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Participants will be treated with zolbetuximab on a 21-day cycle in which zolbetuximab will be administered as a single agent every 3 weeks until disease progression, toxicity requiring cessation, start of another anti-cancer treatment or other treatment discontinuation criteria are met.

Participants will be treated with zolbetuximab and mFOLFOX6 on a 42-day cycle in which zolbetuximab is administered on days 1 and 22, and mFOLFOX6 is administered on days 1, 15 and 29; however, for the first cycle, zolbetuximab will be administered on day 3 (instead of day 1) to allow for pharmacokinetic collection. Participants will receive up to 12 mFOLFOX6 treatments (4 cycles). Beginning at cycle 5, participants may continue on 5-FU and leucovorin or folinic acid along with zolbetuximab for the remainder of the study per investigator's discretion. mFOLFOX6 treatment includes oxaliplatin: intravenous \[IV\] infusion, leucovorin: IV infusion, fluorouracil bolus: IV bolus, fluorouracil infusion: continuous IV infusion.

Participants will be treated with zolbetuximab and pembrolizumab on a 21-day cycle. Loading dose of zolbetuximab will be administered at cycle 1, day 1 followed by maintenance dose of zolbetuximab once every 3 weeks (Q3W). Pembrolizumab will be administered to 3 to 6 subjects at a intravenously on day 1 of every 21-day cycle and will be infused 1 hour after the zolbetuximab infusion is completed. Tolerability and safety of zolbetuximab in combination with pembrolizumab will be evaluated during the 3-week dose-limiting toxicity (DLT) assessment period. If this cycle 1 dose is not tolerable, a lower dose of zolbetuximab in combination with pembrolizumab will subsequently be evaluated.

Participants will be treated with zolbetuximab and mFOLFOX6, nivolumab on a 42-day cycle. Cohort 4A: Loading dose of zolbetuximab in combination with nivolumab and mFOLFOX6 on cycle 1 day 1, followed by zolbetuximab in combination with nivolumab and mFOLFOX6 q2w \[days 15 and 29\] (1 cycle = 6 weeks). Tolerability and safety of zolbetuximab in combination with nivolumab, mFOLFOX6 will be evaluated during the 3-week DLT assessment period. If cycle 1 dose is not tolerable, a lower dose of dose zolbetuximab in combination with nivolumab and mFOLFOX6 will be subsequently evaluated. Cohort 4B: Subjects will be treated with the combination of zolbetuximab, mFOLFOX6 and nivolumab at the dose deemed tolerable in Cohort 4A. Subjects will receive up to 12 mFOLFOX6 treatments (4 cycles). For Cohorts 4A and 4B, beginning at cycle 5, subjects may continue on 5-FU and leucovorin or folinic acid along with zolbetuximab and nivolumab for the remainder of the study per investigator's discretion.

Participants will be treated with zolbetuximab \& FLOT for a total of eight 2-week cycles. 4 cycles preoperatively \& 4 cycles postoperatively 6-12 weeks after surgery.

Preoperative: Participants will receive zolbetuximab loading dose on cycle 1 day 1, followed by FLOT on cycle 1 day 2. For cycles 2-4, participants may receive zolbetuximab maintenance dose in combination with FLOT, dosed on day 1 of each cycle. However, dosing may be split over 2 days with zolbetuximab administration on day 1 \& FLOT on day 2.

Post operative: Participants will receive zolbetuximab loading dose on cycle 5 day 1, followed by FLOT on cycle 5 day 2. For cycles 6-8, participants may receive zolbetuximab maintenance dose in combination with FLOT, dosed on day 1 of each cycle. However, dosing may be split over 2 days with zolbetuximab administration on day 1 and FLOT on day 2. For participants who experience a DLT during preoperative treatment on the loading dose, the postoperative loading dose may be lowered.

Zolbetuximab will be administered as a minimum 2-hour IV infusion.

zolbetuximab

Oxaliplatin will be administered as a 2-hour IV infusion.

oxaliplatin

Leucovorin will be administered as a 2-hour IV infusion.

leucovorin

Fluorouracil will be administered as IV bolus over 5 to 15 minutes and continuous IV infusion over 46 to 48 hours or per institutional guidelines.

fluorouracil

Pembrolizumab will be administered intravenously over 30 minutes.

Folnic acid will be administered as a 2-hour IV infusion.

folinic acid

Nivolumab will be administered intravenously according to institutional standards.

nivolumab

Docetaxel will be administered as a 1-hour IV infusion.

Astellas Pharma Global Development

Global Medical Lead

The purpose of this study is to determine the Objective Response Rate (ORR) of zolbetuzimab as a single agent as assessed by an independent central reader. This study will also assess the ORR and Progression Free Survival (PFS) of zolbetuximab in combination with mFOLFOX6 (with or without Nivolumab) and in combination with pembrolizumab, assess the safety and tolerability, assess the effects on CLDN18.2 expression and assess the immunogenicity and immunomodulatory effects of zolbetuximab as a single agent and in combination with mFOLFOX6 (with or without Nivolumab) and in combination with pembrolizumab and in combination with fluorouracil, leucovorin or folinic acid, oxaliplatin and docetaxel (FLOT). This study will also evaluate the pharmacokinetics (PK) of zolbetuximab as a single agent and in combination with mFOLFOX6 (with or without Nivolumab) and in combination with pembrolizumab and in combination with fluorouracil, leucovorin or folinic acid, oxaliplatin and docetaxel (FLOT) and PK of oxaliplatin, fluorouracil (5-FU), and pembrolizumab in combination with zolbetuximab, evaluate health-Related Quality of Life (HRQoL), evaluate the Disease Control Rate (DCR), Duration of Response (DOR), PFS of zolbetuximab as a single agent, in combination with mFOLFOX6 (with or without Nivolumab) and in combination with pembrolizumab based on both investigator and independent central reader assessment, assess Overall Survival (OS) of zolbetuximab as a single agent and in combination with mFOLFOX6 and nivolumab and in combination with FLOT.

This is a study to assess the antitumor activity of zolbetuximab, an Immunoglobulin (IgG1) chimeric monoclonal antibody directed against CLDN18.2, in subjects with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma and locoregional gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive. For each cohort, the study consists of the following periods: pre-screening; screening; treatment; and follow-up for disease progression (or post-treatment follow-up for disease recurrence, which will be conducted for Cohort 5). In addition, there will be a survival follow-up period for Cohorts 1A, 4B, and 5 participants only. Tolerability of zolbetuximab in combination with pembrolizumab in Japanese participant(s) will be evaluated in Cohort 3A DLT assessment. Tolerability of zolbetuximab in combination with mFOLFOX6 and nivolumab in Japanese subject(s) will be evaluated in Cohort 4B, if Japanese subjects are not enrolled in the Cohort 4A DLT assessment.

Participants will be enrolled to receive zolbetuximab as monotherapy or in combination with mFOLFOX6 (with or without Nivolumab) and in combination with pembrolizumab and in combination with FLOT in an unblinded fashion.

A Study to Assess the Antitumor Activity, Safety, Pharmacokinetics and Biomarkers of Zolbetuximab (IMAB362) in Participants With Claudin (CLDN) 18.2 Positive, Metastatic or Advanced Unresectable Gastric and Gastroesophageal Junction (GEJ) Adenocarcinoma and Locoregional Gastric or GEJ Adenocarcinoma

A Phase 2 Study of Zolbetuximab (IMAB362) as Monotherapy and in Combination With Chemotherapy and/or Immunotherapy in Subjects With Metastatic or Locally Advanced Unresectable Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma and Locoregional Gastric or GEJ Adenocarcinoma Whose Are Claudin (CLDN) 18.2 Positive

Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as compounds terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.

The ORR is defined as the proportion of participants with complete or partial objective response based on Response Evaluation Criteria in Solid Tumors (RECIST) V1.1 (assessed by an independent review committee (IRC)).

AUCinf will be derived from the PK serum samples collected.

AUCinf (%extrap) will be derived from the PK serum samples collected.

AUClast will be derived from the PK serum samples collected.

AUCtau will be derived from the PK serum samples collected.

Cmax will be derived from the PK serum samples collected.

Ctrough will be derived from the PK serum samples collected.

Tmax will be derived from the PK serum samples collected.

T1/2 will be derived from the PK serum samples collected.

Tlast will be derived from the PK serum samples collected.

CL will be derived from the PK serum samples collected.

Vz will be derived from the PK serum samples collected.

AUCinf will be derived from the PK plasma samples collected.

AUCinf (%extrap) will be derived from the PK plasma samples collected.

AUClast will be derived from the PK plasma samples collected.

Cmax will be derived from the PK plasma samples collected.

Tmax will be derived from the PK plasma samples collected.

T1/2 will be derived from the PK plasma samples collected.

Tlast will be derived from the PK plasma samples collected.

TL will be derived from the PK plasma samples collected.

Vz will be derived from the PK plasma samples collected.

CL will be derived from the PK plasma samples collected.

An AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Number of participants with potentially clinically significant ECG values.

Number of participants with potentially clinically significant vital sign values.

Number of participants with potentially clinically significant ECOG performance status values. ECOG grades 0-5, where 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair and 5 = Dead.

Number of participants with potentially clinically significant laboratory values.

Immunogenicity will be measured by the number of participants that are ADA positive.

The EORTC-QLQ-C30 is a cancer-specific instrument consisting of 5 functional domain scales: physical, role, emotional, social and cognitive.

The EORTC-QLQ-OG25 instrument evaluates GC- and GEJC-specific symptoms such as stomach discomfort, difficulties eating and swallowing and indigestion.

The GP instrument is a single assessment of overall pain.

The EQ-5D-5L is a standardized instrument developed by the EuroQol Group for use as a generic, preference-based measure of health outcomes. The EQ-5D-5L is a 5-item self-reported measure of functioning and wellbeing, which assesses 5 dimensions of health, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension comprises 5 levels (no problems, slight problems, moderate problems, severe problems, extreme problems). A unique EQ-5D-5L health state is defined by combining 1 level from each of the 5 dimensions. This questionnaire also records the respondent's self-rated health status on a vertical graduated (0 = the worst health a participant can imagine to 100 = the best health a participant can imagine) visual analogue scale. Responses to the 5 items will also be converted to a weighted health state index (utility score) based on values derived from general population samples.

Health resource utilization questionnaire to assess the number of office visits, hospital stays and other healthcare resource utilization that occur outside of the clinical trial.

The DCR is defined as the proportion of subjects with complete or partial objective response, or stable disease based on RECIST V1.1.

DCR is defined as the proportion of subjects with complete or partial objective response, or stable disease based on RECIST V1.1.

DOR is defined as the time from the date of the first response CR/PR (whichever is first recorded) to the date of radiographical progression/death or date of censoring.

PFS is defined as the time from date of treatment start until the date of radiological disease progression assessed by independent radiographic reviewer (IRR), or until death due to any cause.

The ORR is defined as the proportion of subjects with complete or partial objective response based on RECIST V1.1.

OS is defined as the time from the date of treatment start until the documented date of death from any cause.

Percentage of participants with surgical complications will be reported.

Percentage of participants with surgical mortality as defined by death within 30 days of surgery will be reported.

Percentage of participants able to complete preoperative chemotherapy will be reported.

Percentage of participants with perioperative mortality and morbidity at 30 days and 90 days post last dose will be reported.

Percentage of participants able to start postoperative chemotherapy will be reported.

Percentage of participants able to complete postoperative chemotherapy will be reported.

Radiological response will include complete response and partial response.

Pathological response (ypTNM) will include ypCR, ypPR

DFS is defined as the time from date of treatment start until the date of radiological disease recurrence or until death due to any cause, whichever is earliest.

Minimal residual disease and disease recurrence as measured by circulating tumor DNA (ctDNA) will be summarized.

Spots Global Cancer Trial Database for pharmacokinetics of zolbetuximab