A Phase 1b Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of GS-3583, a FLT3 Agonist Fc Fusion Protein, in Subjects With Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- GS-3583
- Conditions
- Advanced Solid Tumors
- Sponsor
- Gilead Sciences
- Enrollment
- 13
- Locations
- 4
- Primary Endpoint
- Parts 1 and 2: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
Brief Summary
The primary objectives of this study are to characterize the safety and tolerability of GS-3583 as monotherapy, and to determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of GS-3583 as monotherapy in participants with advanced solid tumors.
Investigators
Eligibility Criteria
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
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/Exclusion criteria may apply.
Arms & Interventions
Part 1: Cohort 1: GS-3583 675 μg
Participants with advanced solid tumors will receive GS-3583 675 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 met study treatment discontinuation criteria.
Intervention: GS-3583
Part 1: Cohort 2: GS-3583 2000 μg
Participants with advanced solid tumors will receive 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 met study treatment discontinuation criteria.
Intervention: GS-3583
Part 1: Cohort 3: GS-3583 6000 μg
Participants with advanced solid tumors will receive 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 met study treatment discontinuation criteria.
Intervention: GS-3583
Part 1: Cohort 4: GS-3583 12000 μg
Participants with advanced solid tumors will receive 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 met study treatment discontinuation criteria.
Intervention: GS-3583
Part 1: Cohort 5: GS-3583 20000 μg
Participants with advanced solid tumors will receive 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 met study treatment discontinuation criteria.
Intervention: GS-3583
Part 2: Safety Run-In Cohort A: GS-3583 + Combination Anticancer Therapy
Participants with head and neck squamous cell carcinoma (HNSCC) will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under the curve 5 mg/mL/min on Day 1 of each 28- day cycle up to 6 cycles + 5-5-flourouracil (5-FU) 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: GS-3583
Part 2: Safety Run-In Cohort A: GS-3583 + Combination Anticancer Therapy
Participants with head and neck squamous cell carcinoma (HNSCC) will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under the curve 5 mg/mL/min on Day 1 of each 28- day cycle up to 6 cycles + 5-5-flourouracil (5-FU) 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: Zimberelimab
Part 2: Safety Run-In Cohort A: GS-3583 + Combination Anticancer Therapy
Participants with head and neck squamous cell carcinoma (HNSCC) will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under the curve 5 mg/mL/min on Day 1 of each 28- day cycle up to 6 cycles + 5-5-flourouracil (5-FU) 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: Cisplatin
Part 2: Safety Run-In Cohort A: GS-3583 + Combination Anticancer Therapy
Participants with head and neck squamous cell carcinoma (HNSCC) will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under the curve 5 mg/mL/min on Day 1 of each 28- day cycle up to 6 cycles + 5-5-flourouracil (5-FU) 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: Carboplatin
Part 2: Safety Run-In Cohort A: GS-3583 + Combination Anticancer Therapy
Participants with head and neck squamous cell carcinoma (HNSCC) will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under the curve 5 mg/mL/min on Day 1 of each 28- day cycle up to 6 cycles + 5-5-flourouracil (5-FU) 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: 5-Fluorouracil
Part 2: Safety Run-In Cohort B: GS-3583 + Combination Anticancer Therapy
Participants with non-small cell lung cancer (NSCLC) will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + docetaxel 75 mg/m\^2 on Day 1 of each 21-day cycle until 1 or more criteria for discontinuation are met.
Intervention: GS-3583
Part 2: Safety Run-In Cohort B: GS-3583 + Combination Anticancer Therapy
Participants with non-small cell lung cancer (NSCLC) will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + docetaxel 75 mg/m\^2 on Day 1 of each 21-day cycle until 1 or more criteria for discontinuation are met.
Intervention: Docetaxel
Part 2: Randomized Expansion Cohort A: GS-3583 + Combination Anticancer Therapy
Participants with HNSCC will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under the curve 5 mg/mL/min on Day 1 of each 21-day cycle up to 6 cycles + 5-FU 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: GS-3583
Part 2: Randomized Expansion Cohort A: GS-3583 + Combination Anticancer Therapy
Participants with HNSCC will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under the curve 5 mg/mL/min on Day 1 of each 21-day cycle up to 6 cycles + 5-FU 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: Zimberelimab
Part 2: Randomized Expansion Cohort A: GS-3583 + Combination Anticancer Therapy
Participants with HNSCC will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under the curve 5 mg/mL/min on Day 1 of each 21-day cycle up to 6 cycles + 5-FU 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: Cisplatin
Part 2: Randomized Expansion Cohort A: GS-3583 + Combination Anticancer Therapy
Participants with HNSCC will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under the curve 5 mg/mL/min on Day 1 of each 21-day cycle up to 6 cycles + 5-FU 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: Carboplatin
Part 2: Randomized Expansion Cohort A: GS-3583 + Combination Anticancer Therapy
Participants with HNSCC will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under the curve 5 mg/mL/min on Day 1 of each 21-day cycle up to 6 cycles + 5-FU 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: 5-Fluorouracil
Part 2: Randomized Expansion Cohort A: Combination Anticancer Therapy
Participants with HNSCC will receive ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under th e curve 5 mg/mL/min on Day 1 of each 21-day cycle up to 6 cycles + 5-FU 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: Zimberelimab
Part 2: Randomized Expansion Cohort A: Combination Anticancer Therapy
Participants with HNSCC will receive ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under th e curve 5 mg/mL/min on Day 1 of each 21-day cycle up to 6 cycles + 5-FU 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: Cisplatin
Part 2: Randomized Expansion Cohort A: Combination Anticancer Therapy
Participants with HNSCC will receive ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under th e curve 5 mg/mL/min on Day 1 of each 21-day cycle up to 6 cycles + 5-FU 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: Carboplatin
Part 2: Randomized Expansion Cohort A: Combination Anticancer Therapy
Participants with HNSCC will receive ZIM 360 mg, on Day 1 of each 21-day cycle up to 105 weeks + cisplatin 100 mg/m\^2 of BSA on Day 1 of each 21-day cycle up to 6 cycles + carboplatin area under th e curve 5 mg/mL/min on Day 1 of each 21-day cycle up to 6 cycles + 5-FU 1000 mg/m\^2 of BSA/day on Days 1 to 4 of 21-day cycle up to 6 cycles.
Intervention: 5-Fluorouracil
Part 2: Randomized Expansion Cohort B: GS-3583 + Combination Anticancer Therapy
Participants with NSCLC will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + docetaxel 75 mg/m\^2 on Day 1 of each 21-day cycle until 1 or more criteria for discontinuation are met.
Intervention: GS-3583
Part 2: Randomized Expansion Cohort B: GS-3583 + Combination Anticancer Therapy
Participants with NSCLC will receive GS-3583 at a dose determined in Part 1 on Day 1 of every 21-day cycles for up to 8 cycles + docetaxel 75 mg/m\^2 on Day 1 of each 21-day cycle until 1 or more criteria for discontinuation are met.
Intervention: Docetaxel
Part 2: Randomized Expansion Cohort B: Combination Anticancer Therapy
Participants with NSCLC will receive docetaxel 75 mg/m\^2 on Day 1 of each 21-day cycle until 1 or more criteria for discontinuation are met.
Intervention: Docetaxel
Outcomes
Primary Outcomes
Parts 1 and 2: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs)
Time Frame: 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
Time Frame: 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
Time Frame: 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
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)
Participants were monitored for the development of ADAs throughout their treatment period with GS-3583 and at the end of study.
Secondary Outcomes
- 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))
- 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))
- 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))
- 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))
- Part 2: Confirmed Objective Response Rate (ORR)(First dose date in Part 2 to End of Study (approximately 4.2 months))
- Part 2: Progression-free Survival (PFS)(First dose date in Part 2 to End of Study (approximately 4.2 months))
- Part 2: Duration of Response (DOR)(First dose date in Part 2 to End of Study (approximately 4.2 months))
- Part 2: Overall Survival (OS)(First dose date in Part 2 to End of Study (approximately 4.2 months))
- Part 2: Disease Control Rate (DCR)(First dose date in Part 2 to End of Study (approximately 4.2 months))
- 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))
- 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))