Efficacy and Safety of IMAB362 in Combination With the EOX Regimen for CLDN18.2-positive Gastric Cancer

Astellas Pharma Global Development, Inc.252 enrolled

Overview

The purpose of the trial is to assess the therapeutic effects and the safety profile of IMAB362 combined with EOX (epirubicin, oxaliplatin, capecitabine) as first-line treatment for patients with advanced adenocarcinoma of the stomach, the esophagus or the gastroesophageal junction compared to EOX alone. Furthermore, sufficient binding of IMAB362 to the target cells is necessary for antitumoral activity. Thus, two dose levels ensuring a serum level above the in vitro predicted clinical efficacy threshold will be investigated.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Enrollment

252

Conditions

CLDN18.2-positive Adenocarcinoma of the Gastroesophageal Junction CLDN18.2-positive Adenocarcinoma of Esophagus CLDN18.2-positive Gastric Adenocarcinoma

Interventions

capecitabineDRUG

The daily dose of capecitabine will be 1250 mg/m\^2. Capecitabine tablets to be given once daily at a dose of 625 mg/m\^2 orally in the evening of day 1 of each cycle and twice daily at a dose of 625 mg/m\^2 orally on days 2 to 21 of each cycle; the morning dose of capecitabine on day 1 of each cycle to be omitted due to administration of zolbetuximab, epirubicin and oxaliplatin.

zolbetuximabDRUG

Two different formats of zolbetuximab, comprising different strengths, to be provided. Vials contained 22 mg or 105 mg of zolbetuximab. Prior to administration, zolbetuximab will be reconstituted with 1.1 mL (22 mg zolbetuximab vials) or 5.0 mL (105 mg zolbetuximab vials) water for injection, which will result in a concentration of 20 mg/mL zolbetuximab. The extractable volume per vial will be 1 mL (for 22 mg zolbetuximab vials) or 5 mL (for 105 mg zolbetuximab vials). The reconstituted solution will be further diluted with sodium chloride 0.9% to a final concentration of 2 mg/mL zolbetuximab. Zolbetuximab will be administered as an intravenous infusion over 2 to 3 hours.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Histologically confirmed adenocarcinoma of the stomach, the esophagus or the gastroesophageal junction * Inoperable locally advanced disease or resections with R2 outcome or recurrent or metastatic disease. * CLDN18.2 expression confirmed by immunohistochemistry in paraffin embedded tumor tissue sample. * Measurable and/or non-measurable disease as defined according to RECISTv1.1 * Age ≥ 18 years * Written Informed Consent Form * ECOG performance status (PS) 0-1 * Life expectancy \> 3 months * HER2/neu negative patients and patients with HER2/neu positive status but not eligible to trastuzumab therapy in discretion of the investigator. * Adequate cardiac, hepatic, renal, hematologic function. Exclusion Criteria: * Prior severe allergic reaction or intolerance to a monoclonal antibody, to the chemotherapeutics used in this study or any excipient in the respective formulations. * Previous chemotherapy for advanced disease. * Previous perioperative chemotherapy with curative intention within 6 months of start of study treatment. If interval is longer than 6 months (counted from the stop date of the perioperative chemotherapy), patients are allowed. * Known HIV infection or known symptomatic hepatitis (A, B, C). * Symptomatic cerebral metastases. * Pregnancy or breastfeeding. * Previous treatments with maximum cumulative doses of epirubicin \> 500 mg/m² and/or other anthracyclines and anthracenediones. * Known dihydropyrimidine dehydrogenase (DPD) deficiency.

Locations (48)

Site BUL004

Plovdiv, Bulgaria

Site BUL001

Sofia, Bulgaria

Site BUL003

Sofia, Bulgaria

Site BUL005

Sofia, Bulgaria

Site BUL002

Varna, Bulgaria

Site CZE002

Olomouc, Czechia

Outcomes

Primary Outcomes

Progression-free survival (PFS)

PFS is defined as the time from randomization to the first observation of disease progression (based on central reading) or death from any cause (as assessed by the independent reviewer). Participants without documented progression or death will be censored as of the last tumor evaluation determining lack of progression.

Time frame: From randomization to the data cut-off date of 31JAN2019; maximum time on follow-up was, 68.2, 47.2 & 59.6 months in the EOX, EOX+Zolbetuximab 600 mg, and EOX+Zolbetuximab 1000 mg treatment groups respectively.

Number of Participants with Adverse Events (AEs)

An AE is defined as any unintended or undesirable, noxious or pathological change, compared to pre-existing conditions, experienced by a participant during a clinical study or the follow-up period, regardless of relationship to study medication. Treatment-emergent adverse event (TEAE) are those AEs that started or worsened after the first dose of study medication.

Time frame: From the first dose of study drug administration up to 30 days after the last study medication administration (up to 1791 days).

Secondary Outcomes

Clinical PFS

Clinical PFS (CPFS) is defined as the time from randomization to the first observation of disease progression, either confirmed by computed tomography (CT) scans or by clinical evaluation, or death from any cause (as assessed by the independent reviewer with clinical PD considered as an event). Participants without documented progression or death will be censored as of the last tumor evaluation determining lack of progression.

Overall Survival Rate at 12 Months

Overall survival rate at 12 months after therapy initiation is defined as a proportion of participants alive after 12 months from first dose of any study drug.

Time frame: Up to 12 months

Overall Survival (OS)

OS is defined as the time from randomization to death from any cause or last contact (if alive).

Time to Progression (TTP)

TTP is defined as the time from randomization to the first observation of disease progression (based on central reading as assessed by the investigator reviewer). Participants without documented progression will be censored as of the last tumor evaluation determining lack of progression.

Objective Tumor Response Rate (ORR)

ORR is defined as the fraction of participants with a complete response (CR) or partial response (PR), according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (as assessed by the investigator reviewer). CR according to RECIST v1.1 is defined as the disappearance of all target lesions, any pathological lymph node must have reduction in short axis to \< 10 mm, disappearance of all non-target lesions and normalization of tumor marker level should occur as well as no simultaneous appearance of new lesions. PR according to RECIST v1.1 is defined as at least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the screening sum longest diameter and no simultaneous increase in the size of any lesion or the appearance of new lesions.

Time frame: Up to week 94

Disease Control Rate (DCR)

DCR is defined as the fraction of participants with CR or PR or stable disease (SD) according to RECIST v1.1 (as assessed by the investigator reviewer). SD according to RECIST v1.1 is defined as neither sufficient shrinkage to qualify for PR or CR nor sufficient increase to qualify for PD, taking as reference the smallest sum longest diameter recorded since treatment started, measurements must meet the SD criteria at least once after study entry at a minimum interval not less than 6 weeks, no simultaneous increase in the size of any lesion or the appearance of new lesions should occur, evaluable lesions must remain stable or regress for this category.

Time frame: Up to week 94

Duration of Response (DOR)

DOR will be determined as the time when criteria for CR or PR are first met until the first date that recurrent or progressive disease or death occurs (as assessed by the independent reviewer).