Study to Evaluate the Safety and Tolerability of Andecaliximab as Monotherapy and in Combination With Anti-Cancer Agents in Japanese Participants With Gastric or Gastroesophageal Junction Adenocarcinoma

Study Overview
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Brief Summary
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The primary objective of this study is to characterize the safety and tolerability of andecaliximab as monotherapy and in combination with anti-cancer agents in Japanese participants with inoperable advanced or recurrent gastric or recurrent gastroesophageal junction (GEJ) adenocarcinoma.

Official Title
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A Phase 1b Study to Evaluate the Safety and Tolerability of Andecaliximab (GS-5745) as Monotherapy and in Combination With Anti-Cancer Agents in Japanese Subjects With Gastric or Gastroesophageal Junction Adenocarcinoma

Conditions
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Gastric Adenocarcinoma

Intervention / Treatment
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* Drug: Andecaliximab
* Drug: S-1
* Drug: Cisplatin
* Drug: Oxaliplatin
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Must have been born in Japan and must not have lived outside of Japan for a period > 1 year in the 5 years prior to Day 1 Must be able to trace their maternal and paternal ancestry of parents and grandparents as ethnically Japanese Histologically confirmed inoperable advanced gastric adenocarcinoma (including adenocarcinoma of the GEJ) or relapsed gastric adenocarcinoma Cohorts 1, 2, and 3: Human Epidermal Growth Factor Receptor 2 (HER2)-negative tumor (primary tumor or metastatic lesion). Enrollment in Cohort 4 is not restricted by HER2 status (adults with HER2-positive, HER2-negative, or unknown HER2 status are eligible) Cohort 1: Prior antitumor therapy or cytotoxic chemotherapy is acceptable. Individuals who are not eligible to receive standard treatments should enroll on the study. Cohorts 2 and 3: Prior antitumor therapy or cytotoxic chemotherapy for metastatic disease is not acceptable. Individuals must be chemo-naive in the metastatic setting Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1 Adequate baseline organ function (within 28 days prior to Day 1) Coagulation: International Normalized Ratio (INR) ≤ 1.5 (unless receiving anticoagulation therapy) For females of childbearing potential, willingness to use a protocol-recommended method of contraception from the screening visit throughout the study treatment period and for defined periods following the last dose of andecaliximab and/or anti-cancer agent(s) For males of childbearing potential having intercourse with females of childbearing potential, willingness to use a protocol-recommended method of contraception from the start of andecaliximab, throughout the study treatment period, and for protocol defined periods following the last dose of andecaliximab and/or anti-cancer agent(s) Willingness to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions In addition to the applicable criteria above, participants in Cohort 4 must meet additional inclusion criteria to be eligible for participation in this study: Measurable gastric or GEJ adenocarcinoma Must have progressed on at least 1 prior systemic therapy or line of treatment for unresectable/metastatic disease. Activated partial thromboplastin (aPTT) ≤ 1.5 times the upper limit of normal Thyroid function tests should be within normal limits. Key Exclusion Criteria: History or evidence of a clinically significant disorder, condition, or disease that, in the opinion of the investigator and medical monitor would pose a risk to participant safety or interfere with the study evaluations, procedures, or completion Pregnant or lactating. Enrollment of lactating females after discontinuation of breastfeeding is not acceptable. Individuals with known central nervous system (CNS) metastases, unless metastases are treated and stable and the individual does not require systemic steroids Radiotherapy within 28 days of Day 1 Myocardial infarction, symptomatic congestive heart failure (New York Heart Association Classification > Class II), unstable angina, or serious uncontrolled cardiac arrhythmia within the last 6 months of Day 1 History of major surgery within 28 days of Day 1 Serious systemic fungal, bacterial, viral, or other infection that is not controlled or requires IV antibiotics Individuals known to be positive for human immunodeficiency virus (HIV), hepatitis C infection (per local standard diagnostic criteria), or acute or chronic hepatitis B infection (per local standard diagnostic criteria) In addition to the applicable criteria above, participants in Cohort 4 who meet any of the following exclusion criteria will not be enrolled in this study Have received only neoadjuvant or adjuvant therapy for gastric adenocarcinoma Prior treatment with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) agents, anti-programmed cell death protein 1 (anti PD-1) or anti-programmed cell death ligand 1 (anti-PD-L1) agents, anti-programmed cell death ligand 2 (anti-PD-L2) agents, anti-matrix metalloprotease (anti-MMP) agents, or other immunomodulatory therapies NOTE: Other protocol defined Inclusion/ Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 20 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: ADX<br>Participants will receive andecaliximab (ADX) 800 mg every 2 weeks on Days 1 and 15 of each 28-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug. | Drug: Andecaliximab<br>* Administered via intravenous (IV) infusion (approximately 30 minutes)<br>* Other names: GS-5745;|
| Experimental: Cohort 2: ADX + S-1 + Cisplatin<br>Participants will receive ADX 800 mg every 2 weeks on Days 1 and 15 of each 28-day treatment cycle in combination with S-1 orally twice daily plus cisplatin chemotherapy (dosage and regimen will be based on participant condition, investigator discretion, institutional practice, and/or the in-country label) until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug. | Drug: Andecaliximab<br>* Administered via intravenous (IV) infusion (approximately 30 minutes)<br>* Other names: GS-5745;Drug: S-1<br>* Administered orally<br>Drug: Cisplatin<br>* Administered via IV infusion on Day 8 of every 5 weeks<br>|
| Experimental: Cohort 3: ADX + S-1 + Oxaliplatin<br>Participants will receive ADX 1200 mg every 3 weeks on Day 1 of each 21-day treatment cycle in combination with chemotherapy (S-1 80 mg/day to 120 mg/day according to the body surface area orally twice daily for first 14 days of 21 day cycle plus oxaliplatin 100 mg/m^2) until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study. | Drug: Andecaliximab<br>* Administered via intravenous (IV) infusion (approximately 30 minutes)<br>* Other names: GS-5745;Drug: S-1<br>* Administered orally<br>Drug: Oxaliplatin<br>* Administered via IV infusion for over 2 hours on Day 1 of each 21-day cycle<br>|
| Experimental: Cohort 4: ADX + Nivolumab<br>Participants will receive ADX 800 mg every 2 weeks followed by chemotherapy (nivolumab 3 mg/kg) on Days 1 and 15 of each 28-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, or other reasons prespecified in the protocol for discontinuation of study drug. | Drug: Andecaliximab<br>* Administered via intravenous (IV) infusion (approximately 30 minutes)<br>* Other names: GS-5745;Drug: Nivolumab<br>* Administered via IV infusion (approximately 60 minutes) every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) | TEAEs are any AEs with an onset date of on or after the date that ADX and if applicable, nivolumab was first administered and no later than 30 days after permanent discontinuation of ADX, or if applicable, 5 months after permanent discontinuation of nivolumab (whichever is later). | First dose date up to 82.4 weeks plus 30 days (or if applicable, up to 5 months after permanent withdrawal of nivolumab) | 
| Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities | Treatment-emergent laboratory abnormalities were defined as values that increase at least one toxicity grade from baseline. If the relevant baseline laboratory value was missing, then any abnormality of at least Grade 1 observed within the specified time frame (first dose date up to 82.4 weeks plus 30 days (or if applicable, up to 5 months after permanent withdrawal of nivolumab)) was considered treatment-emergent.Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 was used for assigning toxicity grades to laboratory results for analysis. | First dose date up to 82.4 weeks plus 30 days (or if applicable, up to 5 months after permanent withdrawal of nivolumab) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Plasma Concentration of Andecaliximab | Plasma concentration is defined as the measured drug concentration. Blood samples were drawn at pre-dose and 30 (±15) minutes after infusion on Day 1 of Cycles 2, 3, 5; End of study (EOS) (3 years and 1 month); Cycle 1 only: 30 (±15) minutes after infusion on Day 1; anytime on Day 2, 4, and 8; pre-dose and 30 (±15) minutes post infusion on Day 15. The duration of each cycle for Cohort 1, 2, and 4 was 28 days and for Cohort 3 was 21 days. Infusion duration = 30 to 35 minutes. min=minutes D=Days C=Cycle | Pre-dose and 30 (±15) min after infusion on C2D1, C3D1, C5D1; EOS (3 years and 1 month); C1 only: 30 (±15) min after infusion on D1; anytime on D2, D4 and D8; Pre-dose and 30 (±15) minutes post infusion on D15 | 
| PK Parameter: Cmax of Andecaliximab | Cmax is defined as the maximum concentration of drug. | Cycle 1 only: 30 (± 15) minutes after the end of infusion on Day 1; anytime on Days 2, 4, and 8; prior to dosing on Day 15 (Cycle length= 28 days) (infusion duration= 30 to 35 minutes) | 
| PK Parameter: AUClast of Andecaliximab | AUClast is defined as the area under the concentration versus time curve to the last measurable concentration of drug from time zero to the last observable concentration. | Cycle 1 only: 30 (± 15) minutes after the end of infusion on Day 1; anytime on Days 2, 4, and 8; prior to dosing on Day 15 (Cycle length= 28 days) (infusion duration= 30 to 35 minutes) | 
| PK Parameter: AUC0-336h of Andecaliximab | AUC0-336h is defined as the area under the concentration versus time curve from time zero to time 336 hour. | Cycle 1 only: 30 (± 15) minutes after the end of infusion on Day 1; anytime on Days 2, 4, and 8; prior to dosing on Day 15 (Cycle length= 28 days) (infusion duration= 30 to 35 minutes) | 
| Number of Participants With Positive Anti-Andecaliximab Antibodies |  | Pre-dose on Day 1 of Cycles 1, 2, 3, 5, 7 and every third cycle and anytime at EOT (82.4 weeks) and EOS visit (maximum: 3 years and 1 month) (Each Cycle= 28 days for Cohort 1, 2 and 4; 21 days for Cohort 3) |