Advanced Solid Tumors
Conditions
Brief summary
The primary objectives of this study are to characterize the safety and tolerability of evixapodlin (formerly GS-4224) and to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of evixapodlin in participants with advanced solid tumors.
Detailed description
This was a planned Phase 1/2 study. However, Phase 2 was not conducted because the study was closed due to sponsor decision prior to opening the dose expansion cohort and hence, RP2D analysis was not performed.
Interventions
DRUGEvixapodlin
Tablets administered orally.
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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 twice a day (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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase | Day 1 through Day 21 | A DLT was 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 evixapodlin * 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
| Measure | Time frame | Description |
|---|---|---|
| PK Parameter: Cmax of Evixapodlin During the Dose Escalation Phase | Intensive PK: Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose (400-1500 QD mg cohorts) on C1D1 & D15 | Cmax was defined as the maximum observed drug concentration. |
| PK Parameter: Ctrough of Evixapodlin During the Dose Escalation Phase | Intensive PK: Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose (400-1500 QD mg cohorts) on C1D1 & D15 | Ctrough is defined as the observed concentration at the end of the dosing interval. |
| Pharmacokinetic (PK) Parameter: AUCtau of Evixapodlin During the Dose Escalation Phase | Intensive PK: Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 hours (h) postdose (400-1500 once daily [QD] mg cohorts) on Cycle (C) 1 Day (D) 1 & D15 | AUCtau was defined as area under the concentration-time curve from time zero to the end of the dosing interval. |
| Percentage of Participants Experiencing ≥ Grade 3 Treatment-Emergent Adverse Events During the Dose Expansion Phase | 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 | First dose date through end of treatment plus 30 days, approximately 5 years | — |
| PK Parameter: Tmax of Evixapodlin During the Dose Escalation Phase | Intensive PK: Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose (400-1500 QD mg cohorts) on C1D1 & D15 | Tmax is defined as the time to maximum observed concentration. |
Countries
New Zealand, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in New Zealand and the United States. The first participant was screened on 26 August 2019. The last study visit occurred on 30 March 2021.
Pre-assignment details
29 participants were screened. The participants took part in the Phase 1 (Dose Escalation) of the study only. No participants were enrolled in the Phase 1 Cohort 5 and Cohort 2 substudy and the study was terminated due to sponsor decision before the planned Dose Expansion Phase 2 started.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Evixapodlin 400 mg (Phase 1) Participants received evixapodlin 400 mg once daily for 21 days of each cycle (observed maximum duration was approximately 21 weeks). | 3 |
| Cohort 2: Evixapodlin 700 mg (Phase 1) Participants received evixapodlin 700 mg once daily for 21 days of each cycle (observed maximum duration was approximately 10 weeks). | 3 |
| Cohort 3: Evixapodlin 1000 mg (Phase 1) Participants received evixapodlin 1000 mg once daily for 21 days of each cycle (observed maximum duration was approximately 39 weeks). | 6 |
| Cohort 4: Evixapodlin 1500 mg (Phase 1) Participants received evixapodlin 1500 mg once daily for 21 days of each cycle (observed maximum duration was approximately 19 weeks). | 3 |
| Cohort 1 Substudy: Evixapodlin 400 mg (Phase 1) Participants received evixapodlin 400 mg once daily for 21 days of each cycle (observed maximum duration was approximately 39 weeks). | 2 |
| Cohort 3 Substudy: Evixapodlin 1000 mg (Phase 1) Participants received evixapodlin 1000 mg once daily for 21 days of each cycle (observed maximum duration was approximately 10 weeks). | 1 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrew consent | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Cohort 1: Evixapodlin 400 mg (Phase 1) | Cohort 2: Evixapodlin 700 mg (Phase 1) | Cohort 3: Evixapodlin 1000 mg (Phase 1) | Cohort 4: Evixapodlin 1500 mg (Phase 1) | Cohort 1 Substudy: Evixapodlin 400 mg (Phase 1) | Cohort 3 Substudy: Evixapodlin 1000 mg (Phase 1) | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 55.3 years STANDARD_DEVIATION 28.29 | 65.3 years STANDARD_DEVIATION 15.53 | 61.2 years STANDARD_DEVIATION 5.67 | 70.0 years STANDARD_DEVIATION 11.53 | 64.0 years STANDARD_DEVIATION 12.73 | 42.0 years | 61.6 years STANDARD_DEVIATION 14.23 |
| Race/Ethnicity, Customized Ethnicity | NA Participants | NA Participants | NA Participants | NA Participants | NA Participants | NA Participants | NA Participants |
| Race/Ethnicity, Customized Race | NA Participants | NA Participants | NA Participants | NA Participants | NA Participants | NA Participants | NA Participants |
| Region of Enrollment New Zealand | 1 participants | 2 participants | 5 participants | 2 participants | 2 participants | 0 participants | 12 participants |
| Region of Enrollment United States | 2 participants | 1 participants | 1 participants | 1 participants | 0 participants | 1 participants | 6 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 4 Participants | 3 Participants | 2 Participants | 1 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 3 | 0 / 2 | 1 / 1 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 6 / 6 | 3 / 3 | 2 / 2 | 0 / 1 |
| serious Total, serious adverse events | 0 / 3 | 1 / 3 | 1 / 6 | 1 / 3 | 0 / 2 | 1 / 1 |
Outcome results
Primary
Number of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase
A DLT was 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 evixapodlin * 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
Time frame: Day 1 through Day 21
Population: Safety Analysis Set included data from all participants who received at least 1 dose of study treatment, with treatment assignments designated according to the actual treatment received.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Evixapodlin 400 mg (Phase 1) | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase | 0 Participants |
| Cohort 2: Evixapodlin 700 mg (Phase 1) | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase | 0 Participants |
| Cohort 3: Evixapodlin 1000 mg (Phase 1) | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase | 0 Participants |
| Cohort 4: Evixapodlin 1500 mg (Phase 1) | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase | 1 Participants |
| Cohort 1 Substudy: Evixapodlin 400 mg (Phase 1) | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase | 0 Participants |
| Cohort 3 Substudy: Evixapodlin 1000 mg (Phase 1) | Number of Participants Experiencing Dose Limiting Toxicities (DLTs) During the Dose Escalation Phase | 0 Participants |
Secondary
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
Population: The study was closed due to sponsor decision prior to opening the dose expansion phase. Hence, no participants were analyzed in this phase.
Secondary
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
Population: The study was closed due to sponsor decision prior to opening the dose expansion phase. Hence, no participants were analyzed in this phase.
Secondary
Pharmacokinetic (PK) Parameter: AUCtau of Evixapodlin During the Dose Escalation Phase
AUCtau was defined as area under the concentration-time curve from time zero to the end of the dosing interval.
Time frame: Intensive PK: Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 hours (h) postdose (400-1500 once daily [QD] mg cohorts) on Cycle (C) 1 Day (D) 1 & D15
Population: PK Analysis Set included participants in the Safety Analysis Set who had received the study drug and have at least 1 sample with detectable drug concentration. Data for Cohort 1 included participants from Cohort 1 and Substudy Cohort 1. PK data were not collected for Cohort 3 Substudy group due to discontinuation of the development program.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Evixapodlin 400 mg (Phase 1) | Pharmacokinetic (PK) Parameter: AUCtau of Evixapodlin During the Dose Escalation Phase | C1D1 | 6543.1 h*ng/mL | Standard Deviation 1783.07 |
| Cohort 1: Evixapodlin 400 mg (Phase 1) | Pharmacokinetic (PK) Parameter: AUCtau of Evixapodlin During the Dose Escalation Phase | C1D15 | 9269.8 h*ng/mL | Standard Deviation 2693.53 |
| Cohort 2: Evixapodlin 700 mg (Phase 1) | Pharmacokinetic (PK) Parameter: AUCtau of Evixapodlin During the Dose Escalation Phase | C1D15 | 13508.4 h*ng/mL | Standard Deviation 3126.8 |
| Cohort 2: Evixapodlin 700 mg (Phase 1) | Pharmacokinetic (PK) Parameter: AUCtau of Evixapodlin During the Dose Escalation Phase | C1D1 | 8703.8 h*ng/mL | Standard Deviation 3717.93 |
| Cohort 3: Evixapodlin 1000 mg (Phase 1) | Pharmacokinetic (PK) Parameter: AUCtau of Evixapodlin During the Dose Escalation Phase | C1D1 | 12241.8 h*ng/mL | Standard Deviation 2793.17 |
| Cohort 3: Evixapodlin 1000 mg (Phase 1) | Pharmacokinetic (PK) Parameter: AUCtau of Evixapodlin During the Dose Escalation Phase | C1D15 | 19380.8 h*ng/mL | Standard Deviation 5261.89 |
| Cohort 4: Evixapodlin 1500 mg (Phase 1) | Pharmacokinetic (PK) Parameter: AUCtau of Evixapodlin During the Dose Escalation Phase | C1D1 | 19132.6 h*ng/mL | Standard Deviation 596.64 |
| Cohort 4: Evixapodlin 1500 mg (Phase 1) | Pharmacokinetic (PK) Parameter: AUCtau of Evixapodlin During the Dose Escalation Phase | C1D15 | 27664.5 h*ng/mL | Standard Deviation 7758.37 |
Secondary
PK Parameter: Cmax of Evixapodlin During the Dose Escalation Phase
Cmax was defined as the maximum observed drug concentration.
Time frame: Intensive PK: Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose (400-1500 QD mg cohorts) on C1D1 & D15
Population: Participants in PK Analysis Set were analyzed. Data for Cohort 1 included participants from Cohort 1 and Substudy Cohort 1. PK data were not collected for Cohort 3 Substudy group due to discontinuation of the development program.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Evixapodlin 400 mg (Phase 1) | PK Parameter: Cmax of Evixapodlin During the Dose Escalation Phase | C1D1 | 1090.4 ng/mL | Standard Deviation 355.12 |
| Cohort 1: Evixapodlin 400 mg (Phase 1) | PK Parameter: Cmax of Evixapodlin During the Dose Escalation Phase | C1D15 | 1193.8 ng/mL | Standard Deviation 605.87 |
| Cohort 2: Evixapodlin 700 mg (Phase 1) | PK Parameter: Cmax of Evixapodlin During the Dose Escalation Phase | C1D15 | 1580.0 ng/mL | Standard Deviation 245.76 |
| Cohort 2: Evixapodlin 700 mg (Phase 1) | PK Parameter: Cmax of Evixapodlin During the Dose Escalation Phase | C1D1 | 1468.7 ng/mL | Standard Deviation 497.74 |
| Cohort 3: Evixapodlin 1000 mg (Phase 1) | PK Parameter: Cmax of Evixapodlin During the Dose Escalation Phase | C1D1 | 1918.3 ng/mL | Standard Deviation 377.59 |
| Cohort 3: Evixapodlin 1000 mg (Phase 1) | PK Parameter: Cmax of Evixapodlin During the Dose Escalation Phase | C1D15 | 2051.7 ng/mL | Standard Deviation 686.89 |
| Cohort 4: Evixapodlin 1500 mg (Phase 1) | PK Parameter: Cmax of Evixapodlin During the Dose Escalation Phase | C1D1 | 2116.7 ng/mL | Standard Deviation 55.08 |
| Cohort 4: Evixapodlin 1500 mg (Phase 1) | PK Parameter: Cmax of Evixapodlin During the Dose Escalation Phase | C1D15 | 2480.0 ng/mL | Standard Deviation 278.75 |
Secondary
PK Parameter: Ctrough of Evixapodlin During the Dose Escalation Phase
Ctrough is defined as the observed concentration at the end of the dosing interval.
Time frame: Intensive PK: Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose (400-1500 QD mg cohorts) on C1D1 & D15
Population: Participants in the PK Analysis Set were analyzed. Data for Cohort 1 included participants from Cohort 1 and Substudy Cohort 1. PK data were not collected for Cohort 3 Substudy group due to discontinuation of the development program.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Evixapodlin 400 mg (Phase 1) | PK Parameter: Ctrough of Evixapodlin During the Dose Escalation Phase | C1D1 | 40.3 ng/mL | Standard Deviation 9.8 |
| Cohort 1: Evixapodlin 400 mg (Phase 1) | PK Parameter: Ctrough of Evixapodlin During the Dose Escalation Phase | C1D15 | 109.8 ng/mL | Standard Deviation 35.61 |
| Cohort 2: Evixapodlin 700 mg (Phase 1) | PK Parameter: Ctrough of Evixapodlin During the Dose Escalation Phase | C1D15 | 198.7 ng/mL | Standard Deviation 57.98 |
| Cohort 2: Evixapodlin 700 mg (Phase 1) | PK Parameter: Ctrough of Evixapodlin During the Dose Escalation Phase | C1D1 | 56.2 ng/mL | Standard Deviation 18.05 |
| Cohort 3: Evixapodlin 1000 mg (Phase 1) | PK Parameter: Ctrough of Evixapodlin During the Dose Escalation Phase | C1D1 | 111.9 ng/mL | Standard Deviation 43.92 |
| Cohort 3: Evixapodlin 1000 mg (Phase 1) | PK Parameter: Ctrough of Evixapodlin During the Dose Escalation Phase | C1D15 | 318.5 ng/mL | Standard Deviation 88.44 |
| Cohort 4: Evixapodlin 1500 mg (Phase 1) | PK Parameter: Ctrough of Evixapodlin During the Dose Escalation Phase | C1D1 | 180.3 ng/mL | Standard Deviation 21.5 |
| Cohort 4: Evixapodlin 1500 mg (Phase 1) | PK Parameter: Ctrough of Evixapodlin During the Dose Escalation Phase | C1D15 | 472.7 ng/mL | Standard Deviation 112.88 |
Secondary
PK Parameter: Tmax of Evixapodlin During the Dose Escalation Phase
Tmax is defined as the time to maximum observed concentration.
Time frame: Intensive PK: Predose, 0.5, 1, 1.5, 2.5, 4, 6, 24 h postdose (400-1500 QD mg cohorts) on C1D1 & D15
Population: Participants in PK Analysis Set were analyzed. Data for Cohort 1 included participants from Cohort 1 and Substudy Cohort 1. PK data were not collected for Cohort 3 Substudy group due to discontinuation of the development program.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1: Evixapodlin 400 mg (Phase 1) | PK Parameter: Tmax of Evixapodlin During the Dose Escalation Phase | C1D1 | 1.00 hours |
| Cohort 1: Evixapodlin 400 mg (Phase 1) | PK Parameter: Tmax of Evixapodlin During the Dose Escalation Phase | C1D15 | 1.50 hours |
| Cohort 2: Evixapodlin 700 mg (Phase 1) | PK Parameter: Tmax of Evixapodlin During the Dose Escalation Phase | C1D15 | 1.50 hours |
| Cohort 2: Evixapodlin 700 mg (Phase 1) | PK Parameter: Tmax of Evixapodlin During the Dose Escalation Phase | C1D1 | 1.53 hours |
| Cohort 3: Evixapodlin 1000 mg (Phase 1) | PK Parameter: Tmax of Evixapodlin During the Dose Escalation Phase | C1D1 | 1.52 hours |
| Cohort 3: Evixapodlin 1000 mg (Phase 1) | PK Parameter: Tmax of Evixapodlin During the Dose Escalation Phase | C1D15 | 1.51 hours |
| Cohort 4: Evixapodlin 1500 mg (Phase 1) | PK Parameter: Tmax of Evixapodlin During the Dose Escalation Phase | C1D1 | 2.50 hours |
| Cohort 4: Evixapodlin 1500 mg (Phase 1) | PK Parameter: Tmax of Evixapodlin During the Dose Escalation Phase | C1D15 | 4.00 hours |