Advanced Solid Tumors
Conditions
Brief summary
This study is planned to be conducted in 2 parts: Part 1: Dose Escalation and Part 2: Safety Run-In and Randomized Expansion. The primary objectives of Part 1 are 1) To characterize the safety and tolerability of GS-3583 as monotherapy in participants with advanced solid tumors. 2) To determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of GS-3583 as monotherapy in participants with advanced solid tumors. The primary objectives of Part 2 is to assess the safety and tolerability and to determine the RP2D of GS-3583 in combination with zimberelimab (ZIM) and platinum (cisplatin or carboplatin) + 5-fluorouracil (5-FU) chemotherapy in participants with head and neck squamous cell carcinoma (HNSCC) (Cohort A) or in combination with docetaxel in participants with non-small cell lung cancer (NSCLC) (Cohort B).
Interventions
DRUGGS-3583
Administered as an intravenous (IV) infusion
DRUGZimberelimab
Administered as an IV infusion
DRUGCisplatin
Administered as an IV infusion
DRUGCarboplatin
Administered as an IV infusion
DRUG5-Fluorouracil
Administered as an IV infusion
DRUGDocetaxel
Administered as an IV infusion
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: * Histologically or cytologically confirmed locally advanced or metastatic malignant solid tumor that is refractory to or intolerant of standard therapy or for which no standard therapy is available * Have measurable disease on imaging based on Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) * Eastern Cooperative oncology Group (ECOG) performance status of ≤ 2 * Life expectancy of ≥ 3 months, in the opinion of the investigator * Adequate organ function as assessed by hematological, renal, and hepatic parameters, and no clinically significant coagulopathy Key
Exclusion criteria
* Received prior systemic cytotoxic chemotherapy, biological therapy, radiotherapy, or major surgery within 3 weeks of Cycle 1 Day 1; a 1-week washout is permitted for palliative radiation to non-central nervous system (CNS) disease with sponsor approval * Known severe hypersensitivity reactions (NCI CTCAE Grade ≥ 3) to fully human monoclonal antibodies or fusion proteins, GS-3583 formulation excipients, or severe reaction to immuno-oncology agents, such as colitis or pneumonitis requiring treatment with corticosteroids, any history of anaphylaxis, or uncontrolled asthma * Concurrent active malignancy other than nonmelanoma skin cancer, carcinoma in situ of the cervix, or superficial bladder cancer who has undergone potentially curative therapy with no evidence of disease. Individuals with other previous malignancies are eligible if disease free for \> 2 years. * Previous history of hematological malignancy, monoclonal gammopathy of unknown significance (MGUS) or other preleukemic states (Presence of clonal hematopoiesis of indeterminate potential (CHIP)/age related clonal hematopoiesis (ARCH) is acceptable) * Known CNS metastasis(es), unless metastases are treated and stable and the individual does not require systemic corticosteroids for management of CNS symptoms at least 1 week prior to study treatment. Individuals with history of carcinomatous meningitis are excluded regardless of clinical stability. * Active or history of autoimmune disease that has required systemic treatment within 2 years of the start of study treatment (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) * Note: Individuals with diabetes type 1, vitiligo, psoriasis, hypothyroid disease, or hyperthyroid disease, not requiring immunosuppressive treatment are eligible. Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Parts 1 and 2: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | Part 1: Day 1 through Day 28; Part 2: Day 1 through Day 21 | DLT was defined as any toxicity (hematologic, non-hematologic, dosing/procedures-related toxicities, or grade 5 event (ie death)) occurring with GS-3583 monotherapy during the DLT assessment period (from Day 1 up to Day 28) considered at least possibly related to GS-3583 monotherapy. |
| Parts 1 and 2: Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | First dose date up to last dose date plus 90 days (Up to 4 months) | TEAEs were AEs with onset dates on or after the first dose and up to 90 days after the date of the last dose of study treatment or the day before initiation of subsequent therapy, whichever occurred first. TEAEs severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. Participants were counted at the highest AE grade experienced. |
| Parts 1 and 2: Percentage of Participants With Laboratory Abnormalities According to the NCI CTCAE Version 5.0 | First dose date up to last dose date plus 90 days (Up to 4 months) | A treatment-emergent laboratory abnormality was defined as an increase of at least 1 toxicity grade from baseline at any time, up to 90 days after the last dose of study drug or the day before initiation of subsequent therapy, whichever occurred first. A treatment-emergent laboratory abnormality severity was graded according to the NCI CTCAE version 5.0. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. Participants were counted at the highest AE grade experienced. |
| Parts 1 and 2: Percentage of Participants With GS-3583 Anti-drug Antibodies (ADAs) at Any Visit | Cycles 1and 3,pre-dose,End of Infusion (EOI);2,6 hours;Days 2,3,5,8,15 post Day 1EOI;Day 15:Cycle 1:predose and EOI;2 hours post EOI;Cycle 3:336 hours and Day 24 post EOI(Cycle length = 28 days in Part 1; 21 days for Part 2;infusion duration=60 minutes) | Participants were monitored for the development of ADAs throughout their treatment period with GS-3583 and at the end of study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Progression-free Survival (PFS) | First dose date in Part 2 to End of Study (approximately 4.2 months) | PFS is defined as the time from first dose date until first date of disease progression (PD) or death from any cause, whichever comes first as measured per RECIST V1.1 as assessed by the investigator. Per RECIST V1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Part 2: Duration of Response (DOR) | First dose date in Part 2 to End of Study (approximately 4.2 months) | DOR was defined as time of first response (CR or PR) per RECIST V1.1 as assessed by the investigator until the date of first documented disease progression or death, whichever comes first. Per RECIST V1.1, CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Part 2: Overall Survival (OS) | First dose date in Part 2 to End of Study (approximately 4.2 months) | Overall survival is defined as the time from randomization until death from any cause. |
| Part 1: Pharmacokinetic (PK) Parameter: AUCtau of GS-3583 | Cycles 1 and 3, pre-dose, EOI; 2, 6 hours; Days 2, 3, 5, 8, 15 post Day 1 EOI; Day 15:Cycle 1:predose and EOI; 2 hours post EOI;Cycle 3:336 hours and Day 24 post EOI (Cycle length for all cycles=28 days in Part 1; Infusion duration=60 minutes) | AUCtau is defined as the area under the concentration versus time curve over the dosing interval where tau = 15 days. |
| Part 2: PK Parameters: Cmax for GS-3583 | Safety-run In:Cycles 1 and 3: Day 1, predose, EOI; 2, 6 hours, Days 8, 15; Part 2 all arms:Cycles 2 and 5: Day 1 predose, EOI and every odd cycles; 60-day FU; (Cycle length of all cycles = 21 days in Part 2; Infusion duration=60 minutes) | Cmax is defined as the maximum observed serum concentration of drug. |
| Part 2: PK Parameter: Tmax for GS-3583 | Safety-run In: Cycles 1, and 3: Day 1, predose, EOI; 2, 6 hours, Days 8, Day 15; Part 2: all arms: Cycles 2 and 5: Day 1 predose, EOI and every odd cycles; 6-day FU; (Cycle length of all cycles = 21 days in Part 2; Infusion duration=60 minutes) | Tmax is defined as the time (observed time point) of the occurrence of Cmax. |
| Part 2: PK Parameter: AUCtau of GS-3583 | Safety-run In: Cycles 1, and 3: Day 1, predose, EOI; 2, 6 hours, Days 8, Day 15; Part 2: all arms: Cycles 2 and 5: Day 1 predose, EOI and every odd cycles; 6-day FU; (Cycle length of all cycles = 21 days in Part 2; Infusion duration=60 minutes) | AUCtau is defined as the area under the concentration versus time curve over the dosing interval. |
| Part 2: Disease Control Rate (DCR) | First dose date in Part 2 to End of Study (approximately 4.2 months) | DCR was defined as percentage of participants with a best overall confirmed response of CR or PR or stable disease. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. |
| Part 1: PK Parameter: Cmax of GS-3583 | Cycles 1 and 3,pre-dose,EOI;2, 6 hours;Days 2, 3, 5, 8, 15 post Day 1 EOI;Day 15:Cycle 1:predose and EOI;2 hours post EOI;Cycle 3:336 hours and Day 24 post EOI (Cycle length for all cycles=28 days in Part 1;Infusion duration=60 minutes) | Cmax is defined as the maximum observed plasma concentration. |
| Part 1: PK Parameter: Tmax of GS-3583 | Cycles 1 and 3, pre-dose, EOI; 2, 6 hours; Days 2, 3, 5, 8, 15 post Day 1 EOI; Day 15:Cycle 1:predose and EOI; 2 hours post EOI; Cycle 3:336 hours and Day 24 post EOI (Cycle length for all cycles=28 days in Part 1; infusion duration=60 minutes) | Tmax is defined as the time to reach maximum observed plasma concentration (Tmax). |
| Part 2: Confirmed Objective Response Rate (ORR) | First dose date in Part 2 to End of Study (approximately 4.2 months) | Confirmed ORR is defined as the percentage of participants who have achieved confirmed CR or PR according to RECIST V1.1 and assessed by the investigator. Per RECIST V1.1, CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled at study sites in the United States. This study was planned to be conducted in 2 parts: Part 1: Dose Escalation Part and Part 2: Safety Run-In and Randomized Expansion Part. Due to early termination of the study, Part 2 was not conducted. Results are reported only for Part 1 of the study.
Pre-assignment details
22 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Cohort 2: GS-3583 2000 μg Participants received GS-3583 2000 μg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 13 cycles (up to 52 weeks) or until the participant meets study treatment discontinuation criteria. | 3 |
| Part 1: Cohort 3: GS-3583 6000 μg Participants received GS-3583 6000 μg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 13 cycles (up to 52 weeks) or until the participant meets study treatment discontinuation criteria. | 3 |
| Part 1: Cohort 4: GS-3583 12000 μg Participants received GS-3583 12000 μg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 13 cycles (up to 52 weeks) or until the participant meets study treatment discontinuation criteria. | 3 |
| Part 1: Cohort 5: GS-3583 20000 μg Participants received GS-3583 20000 μg on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 13 cycles (up to 52 weeks) or until the participant meets study treatment discontinuation criteria. | 4 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 3 | 2 | 2 | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Study Terminated by Sponsor | 0 | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrew Consent | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Part 1: Cohort 2: GS-3583 2000 μg | Part 1: Cohort 3: GS-3583 6000 μg | Part 1: Cohort 4: GS-3583 12000 μg | Part 1: Cohort 5: GS-3583 20000 μg |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 3 Participants | 2 Participants | 1 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants |
| Age, Continuous | 66 years STANDARD_DEVIATION 11.8 | 72 years STANDARD_DEVIATION 1.2 | 63 years STANDARD_DEVIATION 17.6 | 58 years STANDARD_DEVIATION 15.3 | 70 years STANDARD_DEVIATION 7.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 3 Participants | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 3 Participants | 3 Participants | 3 Participants | 3 Participants |
| Region of Enrollment United States | 13 participants | 3 participants | 3 participants | 3 participants | 4 participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 3 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 7 Participants | 1 Participants | 0 Participants | 3 Participants | 3 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 0 | 3 / 3 | 2 / 3 | 2 / 3 | 2 / 4 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| other Total, other adverse events | 0 / 0 | 3 / 3 | 3 / 3 | 3 / 3 | 4 / 4 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 2 / 3 | 1 / 3 | 2 / 3 | 1 / 4 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Parts 1 and 2: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)
DLT was defined as any toxicity (hematologic, non-hematologic, dosing/procedures-related toxicities, or grade 5 event (ie death)) occurring with GS-3583 monotherapy during the DLT assessment period (from Day 1 up to Day 28) considered at least possibly related to GS-3583 monotherapy.
Time frame: Part 1: Day 1 through Day 28; Part 2: Day 1 through Day 21
Population: DLT Evaluable Analysis Set included all participants who were enrolled for dose escalation, received all prescribed treatments and completed safety procedures through DLT assessment period (from Day 1 through Day 28 inclusive of the last day) or experienced a DLT prior to end of DLT assessment period as specified in protocol. No participants were enrolled in Part 2, so, data are reported for Part 1 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort 2: GS-3583 2000 μg | Parts 1 and 2: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 percentage of participants |
| Part 1: Cohort 3: GS-3583 6000 μg | Parts 1 and 2: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 percentage of participants |
| Part 1: Cohort 4: GS-3583 12000 μg | Parts 1 and 2: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 percentage of participants |
| Part 1: Cohort 5: GS-3583 20000 μg | Parts 1 and 2: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs) | 0 percentage of participants |
Primary
Parts 1 and 2: Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
TEAEs were AEs with onset dates on or after the first dose and up to 90 days after the date of the last dose of study treatment or the day before initiation of subsequent therapy, whichever occurred first. TEAEs severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. Participants were counted at the highest AE grade experienced.
Time frame: First dose date up to last dose date plus 90 days (Up to 4 months)
Population: The Safety Analysis Set included all the participants who received at least 1 dose of study drug. No participants were enrolled in Part 2, so, data are reported for Part 1 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort 2: GS-3583 2000 μg | Parts 1 and 2: Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | 100 percentage of participants |
| Part 1: Cohort 3: GS-3583 6000 μg | Parts 1 and 2: Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | 100 percentage of participants |
| Part 1: Cohort 4: GS-3583 12000 μg | Parts 1 and 2: Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | 100 percentage of participants |
| Part 1: Cohort 5: GS-3583 20000 μg | Parts 1 and 2: Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 | 100 percentage of participants |
Primary
Parts 1 and 2: Percentage of Participants With GS-3583 Anti-drug Antibodies (ADAs) at Any Visit
Participants were monitored for the development of ADAs throughout their treatment period with GS-3583 and at the end of study.
Time frame: Cycles 1and 3,pre-dose,End of Infusion (EOI);2,6 hours;Days 2,3,5,8,15 post Day 1EOI;Day 15:Cycle 1:predose and EOI;2 hours post EOI;Cycle 3:336 hours and Day 24 post EOI(Cycle length = 28 days in Part 1; 21 days for Part 2;infusion duration=60 minutes)
Population: Immunogenicity Analysis Set included all enrolled participants who received at least 1 dose of study drug and have at least 1 non-missing ADA test result. No participants were enrolled in Part 2, so, data are reported for Part 1 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort 2: GS-3583 2000 μg | Parts 1 and 2: Percentage of Participants With GS-3583 Anti-drug Antibodies (ADAs) at Any Visit | 33.3 percentage of participants |
| Part 1: Cohort 3: GS-3583 6000 μg | Parts 1 and 2: Percentage of Participants With GS-3583 Anti-drug Antibodies (ADAs) at Any Visit | 33.3 percentage of participants |
| Part 1: Cohort 4: GS-3583 12000 μg | Parts 1 and 2: Percentage of Participants With GS-3583 Anti-drug Antibodies (ADAs) at Any Visit | 0 percentage of participants |
| Part 1: Cohort 5: GS-3583 20000 μg | Parts 1 and 2: Percentage of Participants With GS-3583 Anti-drug Antibodies (ADAs) at Any Visit | 0 percentage of participants |
Primary
Parts 1 and 2: Percentage of Participants With Laboratory Abnormalities According to the NCI CTCAE Version 5.0
A treatment-emergent laboratory abnormality was defined as an increase of at least 1 toxicity grade from baseline at any time, up to 90 days after the last dose of study drug or the day before initiation of subsequent therapy, whichever occurred first. A treatment-emergent laboratory abnormality severity was graded according to the NCI CTCAE version 5.0. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life-threatening; Grade 5: Fatal. Participants were counted at the highest AE grade experienced.
Time frame: First dose date up to last dose date plus 90 days (Up to 4 months)
Population: The Safety Analysis Set will include all participants who received at least 1 dose of study drug. No participants were enrolled in Part 2, so, data are reported for Part 1 only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Cohort 2: GS-3583 2000 μg | Parts 1 and 2: Percentage of Participants With Laboratory Abnormalities According to the NCI CTCAE Version 5.0 | 100 percentage of participants |
| Part 1: Cohort 3: GS-3583 6000 μg | Parts 1 and 2: Percentage of Participants With Laboratory Abnormalities According to the NCI CTCAE Version 5.0 | 100 percentage of participants |
| Part 1: Cohort 4: GS-3583 12000 μg | Parts 1 and 2: Percentage of Participants With Laboratory Abnormalities According to the NCI CTCAE Version 5.0 | 100 percentage of participants |
| Part 1: Cohort 5: GS-3583 20000 μg | Parts 1 and 2: Percentage of Participants With Laboratory Abnormalities According to the NCI CTCAE Version 5.0 | 100 percentage of participants |
Secondary
Part 1: Pharmacokinetic (PK) Parameter: AUCtau of GS-3583
AUCtau is defined as the area under the concentration versus time curve over the dosing interval where tau = 15 days.
Time frame: Cycles 1 and 3, pre-dose, EOI; 2, 6 hours; Days 2, 3, 5, 8, 15 post Day 1 EOI; Day 15:Cycle 1:predose and EOI; 2 hours post EOI;Cycle 3:336 hours and Day 24 post EOI (Cycle length for all cycles=28 days in Part 1; Infusion duration=60 minutes)
Population: The PK Analysis Set included all enrolled participants who received at least 1 dose of study drug and have at least 1 non-missing postdose concentration value reported by the PK laboratory. Data for Cycle 3 is not reported due to participant's confidentiality reasons, as there was only 1 or 2 participants in each of these groups during Cycle 3.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort 2: GS-3583 2000 μg | Part 1: Pharmacokinetic (PK) Parameter: AUCtau of GS-3583 | Cycle 1 | 82100 h*ng/mL | Standard Deviation 19900 |
| Part 1: Cohort 3: GS-3583 6000 μg | Part 1: Pharmacokinetic (PK) Parameter: AUCtau of GS-3583 | Cycle 1 | 249000 h*ng/mL | Standard Deviation 124000 |
| Part 1: Cohort 4: GS-3583 12000 μg | Part 1: Pharmacokinetic (PK) Parameter: AUCtau of GS-3583 | Cycle 1 | 352000 h*ng/mL | Standard Deviation 41300 |
| Part 1: Cohort 5: GS-3583 20000 μg | Part 1: Pharmacokinetic (PK) Parameter: AUCtau of GS-3583 | Cycle 1 | 832000 h*ng/mL | Standard Deviation 223000 |
Secondary
Part 1: PK Parameter: Cmax of GS-3583
Cmax is defined as the maximum observed plasma concentration.
Time frame: Cycles 1 and 3,pre-dose,EOI;2, 6 hours;Days 2, 3, 5, 8, 15 post Day 1 EOI;Day 15:Cycle 1:predose and EOI;2 hours post EOI;Cycle 3:336 hours and Day 24 post EOI (Cycle length for all cycles=28 days in Part 1;Infusion duration=60 minutes)
Population: The PK Analysis Set included all enrolled participants who received at least 1 dose of study drug and have at least 1 non-missing postdose concentration value reported by the PK laboratory. Data for Cycle 3 is not reported due to participant's confidentiality reasons, as there was only 1 or 2 participants in each of these groups during Cycle 3.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Cohort 2: GS-3583 2000 μg | Part 1: PK Parameter: Cmax of GS-3583 | Cycle 1 | 643 ng/mL | Standard Deviation 36.3 |
| Part 1: Cohort 3: GS-3583 6000 μg | Part 1: PK Parameter: Cmax of GS-3583 | Cycle 1 | 1860 ng/mL | Standard Deviation 562 |
| Part 1: Cohort 4: GS-3583 12000 μg | Part 1: PK Parameter: Cmax of GS-3583 | Cycle 1 | 2520 ng/mL | Standard Deviation 244 |
| Part 1: Cohort 5: GS-3583 20000 μg | Part 1: PK Parameter: Cmax of GS-3583 | Cycle 1 | 5800 ng/mL | Standard Deviation 1460 |
Secondary
Part 1: PK Parameter: Tmax of GS-3583
Tmax is defined as the time to reach maximum observed plasma concentration (Tmax).
Time frame: Cycles 1 and 3, pre-dose, EOI; 2, 6 hours; Days 2, 3, 5, 8, 15 post Day 1 EOI; Day 15:Cycle 1:predose and EOI; 2 hours post EOI; Cycle 3:336 hours and Day 24 post EOI (Cycle length for all cycles=28 days in Part 1; infusion duration=60 minutes)
Population: The PK Analysis Set included all enrolled participants who received at least 1 dose of study drug and have at least 1 non-missing postdose concentration value reported by the PK laboratory. Data for Cycle 3 is not reported due to participant's confidentiality reasons, as there was only 1 or 2 participants in each of these groups during Cycle 3.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1: Cohort 2: GS-3583 2000 μg | Part 1: PK Parameter: Tmax of GS-3583 | Cycle 1 | 1.1 hours (h) |
| Part 1: Cohort 3: GS-3583 6000 μg | Part 1: PK Parameter: Tmax of GS-3583 | Cycle 1 | 2.0 hours (h) |
| Part 1: Cohort 4: GS-3583 12000 μg | Part 1: PK Parameter: Tmax of GS-3583 | Cycle 1 | 1.1 hours (h) |
| Part 1: Cohort 5: GS-3583 20000 μg | Part 1: PK Parameter: Tmax of GS-3583 | Cycle 1 | 1.7 hours (h) |
Secondary
Part 2: Confirmed Objective Response Rate (ORR)
Confirmed ORR is defined as the percentage of participants who have achieved confirmed CR or PR according to RECIST V1.1 and assessed by the investigator. Per RECIST V1.1, CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: First dose date in Part 2 to End of Study (approximately 4.2 months)
Population: No participants were enrolled in Part 2 of the study, so, data was not collected for this outcome measure.
Secondary
Part 2: Disease Control Rate (DCR)
DCR was defined as percentage of participants with a best overall confirmed response of CR or PR or stable disease. CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: First dose date in Part 2 to End of Study (approximately 4.2 months)
Population: No participants were enrolled in Part 2 of the study, so, data was not collected for this outcome measure.
Secondary
Part 2: Duration of Response (DOR)
DOR was defined as time of first response (CR or PR) per RECIST V1.1 as assessed by the investigator until the date of first documented disease progression or death, whichever comes first. Per RECIST V1.1, CR is defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that was the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: First dose date in Part 2 to End of Study (approximately 4.2 months)
Population: No participants were enrolled in Part 2 of the study, so, data was not collected for this outcome measure.
Secondary
Part 2: Overall Survival (OS)
Overall survival is defined as the time from randomization until death from any cause.
Time frame: First dose date in Part 2 to End of Study (approximately 4.2 months)
Population: No participants were enrolled in Part 2 of the study, so, data was not collected for this outcome measure.
Secondary
Part 2: PK Parameter: AUCtau of GS-3583
AUCtau is defined as the area under the concentration versus time curve over the dosing interval.
Time frame: Safety-run In: Cycles 1, and 3: Day 1, predose, EOI; 2, 6 hours, Days 8, Day 15; Part 2: all arms: Cycles 2 and 5: Day 1 predose, EOI and every odd cycles; 6-day FU; (Cycle length of all cycles = 21 days in Part 2; Infusion duration=60 minutes)
Population: No participants were enrolled in Part 2 of the study, so, data was not collected for this outcome measure.
Secondary
Part 2: PK Parameters: Cmax for GS-3583
Cmax is defined as the maximum observed serum concentration of drug.
Time frame: Safety-run In:Cycles 1 and 3: Day 1, predose, EOI; 2, 6 hours, Days 8, 15; Part 2 all arms:Cycles 2 and 5: Day 1 predose, EOI and every odd cycles; 60-day FU; (Cycle length of all cycles = 21 days in Part 2; Infusion duration=60 minutes)
Population: No participants were enrolled in Part 2 of the study, so, data was not collected for this outcome measure.
Secondary
Part 2: PK Parameter: Tmax for GS-3583
Tmax is defined as the time (observed time point) of the occurrence of Cmax.
Time frame: Safety-run In: Cycles 1, and 3: Day 1, predose, EOI; 2, 6 hours, Days 8, Day 15; Part 2: all arms: Cycles 2 and 5: Day 1 predose, EOI and every odd cycles; 6-day FU; (Cycle length of all cycles = 21 days in Part 2; Infusion duration=60 minutes)
Population: No participants were enrolled in Part 2 of the study, so, data was not collected for this outcome measure.
Secondary
Part 2: Progression-free Survival (PFS)
PFS is defined as the time from first dose date until first date of disease progression (PD) or death from any cause, whichever comes first as measured per RECIST V1.1 as assessed by the investigator. Per RECIST V1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time frame: First dose date in Part 2 to End of Study (approximately 4.2 months)
Population: No participants were enrolled in Part 2 of the study, so, data was not collected for this outcome measure.