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Safety, Tolerability, Pharmacokinetics, and Efficacy of GS-4224 in Participants With Advanced Solid Tumors

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ClinicalTrials.gov Identifier: NCT04049617
Recruitment Status : Recruiting
First Posted : August 8, 2019
Last Update Posted : September 2, 2019
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

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

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: GS-4224 Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 76 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : August 26, 2019
Estimated Primary Completion Date : August 2024
Estimated Study Completion Date : August 2024

Arm Intervention/treatment
Experimental: GS-4224

Dose Escalation (Phase 1b):

Participants will be sequentially enrolled in a dose escalation design to receive GS-4224 starting at ≤ 400 mg. Subsequent doses of ≤700 mg and ≤ 1000 mg are planned based on safety and tolerability of each dose level.

Dose Expansion (Phase 2):

Dose expansion will begin when the RP2D has been determined.

Drug: GS-4224
Tablets administered orally once daily




Primary Outcome Measures :
  1. Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase [ Time Frame: Day 1 through Day 21 ]

    A DLT is 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 GS-4224
    • 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


Secondary Outcome Measures :
  1. Pharmacokinetic (PK) Parameter: Tlast of GS-4224 During the Dose Escalation Phase [ Time Frame: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 24 hours postdose on Cycle 1 Days 1 and 15 (each cycle is 21 days). ]
    Tlast is defined as the time (observed time point) of Clast.

  2. PK Parameter: Tmax of GS-4224 During the Dose Escalation Phase [ Time Frame: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 24 hours postdose on Cycle 1 Days 1 and 15 (each cycle is 21 days). ]
    Tmax is defined as the time (observed time point) of Cmax.

  3. PK Parameter: Cmax of GS-4224 During the Dose Escalation Phase [ Time Frame: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 24 hours postdose on Cycle 1 Days 1 and 15 (each cycle is 21 days). ]
    Cmax is defined as the maximum observed concentration of drug.

  4. PK Parameter: Ctau of GS-4224 During the Dose Escalation Phase [ Time Frame: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 24 hours postdose on Cycle 1 Days 1 and 15 (each cycle is 21 days). ]
    Ctau is defined as the observed drug concentration at the end of the dosing interval.

  5. PK Parameter: AUClast of GS-4224 During the Dose Escalation Phase [ Time Frame: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 24 hours postdose on Cycle 1 Days 1 and 15 (each cycle is 21 days). ]
    AUClast is defined as the concentration of drug from time zero to the last observable concentration.

  6. PK Parameter: AUCtau of GS-4224 During the Dose Escalation Phase [ Time Frame: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 24 hours postdose on Cycle 1 Days 1 and 15 (each cycle is 21 days). ]
    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

  7. PK Parameter: t1/2 of GS-4224 During the Dose Escalation Phase [ Time Frame: Predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4.5, 6, 24 hours postdose on Cycle 1 Days 1 and 15 (each cycle is 21 days). ]
    t1/2 is defined as the estimate of the terminal elimination half-life of the drug.

  8. Percentage of Participants Experiencing ≥ Grade 3 Treatment-Emergent Adverse Events During the Dose Expansion Phase [ Time Frame: First dose date through end of treatment plus 30 days, approximately 5 years ]
  9. Percentage of Participants Experiencing ≥ Grade 3 Treatment-Emergent Laboratory Abnormalities During the Dose Expansion Phase [ Time Frame: First dose date through end of treatment plus 30 days, approximately 5 years ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 Cohort: 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.
  • Dose Escalation Biopsy Substudy: Documented ligand 1 of programmed cell death protein 1 (PD-L1) expression in the tumor (tumor proportion score (TPS) or combined positive score (CPS) > 10%).
  • 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 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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04049617


Contacts
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Contact: Gilead Clinical Study Information Center 1-833-445-3230 (GILEAD-0) GileadClinicalTrials@gilead.com

Locations
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United States, Texas
NEXT Oncology Recruiting
San Antonio, Texas, United States, 78229
United States, Washington
Northwest Medical Specialties, PLLC Recruiting
Tacoma, Washington, United States, 98405
Sponsors and Collaborators
Gilead Sciences
Investigators
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Study Director: Gilead Study Director Gilead Sciences

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Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT04049617     History of Changes
Other Study ID Numbers: GS-US-494-5484
First Posted: August 8, 2019    Key Record Dates
Last Update Posted: September 2, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasms