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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 : Terminated (Gilead decision to terminate)
First Posted : August 8, 2019
Last Update Posted : April 26, 2021
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)
Actual Enrollment : 18 participants
Allocation: N/A
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
Actual Primary Completion Date : March 30, 2021
Actual Study Completion Date : March 30, 2021

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 once a day (QD). Subsequent doses of 700 mg QD, 1000 mg QD, 1500 mg QD, and 1000 mg twice a day (BID) are planned based on the 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.




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: Intensive PK:Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose(400-1500 mg cohorts) or Predose, 0.5, 1, 1.5, 2.5, 4, 6, 12 h postdose(1000 mg cohort) on C1D1 & D15;Sparse PK: Predose on C1D2, & C2 to C5D1, EOT, 30D FU Visit & 30 min-4 h Postdose on C1D1 &D8 ]

    Tlast is defined as the time (observed time point) of Clast.

    Intensive PK: Predose and 0.5, 1, 1.5, 2.5, 4, 6, 24 hours postdose (400-1500 mg QD cohorts only) or Predose and 0.5, 1, 1.5, 2.5, 4, 6, 12 hours postdose (1000 mg BID cohort only) on Cycle 1 Days 1 and 15

    Sparse PK (Phase 2 and participants who do not have intensive PK collection in Phase 1b): Predose on Cycle 1 Day 2, and on Cycles 2 to 5 Day 1, End of Treatment (last dose date ± 7 days) and 30-day Follow-up Visit (30 ± 7 days after last dose date) and 30 minutes to 4 hours Postdose on Cycle 1 Days 1 and 8

    Each cycle is 21 days

    C=Cycle(s)

    D=Day

    EOT= End of Treatment

    FU= Follow-up

    min=minutes

    h=hour(s)


  2. PK Parameter: Tmax of GS-4224 During the Dose Escalation Phase [ Time Frame: Intensive PK:Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose(400-1500 mg cohorts) or Predose, 0.5, 1, 1.5, 2.5, 4, 6, 12 h postdose(1000 mg cohort) on C1D1 & D15;Sparse PK: Predose on C1D2, & C2 to C5D1, EOT, 30D FU Visit & 30 min-4 h Postdose on C1D1 &D8 ]

    Tmax is defined as the time (observed time point) of Cmax.

    Intensive PK: Predose and 0.5, 1, 1.5, 2.5, 4, 6, 24 hours postdose (400-1500 mg QD cohorts only) or Predose and 0.5, 1, 1.5, 2.5, 4, 6, 12 hours postdose (1000 mg BID cohort only) on Cycle 1 Days 1 and 15

    Sparse PK (Phase 2 and participants who do not have intensive PK collection in Phase 1b): Predose on Cycle 1 Day 2, and on Cycles 2 to 5 Day 1, End of Treatment (last dose date ± 7 days) and 30-day Follow-up Visit (30 ± 7 days after last dose date) and 30 minutes to 4 hours Postdose on Cycle 1 Days 1 and 8

    Each cycle is 21 days

    C=Cycle(s)

    D=Day

    EOT= End of Treatment

    FU= Follow-up

    min=minutes

    h=hour(s)


  3. PK Parameter: Cmax of GS-4224 During the Dose Escalation Phase [ Time Frame: Intensive PK:Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose(400-1500 mg cohorts) or Predose, 0.5, 1, 1.5, 2.5, 4, 6, 12 h postdose(1000 mg cohort) on C1D1 & D15;Sparse PK: Predose on C1D2, & C2 to C5D1, EOT, 30D FU Visit & 30 min-4 h Postdose on C1D1 &D8 ]

    Cmax is defined as the maximum observed concentration of drug.

    Intensive PK: Predose and 0.5, 1, 1.5, 2.5, 4, 6, 24 hours postdose (400-1500 mg QD cohorts only) or Predose and 0.5, 1, 1.5, 2.5, 4, 6, 12 hours postdose (1000 mg BID cohort only) on Cycle 1 Days 1 and 15

    Sparse PK (Phase 2 and participants who do not have intensive PK collection in Phase 1b): Predose on Cycle 1 Day 2, and on Cycles 2 to 5 Day 1, End of Treatment (last dose date ± 7 days) and 30-day Follow-up Visit (30 ± 7 days after last dose date) and 30 minutes to 4 hours Postdose on Cycle 1 Days 1 and 8

    Each cycle is 21 days

    C=Cycle(s)

    D=Day

    EOT= End of Treatment

    FU= Follow-up

    min=minutes

    h=hour(s)


  4. PK Parameter: Ctrough of GS-4224 During the Dose Escalation Phase [ Time Frame: Intensive PK:Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose(400-1500 mg cohorts) or Predose, 0.5, 1, 1.5, 2.5, 4, 6, 12 h postdose(1000 mg cohort) on C1D1 & D15;Sparse PK: Predose on C1D2, & C2 to C5D1, EOT, 30D FU Visit & 30 min-4 h Postdose on C1D1 &D8 ]

    Ctrough is defined as the observed drug concentration at the end of the dosing interval.

    Intensive PK: Predose and 0.5, 1, 1.5, 2.5, 4, 6, 24 hours postdose (400-1500 mg QD cohorts only) or Predose and 0.5, 1, 1.5, 2.5, 4, 6, 12 hours postdose (1000 mg BID cohort only) on Cycle 1 Days 1 and 15

    Sparse PK (Phase 2 and participants who do not have intensive PK collection in Phase 1b): Predose on Cycle 1 Day 2, and on Cycles 2 to 5 Day 1, End of Treatment (last dose date ± 7 days) and 30-day Follow-up Visit (30 ± 7 days after last dose date) and 30 minutes to 4 hours Postdose on Cycle 1 Days 1 and 8

    Each cycle is 21 days

    C=Cycle(s)

    D=Day

    EOT= End of Treatment

    FU= Follow-up

    min=minutes

    h=hour(s)


  5. PK Parameter: AUClast of GS-4224 During the Dose Escalation Phase [ Time Frame: Intensive PK:Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose(400-1500 mg cohorts) or Predose, 0.5, 1, 1.5, 2.5, 4, 6, 12 h postdose(1000 mg cohort) on C1D1 & D15;Sparse PK: Predose on C1D2, & C2 to C5D1, EOT, 30D FU Visit & 30 min-4 h Postdose on C1D1 &D8 ]

    AUClast is defined as the concentration of drug from time zero to the last observable concentration.

    Intensive PK: Predose and 0.5, 1, 1.5, 2.5, 4, 6, 24 hours postdose (400-1500 mg QD cohorts only) or Predose and 0.5, 1, 1.5, 2.5, 4, 6, 12 hours postdose (1000 mg BID cohort only) on Cycle 1 Days 1 and 15

    Sparse PK (Phase 2 and participants who do not have intensive PK collection in Phase 1b): Predose on Cycle 1 Day 2, and on Cycles 2 to 5 Day 1, End of Treatment (last dose date ± 7 days) and 30-day Follow-up Visit (30 ± 7 days after last dose date) and 30 minutes to 4 hours Postdose on Cycle 1 Days 1 and 8

    Each cycle is 21 days

    C=Cycle(s)

    D=Day

    EOT= End of Treatment

    FU= Follow-up

    min=minutes

    h=hour(s)


  6. PK Parameter: AUCtau of GS-4224 During the Dose Escalation Phase [ Time Frame: Intensive PK:Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose(400-1500 mg cohorts) or Predose, 0.5, 1, 1.5, 2.5, 4, 6, 12 h postdose(1000 mg cohort) on C1D1 & D15;Sparse PK: Predose on C1D2, & C2 to C5D1, EOT, 30D FU Visit & 30 min-4 h Postdose on C1D1 &D8 ]

    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval).

    Intensive PK: Predose and 0.5, 1, 1.5, 2.5, 4, 6, 24 hours postdose (400-1500 mg QD cohorts only) or Predose and 0.5, 1, 1.5, 2.5, 4, 6, 12 hours postdose (1000 mg BID cohort only) on Cycle 1 Days 1 and 15

    Sparse PK (Phase 2 and participants who do not have intensive PK collection in Phase 1b): Predose on Cycle 1 Day 2, and on Cycles 2 to 5 Day 1, End of Treatment (last dose date ± 7 days) and 30-day Follow-up Visit (30 ± 7 days after last dose date) and 30 minutes to 4 hours Postdose on Cycle 1 Days 1 and 8

    Each cycle is 21 days

    C=Cycle(s)

    D=Day

    EOT= End of Treatment

    FU= Follow-up

    min=minutes

    h=hour(s)


  7. PK Parameter: t1/2 of GS-4224 During the Dose Escalation Phase [ Time Frame: Intensive PK:Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose(400-1500 mg cohorts) or Predose, 0.5, 1, 1.5, 2.5, 4, 6, 12 h postdose(1000 mg cohort) on C1D1 & D15;Sparse PK: Predose on C1D2, & C2 to C5D1, EOT, 30D FU Visit & 30 min-4 h Postdose on C1D1 &D8 ]

    t1/2 is defined as the estimate of the terminal elimination half-life of the drug.

    Intensive PK: Predose and 0.5, 1, 1.5, 2.5, 4, 6, 24 hours postdose (400-1500 mg QD cohorts only) or Predose and 0.5, 1, 1.5, 2.5, 4, 6, 12 hours postdose (1000 mg BID cohort only) on Cycle 1 Days 1 and 15

    Sparse PK (Phase 2 and participants who do not have intensive PK collection in Phase 1b): Predose on Cycle 1 Day 2, and on Cycles 2 to 5 Day 1, End of Treatment (last dose date ± 7 days) and 30-day Follow-up Visit (30 ± 7 days after last dose date) and 30 minutes to 4 hours Postdose on Cycle 1 Days 1 and 8

    Each cycle is 21 days

    C=Cycle(s)

    D=Day

    EOT= End of Treatment

    FU= Follow-up

    min=minutes

    h=hour(s)


  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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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 and 1000 mg 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.


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


Locations
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United States, California
California Care Associates for Research and Excellence Inc
Encinitas, California, United States, 92024
United States, Texas
NEXT Oncology
San Antonio, Texas, United States, 78229
United States, Washington
Northwest Medical Specialties, PLLC
Tacoma, Washington, United States, 98405
New Zealand
Auckland City Hospital
Auckland, New Zealand, 1023
Christchurch Clinical Studies Trust, LLC
Christchurch, New Zealand, 8011
Auckland Clinical Studies Ltd
Grafton, Auckland, New Zealand, 1010
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    
Other Study ID Numbers: GS-US-494-5484
2019-004605-27 ( EudraCT Number )
First Posted: August 8, 2019    Key Record Dates
Last Update Posted: April 26, 2021
Last Verified: April 2021
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