eligibility

• Status: Not Recruiting
• Sex: All
• Target Recruitment: 18

Inclusion Criteria

Subjects must meet all of the following inclusion criteria to be eligible for participation in this study. Additional indication-specific inclusion criteria for 1000 mg BID Dose Escalation Cohort and Phase 2 are provided in Appendix 3.
1.Male or female = 18 years of age.
2.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.
3.Dose Expansion and 1000 mg BID Dose Escalation Cohorts: Subjects 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, subjects must agree to have a biopsy taken prior to entering the study to provide adequate tissue.
For the 1000 mg BID dose escalation cohort, subjects with melanoma, Merkel cell, MSI-H cancers, and cHL are not required to have archival or fresh biopsy tissue.
4.Dose Escalation Biopsy Substudy and 1000 mg BID Dose Escalation Cohorts: Documented PD-L1 expression in the tumor (TPS =10% or CPS = 10). See Appendix 3 for the PD-L1 expression requirement for specific tumor types.
a) In the 1000 mg BID cohort, PD-L1 expression will not be required for Merkel cell, melanoma, MSI-H cancers, and cHL.
5.All persisting toxic effects of any prior antitumor therapy resolved to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 Grade = 1 or baseline before the first dose of study drug (with the exception of alopecia [Grade 1 or 2 permitted] and neurotoxicity [Grade 1 or 2 permitted]).
6.Eastern Cooperative Oncology Group (ECOG) Performance Status of = 2.
7.Life expectancy of = 3 months, in the opinion of the investigator.
8.Adequate organ function defined as follows:
a)Hematologic: Platelets = 100 ? 109/L ( =60? 109/L in subjects with HCC); Hemoglobin = 9.0 g/dL; ANC = 1.5 ? 109/L (with without blood transfusion, platelet transfusion, or growth factors within previous 7 days of the hematologic laboratory values obtained at screening visit).
b)Hepatic: AST / ALT = 2.5 ? upper limit of normal (ULN) (if liver metastases are present, = 5 ? ULN); Total or conjugated bilirubin = 1.5 ? ULN.
c)Renal: Creatinine clearance (CLcr) = 45 mL/min as calculated by the Cockcroft Gault method.
9.Coagulation: Subjects on full-dose oral anticoagulation, except warfarin, which is an excluded medication, must be on a stable dose (minimum duration 14 days). Subjects on low molecular weight heparin will be allowed.
10.Negative serum pregnancy test for female subjects.
11.Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse must agree to use protocol specified method(s) of contraception as described in Appendix 5.
12.Females who are nursing must agree to discontinue nursing before the first dose of GS-4224.
13.Able and willing to provide written informed consent to participate in the study.
14.Patients with history of human immunodeficiency virus (HIV) infection should have a CD4+ T-cell count = 350 cells/µL at screening.
15.Patients with serological evidence of chronic hepatitis B virus infection (HBV) should have HBV viral load below the limit of quantification at screening.
16.Patients with serological evidence of hepatitis C virus infection (HCV) should have com

Exclusion Criteria

Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. Additional indication-specific exclusion criteria for 1000 mg BID Dose Escalation Cohort and Phase 2 are provided in Appendix 3.
1)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 subject safety or interfere with the study evaluations, procedures, or completion.
2)Dose Escalation Cohorts: History of = Grade 3 AEs during prior treatment with an immune checkpoint inhibitor, or history of discontinuation of treatment with an immune checkpoint inhibitor due to AEs.
3)Dose Escalation 1000 mg BID and Dose Expansion Cohorts: Prior treatment with an immune checkpoint inhibitor (anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies).
4)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).
5)Positive serum pregnancy test (Appendix 5).
6)Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are clinically stable for at least 4 weeks prior to study entry, have no evidence of new or enlarging brain metastases and if taking corticosteroids, are on stable or decreasing doses for at least 7 days from first dose of study drug.
7)Uncontrolled intercurrent illness including, but not limited to, active uncontrolled infection, active or chronic bleeding event within 28 days prior to first dose of study drug, or psychiatric illness/social situation that would limit compliance with study requirements as judged by treating physician.
8)Myocardial infarction, symptomatic congestive heart failure (New York Heart Association Classification > Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within the last 6 months of first dose of study drug.
9)Major surgery, defined as any surgical procedure that involves general anesthesia and a significant incision (i.e., larger than what is required for placement of central venous access, percutaneous feeding tube, or biopsy) within 28 days of the first dose of study drug.
10)Impairment of GI function or GI disease that may significantly alter the absorption of GS-4224, including any unresolved nausea, vomiting, or diarrhea that is Common Terminology Criteria for Adverse Events (CTCAE) Grade > 1.
11)Symptomatic ascites or pleural effusion. A patient who is clinically stable following treatment for these conditions (including thora- or paracentesis) is eligible.
12)Minor surgical procedure(s) within 7 days of enrollment, or not yet recovered from prior surgery (placement of central venous access device, fine needle aspiration, or endoscopic biliary stent = 1 day before enrollment is acceptable).
13)Prior systemic radiation therapy completed within 4 weeks of the first dose of study drug, prior local radiation therapy completed within 2 weeks of Cycle 1 Day 1 (C1D1), or radiopharmaceuticals (strontium, samarium) within 8 weeks of C1D1.
14)Antitumor therapy (chemotherapy, antibody therapy, molecular targeted therapy) within 21 days or 5 half-lives, whichever is longer, of stu

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified