Study of Dalutrafusp Alfa (Formerly GS-1423) in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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For Phase 1a Part A, the primary objectives are to assess safety and tolerability and to define the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of dalutrafusp alfa (formerly GS-1423) monotherapy in participants with advanced solid tumors. For Phase 1a Part B, the primary objective is to assess safety and tolerability of dalutrafusp alfa monotherapy in participants with advanced solid tumors. For Phase 1b Cohort 1 safety run-in, the primary objective is to assess safety and tolerability and to define the DLT and MTD or RP2D of dalutrafusp alfa in combination with a chemotherapy regimen in participants with advanced gastric or gastroesophageal junction adenocarcinoma. For Phase 1b Cohort 1 post safety run-in, the primary objective is to assess the preliminary efficacy of dalutrafusp alfa in combination with a chemotherapy regimen in participants with advanced gastric or gastroesophageal junction adenocarcinoma, as assessed by the confirmed objective response rate (ORR). For Phase 1b Cohort 2, the primary objective is to assess safety and tolerability of dalutrafusp alfa monotherapy in participants with advanced solid tumors.

Official Title
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A Phase 1a/1b Study of GS-1423, an Anti-CD73-TGFβ-Trap Bifunctional Antibody, as Monotherapy or in Combination With a Chemotherapy Regimen in Subjects With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: Dalutrafusp alfa
* Drug: mFOLFOX6 Regimen
* Drug: Dalutrafusp alfa


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis: For Phase 1a and Phase 1b Cohort 2, have a histologically or cytologically confirmed diagnosis of a locally advanced or metastatic solid tumor for which no standard therapy is available (per local guidance) or standard therapy has failed, or For Phase 1b Cohort 1, have histologically or cytologically confirmed unresectable, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma who have not previously received systemic therapy for advanced disease Measurable disease: Have measurable disease on imaging based on Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 Have a life expectancy of at least 3 months and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Key Exclusion Criteria: Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 3 weeks of the first dose of treatment Has persisting toxicity related to prior therapy of National Cancer Institute-Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE) Grade >1 severity Is expected to require any other form of systemic or localized anticancer therapy while on trial (including maintenance therapy with another agent, radiation therapy, and/or surgical resection) Has 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 Has a known central nervous system metastasis(es), unless metastases are treated and stable and the individual does not require systemic corticosteroids for management of CNS symptoms at least 7 days prior to study treatment. Individuals with history of carcinomatous meningitis are excluded regardless of clinical stability. Has active or history of autoimmune disease that has required systemic treatment within 2 years of the start of trial treatment Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a, Part A - Dose Escalation<br>Part A will consist of dose escalation by an accelerated dosing design and a 3+3 dose escalation scheme. Participants will receive escalating dose levels dalutrafusp alfa of up to 45 mg/kg on Day 1 of each 2-week cycle (Q2W) until the participant meets study treatment discontinuation criteria or for up to 1 year. | Drug: Dalutrafusp alfa<br>* Administered intravenously<br>* Other names: GS-1423;|
| Experimental: Phase 1a, Part B - Flat Dose Regimen<br>Part B will consist of 3 adaptive cohorts. Based on PK, pharmacodynamics, and safety results from the Part A study, participants will be administered a flat dose of dalutrafusp alfa on Day 1 of each cycle QW, Q2W and/or every 3 weeks (Q3W) until the participant meets study treatment discontinuation criteria or for up to 1 year. | Drug: Dalutrafusp alfa<br>* Administered intravenously<br>* Other names: GS-1423;|
| Experimental: Phase 1b, Cohort 1 (Gastric Cancer)<br>Safety run-in: A standard 3+3 dose escalation design will be used to determine the DLT and MTD or RP2D of dalutrafusp alfa in combination with mFOLFOX6. The planned starting dose of dalutrafusp alfa will be targeted to achieve the exposure at -1 dose of RP2D monotherapy (Q2W) determined from Phase 1a. Dalutrafusp alfa will be administered in combination with mFOLFOX6. Post safety run-in: Approximately 70 participants will be enrolled to receive dalutrafusp alfa at the dose level determined from the safety run-in period, in combination with mFOLFOX6 regimen. Participants will receive dalutrafusp alfa on Day 1 of each 14-day cycle up to 2 years until PD, or unacceptable toxicity, substantial noncompliance with study procedures or study drug, study discontinuation or withdrawal from study. Participants will also receive mFOLFOX6 regimen Q2W for up to 12 cycles. | Drug: Dalutrafusp alfa<br>* Administered intravenously<br>* Other names: GS-1423;Drug: mFOLFOX6 Regimen<br>* Chemotherapy regimen of oxaliplatin, 5-fluorouracil [5-FU], and leucovorin<br>|
| Experimental: Phase 1b, Cohort 2 (Paired Biopsy)<br>Participants will receive dalutrafusp alfa at the dose level determined from Phase 1a Q2W until the participants meets study treatment discontinuation criteria or for up to 1 year. | Drug: Dalutrafusp alfa<br>* Administered intravenously<br>* Other names: GS-1423;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a Part A: Percentage of Participants Experiencing Dose Limiting Toxicities (DLTs), Graded Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0) | DLT was defined as: Grade 3 thrombocytopenia with bleeding; Grade ≥ 3 febrile neutropenia; any Grade 4 hematologic laboratory abnormalities/adverse events (AEs) (except Grade 4 lymphopenia and anaemia, Grade 4 neutropenia lasting ≤ 7 days with no fever); Grade 4 non-hematologic AEs; any ≥Grade 2 uveitis, blurred vision, eye pain, and/or reduction of visual acuity that did not respond to topical therapy and did not improve to Grade 1 severity within 2 weeks of topical therapy initiation or required systemic treatment; Grade 3 non-hematologic AEs; any other non-immune-related Grade 3 AE (except any Grade 3 endocrinopathy; Grade 3 AE of tumor flare; transient [≤ 3 days] Grade 3 fatigue, local reactions, headache, nausea, emesis, or diarrhea and/or resolved to Grade ≤ 1; transient Grade 3 flu-like symptoms or fever); inability to receive first 2 doses of GS-1423 or > 2-week delay in starting next cycle of therapy due to a treatment-related toxicity; Grade 5 event (death). | Baseline up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a Part A: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | An AE was any untoward medical occurrence in a participant administered the study drug, which did not necessarily have a causal relationship with the treatment. An AE could therefore, be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. Adverse events might also include pretreatment or posttreatment complications that occurred as a result of protocol-specified procedures or special situations. Preexisting events that increased in severity or change in nature during or as a consequence of participation in the study were also considered AEs. TEAEs were AEs with onset dates on or after the first dose of study drug GS-1423 and up to 30 days after permanent withdrawal of GS-1423. | First dose date up to permanent withdrawal of GS-1423 (maximum duration: 26.3 weeks) plus 30 days | 
| Phase 1a Part A: Percentage of Participants With Treatment-Emergent Grade 3 or 4 Laboratory Abnormalities | Severity was graded per NCI CTCAE v5.0. Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe, Grade 4: Life-threatening or disabling, Grade 5: Death related to AE. | First dose date up to permanent withdrawal of GS-1423 (maximum duration: 26.3 weeks) plus 30 days | 
| Phase 1a Part A: Percentage of Participants With Shift in Clinically Significant Abnormal 12-Lead Electrocardiogram (ECG) From Baseline to Overall Study | The Baseline value was the last available value collected on or prior to first dose of study drug. Percentages were based on participants with values available at both baseline and postbaseline. NCS = Non-clinical significance; CS = Clinical significance. | First dose date up to permanent withdrawal of GS-1423 (maximum duration: 26.3 weeks) plus 30 days | 
| Phase 1a Part A: Pharmacokinetic (PK) Parameter: AUCtau of GS-1423 | AUCtau was defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). | Cycle 1 and Cycle 4: Day 1 (Predose, end of infusion, 2 and 6 hours post start of infusion); Days 2, 3, 5, and 8 (additionally at Day 15 in Cycle 4) | 
| Phase 1a Part A: Percentage of Participants Who Developed Anti-Drug Antibodies (ADAs) |  | Baseline, during the treatment (maximum duration: 26.3 weeks), Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 4 Day 15, Cycle 6 Day 1, 30-day follow-up (30 days after discontinuation of GS-1423), post treatment follow-up (3 months) |