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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

Tracking Information
First Submitted Date  ICMJE July 31, 2019
First Posted Date  ICMJE August 8, 2019
Last Update Posted Date April 26, 2021
Actual Study Start Date  ICMJE August 26, 2019
Actual Primary Completion Date March 30, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 6, 2019)
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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 25, 2020)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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)
  • 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 ]
  • 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 ]
Original Secondary Outcome Measures  ICMJE
 (submitted: August 6, 2019)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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 ]
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Tolerability, Pharmacokinetics, and Efficacy of GS-4224 in Participants With Advanced Solid Tumors
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Advanced Solid Tumors
Intervention  ICMJE Drug: GS-4224
Tablets administered orally.
Study Arms  ICMJE 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.

Intervention: Drug: GS-4224
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: April 23, 2021)
18
Original Estimated Enrollment  ICMJE
 (submitted: August 6, 2019)
76
Actual Study Completion Date  ICMJE March 30, 2021
Actual Primary Completion Date March 30, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE New Zealand,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04049617
Other Study ID Numbers  ICMJE GS-US-494-5484
2019-004605-27 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Gilead Sciences
Study Sponsor  ICMJE Gilead Sciences
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Gilead Study Director Gilead Sciences
PRS Account Gilead Sciences
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP