Description:
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.
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.
Terminated
Phase 1/Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| GS-4224 | GS-4224 |
| Name | Type | Description | Interventions |
|---|---|---|---|
| GS-4224 | Experimental | 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. |
|
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase |
| Time Frame: | Day 1 through Day 21 |
| Safety Issue: | |
| Description: | 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 |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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) |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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) |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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) |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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) |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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) |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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) |
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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) |
| Measure: | 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 |
| Safety Issue: | |
| Description: |
| Measure: | 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 |
| Safety Issue: | |
| Description: |
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Terminated |
| Lead Sponsor: | Gilead Sciences |
April 26, 2021