A Study of Zolbetuximab (IMAB362) Plus CAPOX Compared With Placebo Plus CAPOX as First-line Treatment of Subjects With Claudin (CLDN) 18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

Metastatic Gastroesophageal Junction (GEJ) Adenocarcinoma Clinical Trial

— GLOW  

Official title:

A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of Zolbetuximab (IMAB362) Plus CAPOX Compared With Placebo Plus CAPOX as First-line Treatment of Subjects With Claudin (CLDN) 18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03653507
• Other study ID #: 8951-CL-0302
• Secondary ID: 2018-000519-26CT
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: November 28, 2018
• Est. completion date: March 31, 2025

Study information

• Verified date: May 2024
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the efficacy of zolbetuximab plus capecitabine and oxaliplatin (CAPOX) compared with placebo plus CAPOX (as first-line treatment) as measured by Progression Free Survival (PFS). This study will also evaluate efficacy, physical function, safety, and tolerability of zolbetuximab, as well as its effects on quality of life. Pharmacokinetics (PK) of zolbetuximab and the immunogenicity profile of zolbetuximab will be evaluated as well.

Description:

The study consists of the following periods: screening; treatment; post-treatment follow up, safety follow up, long term and survival follow-up. After the marketing approval in Japan on 26 Mar 2024, this study continued as "post marketing clinical study" in Japan. In the rest of the countries which participated in this study, this study continued as clinical study.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 507
• Est. completion date: March 31, 2025
• Est. primary completion date: October 25, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• A female subject is eligible to participate if she is not pregnant (negative serum pregnancy test at screening; female subjects with elevated serum beta human chorionic gonadotropin (ßhCG) and a demonstrated non-pregnant status through additional testing are eligible) and at least 1 of the following conditions applies:

• Not a woman of childbearing potential (WOCBP) OR

• WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for 9 months after the final administration of oxaliplatin and 6 months after the final administration of all other study drugs.

• Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 6 months after the final study treatment administration.

• Female subject must not donate ova starting at screening and throughout the study period, and for 9 months after the final administration of oxaliplatin and 6 months after the final administration of all other study drugs.

• A male subject with female partner(s) of childbearing potential:

• must agree to use contraception during the treatment period and for 6 months after the final study treatment administration.

• A male subject must not donate sperm during the treatment period and for 6 months after the final study treatment administration.

• Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 6 months after the final study treatment administration.

• Subject has histologically confirmed diagnosis of Gastric or GEJ adenocarcinoma.

• Subject has radiologically confirmed locally advanced unresectable or metastatic disease within 28 days prior to randomization.

• Subject has radiologically evaluable disease (measurable and/or non-measurable disease according to RECIST 1.1), per local assessment, = 28 days prior to randomization. For subjects with only 1 evaluable lesion and prior radiotherapy = 3 months before randomization, the lesion must either be outside the field of prior radiotherapy or have documented progression following radiation therapy.

• Subject's tumor expresses CLDN18.2 in = 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing.

• Subject has a HER2-negative tumor as determined by local or central testing on a gastric or GEJ tumor specimen. (Unique to China: Subject has a known HER2-negative gastric or GEJ tumor.)

• Subject has ECOG performance status 0 or 1.

• Subject has predicted life expectancy = 12 weeks.

• Subject must meet all of the following criteria based on the centrally or locally analyzed laboratory tests collected within 14 days prior to randomization. In the case of multiple sample collections within this period, the most recent sample collection with available results should be used to determine eligibility.

• Hemoglobin (Hb) = 9 g/dl. Subjects requiring transfusions are eligible if they have a post-transfusion Hgb = 9 g/dL.

• Absolute Neutrophil Count (ANC) = 1.5x10^9/L

• Platelets = 100x10^9/L

• Albumin = 2.5 g/dL

• Total Bilirubin = 1.5 x upper limit of normal (ULN) without liver metastases (or < 3.0 x ULN if liver metastases are present)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5 x ULN without liver metastases (or = 5 x ULN if liver metastases are present)

• Estimated creatinine clearance = 30 mL/min

• Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) = 1.5 x ULN (except for subjects receiving anticoagulation therapy)

Exclusion Criteria:

• Subject has received prior systemic chemotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. However, subject may have received either neo-adjuvant or adjuvant chemotherapy, immunotherapy or other systemic anticancer therapies as long as it was completed at least 6 months prior to randomization.

• Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma = 14 days prior to randomization and has not recovered from any related toxicity.

• Subject has received treatment with herbal medications or other treatments that have known antitumor activity within 28 days prior to randomization.

• Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to randomization. Subjects using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone), receiving a single dose of systemic corticosteroids or receiving systemic corticosteroids as premedication for radiologic imaging contrast use are allowed.

• Subject has received other investigational agents or devices within 28 days prior to randomization.

• Subject has prior severe allergic reaction or intolerance to known ingredients of zolbetuximab or other monoclonal antibodies, including humanized or chimeric antibodies.

• Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment.

• Subject has prior severe allergic reaction or intolerance to any component of CAPOX.

• Subject has known dihydropyrimidine dehydrogenase (DPD) deficiency.

• Subject has a complete gastric outlet syndrome or a partial gastric outlet syndrome with persistent/recurrent vomiting.

• Subject has significant gastric bleeding and/or untreated gastric ulcers that exclude the subject from participation.

• Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection or known active hepatitis B (positive hepatitis B surface antigen (HBs Ag)) or C infection. NOTE: Screening for these infections should be conducted per local requirements.

• For subjects who are negative for HBs Ag, but hepatitis B core antibody (HBc Ab) positive, an HB deoxyribonucleic acid (DNA) test will be performed and if positive, the subject will be excluded.

• Subjects with positive hepatitis C virus (HCV) serology, but negative HCV ribonucleic acid (RNA) test are eligible.

• Subjects treated for HCV with undetectable viral load results are eligible.

• Subject has an active autoimmune disease that has required systemic treatment within the past 3 months prior to randomization.

• Subject has active infection requiring systemic therapy that has not completely resolved within 7 days prior to randomization.

• Subject has significant cardiovascular disease, including any of the following:

• Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, stenting, coronary artery bypass graft, cerebrovascular accident (CVA) or hypertensive crisis within 6 months prior to randomization.

• History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointes

• QTc interval > 450 msec for male subjects; QTc interval > 470 msec for female subjects

• History or family history of congenital long QT syndrome

• Cardiac arrhythmias requiring anti-arrhythmic medications (Subject with rate controlled atrial fibrillation for > 1 month prior to randomization are eligible).

• Subject has a history of central nervous system (CNS) metastases and/or carcinomatous meningitis from gastric/GEJ cancer..

• Subject has known peripheral sensory neuropathy > grade 1 unless the absence of deep tendon reflexes is the sole neurological abnormality.

• Subject has had a major surgical procedure = 28 days prior to randomization.

• Subject is without complete recovery from a major surgical procedure = 14 days prior to randomization.

• Subject has psychiatric illness or social situations that would preclude study compliance.

• Subject has another malignancy for which treatment is required.

• Subject has any concurrent disease, infection, or co-morbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data.

Related Conditions & MeSH terms

• Adenocarcinoma
• Locally Advanced Unresectable Gastric Adenocarcinoma or Cancer
• Locally Advanced Unresectable Gastroesophageal Junction (GEJ) Adenocarcinoma or Cancer
• Metastatic Gastric Adenocarcinoma or Cancer
• Metastatic Gastroesophageal Junction (GEJ) Adenocarcinoma

Intervention

Drug:
• zolbetuximab
Zolbetuximab will be administered as a minimum 2-hour IV infusion.
• oxaliplatin
Oxaliplatin will be administered as a 2-hour IV infusion.
• capecitabine
Capecitabine will be administered orally twice daily (bid).
• placebo
Placebo will be administered as a minimum 2-hour IV infusion.

Locations

Country	Name	City	State
Argentina	Site AR54009	Buenos Aires
Argentina	Site AR54006	Pergamino
Argentina	Site AR54001	San Miguel De Tucuman
Argentina	Site AR54004	San Miguel de Tucumán
Argentina	Site AR54003	Viedma
Canada	Site CA15004	Calgary
Canada	Site CA15003	Chicoutimi	Quebec
Canada	Site CA15002	Rimouski	Quebec
China	Site CN86044	Baoding
China	Site CN86035	Beijing
China	Site CN86050	Beijing
China	Site CN86025	Bengbu
China	Site CN86002	Changchun
China	Site CN86049	Changchun
China	Site CN86053	Changchun
China	Site CN86029	Changsha	Hunan
China	Site CN86021	Changzhou
China	Site CN86039	Chengdu
China	Site CN86052	Dalian
China	Site CN86054	Dalian
China	Site CN86015	Fuzhou
China	Site CN86034	Fuzhou	Fujian
China	Site CN86037	Fuzhou	Fujian
China	Site CN86001	Guangzhou
China	Site CN86042	Guangzhou
China	Site CN86051	Haebrin
China	Site CN86032	Haikou	Hainan
China	Site CN86007	Hangzhou	Zhejiang
China	Site CN86036	Hangzhou
China	Site CN86043	Hengyang	Hunan
China	Site CN86038	Linyi
China	Site CN86016	Nanjing
China	Site CN86045	Nanning
China	Site CN86014	Shanghai
China	Site CN86026	Shantou
China	Site CN86047	Shenyang
China	Site CN86017	Shijiazhuang
China	Site CN86027	Suzhou	Jiangsu
China	Site CN86009	Tianjin
China	Site CN86040	Tianjin
China	Site CN86031	Urumchi
China	Site CN86004	Wuhan
China	Site CN86005	Wuhan
China	Site CN86046	Wuxi	Jiangsu
China	Site CN86013	Xi'an
China	Site CN86030	Xiamen
China	Site CN86011	Xuzhou
China	Site CN86012	Zhengzhou	Henan
China	Site CN86024	Zhengzhou
Croatia	Site HR38501	Varazdin
Croatia	Site HR38502	Zagreb
Croatia	Site HR38503	Zagreb
Greece	Site GR30001	Athens
Greece	Site GR30004	Heraklion
Greece	Site GR30003	Larissa
Greece	Site GR30005	Neo Faliro, Piraeus
Greece	Site GR30007	Rio Patras
Greece	Site GR30002	Thessaloniki
Greece	Site GR30006	Thessaloniki
Ireland	Site IE35301	Dublin
Ireland	Site IE35302	Dublin
Japan	Site JP81008	Akashi	Hyogo
Japan	Site JP81002	Chiba
Japan	Site JP81007	Fukuoka-shi	Fukuoka
Japan	Site JP81006	Kashiwa
Japan	Site JP81003	Kawasaki	Kanagawa
Japan	Site JP81004	Kita-gun	Kagawa
Japan	Site JP81012	Koto-ku
Japan	Site JP81009	Matsuyama
Japan	Site JP81010	Suita	Osaka
Japan	Site JP81011	Tsukiji
Japan	Site JP81005	Utsunomiya	Tochigi
Japan	Site JP81001	Yokohama	Kanagawa
Korea, Republic of	Site KR82002	Daegu
Korea, Republic of	Site KR82006	Goyang-si
Korea, Republic of	Site KR82007	Gyeonggi-do
Korea, Republic of	Site KR82014	Incheon
Korea, Republic of	Site KR82008	Jeollanam-do
Korea, Republic of	Site KR82010	Jeonju-si
Korea, Republic of	Site KR82011	Seongnam-si
Korea, Republic of	Site KR82001	Seoul
Korea, Republic of	Site KR82003	Seoul
Korea, Republic of	Site KR82012	Seoul
Korea, Republic of	Site KR82013	Seoul
Korea, Republic of	Site KR82015	Seoul
Korea, Republic of	Site KR82009	Suwon
Malaysia	Site MY60001	Georgetown
Malaysia	Site MY60004	Kota Kinabalu
Malaysia	Site MY60002	Kuala Lumpur
Malaysia	Site MY60003	Kuala Lumpur
Malaysia	Site MY60005	Kuala Lumpur
Netherlands	Site NL31004	Groningen
Netherlands	Site NL31003	Tilburg
Portugal	Site PT35109	Braga
Portugal	Site PT35110	Coimbra
Portugal	Site PT35111	Guimaraes
Portugal	Site PT35102	Lisboa
Portugal	Site PT35106	Lisboa
Portugal	Site PT35105	Porto
Portugal	Site PT35108	Porto
Portugal	Site PT35104	Santa Maria da Feira
Portugal	Site PT35101	Setubal
Portugal	Site PT35107	Vila Real
Romania	Site RO40002	Bucharest
Romania	Site RO40005	Cluj-Napoca
Romania	Site RO40007	Cluj-Napoca
Romania	Site RO40003	Craiova
Romania	Site RO40004	Floresti
Romania	Site RO40001	Iasi
Romania	Site RO40006	Iasi
Romania	Site RO40008	Timisoara
Spain	Site ES34006	Barcelona
Spain	Site ES34009	Barcelona
Spain	Site ES34010	Barcelona
Spain	Site ES34005	Coruña
Spain	Site ES34001	Elche
Spain	Site ES34002	Madrid
Spain	Site ES34003	Madrid
Spain	Site ES34008	Madrid
Spain	Site ES34013	Madrid
Spain	Site ES34011	Malaga
Spain	Site ES34004	Pamplona
Spain	Site ES34007	Valencia
Spain	Site ES34012	Valencia
Taiwan	Site TW88602	Kaohsiung
Taiwan	Site TW88603	Taichung
Taiwan	Site TW88604	Taipei
Taiwan	Site TW88605	Tianan
Thailand	Site TH66002	Bangkok
Thailand	Site TH66005	Bangkok
Thailand	Site TH66007	Bangkok
Thailand	Site TH66009	Bangkok
Thailand	Site TH66011	Laksi
Thailand	Site TH66001	Muang
Thailand	Site TH66003	Muang
Thailand	Site TH66006	Pathumthani
Thailand	Site TH66010	Pathumwan
Thailand	Site TH66004	Songkla
Thailand	Site TH66008	Watthana
Turkey	Site TR90003	Atakum
Turkey	Site TR90004	Balcali
Turkey	Site TR90012	Bornova
Turkey	Site TR90001	Bursa
Turkey	Site TR90002	Istanbul
Turkey	Site TR90010	Istanbul
Turkey	Site TR90015	Istanbul
Turkey	Site TR90007	Konya
Turkey	Site TR90013	Konyaalti
Turkey	Site TR90011	Malatya
Turkey	Site TR90008	Pendik	Istanbul
United Kingdom	Site GB44002	Bristol
United Kingdom	Site GB44004	Cardiff	Wales
United Kingdom	Site GB44001	London
United Kingdom	Site GB44005	Northwood
United States	New Mexico Oncology Hematology	Albuquerque	New Mexico
United States	Prisma Health Cancer Institute	Boiling Springs	South Carolina
United States	Montefiore Medical Center (MMC)	Bronx	New York
United States	Parkland Hospital	Dallas	Texas
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	University of Kansas Cancer Center and Medical Pavilion	Fairway	Kansas
United States	Houston Methodist Cancer Center and Institute of Academic Medicine - Oncology	Houston	Texas
United States	Pacific Cancer Care	Monterey	California
United States	Ochsner Clinic CCOP	New Orleans	Louisiana
United States	Weill Cornell Medical College (WCMC)	New York	New York
United States	Utah Cancer Specialist	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Astellas Pharma Global Development, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Canada,  China,  Croatia,  Greece,  Ireland,  Japan,  Korea, Republic of,  Malaysia,  Netherlands,  Portugal,  Romania,  Spain,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival (PFS)	PFS is defined as the time from the date of randomization until the date of radiological progressive disease (per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 by Independent Review Committee (IRC)) or death from any cause, whichever is earliest.	up to 13 months
Secondary	Overall Survival (OS)	OS is defined as the time from the date of randomization until the date of death from any cause.	up to 23 months
Secondary	Time to confirmed deterioration (TTCD) in participant-reported physical functioning and Global Health Status/Quality of Life (GHS/QoL)	TTCD is measured by EORTC QLQ-C30 and QLQ-OG25 plus STO22 Belching subscale and defined as time to first confirmed deterioration; that is, time from randomization to first clinically meaningful deterioration that is confirmed at the next scheduled visit.	Up to 16 months
Secondary	Objective Response Rate (ORR)	ORR is defined as the proportion of participants who have a best overall response of Complete Response (CR) or Partial Response (PR) as assessed by Independent Review Committee (IRC) per RECIST 1.1.	up to 13 months
Secondary	Duration Of Response (DOR)	DOR, defined as the time from the date of the first response (CR/PR) until the date of progressive disease as assessed by IRC per RECIST 1.1 or date of death from any cause, whichever is earliest.	up to 13 months
Secondary	Safety and tolerability assessed by adverse events (AEs)	An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.	up to 16 months
Secondary	Number of participants with laboratory assessments abnormalities and or adverse events	Number of participants with potentially clinically significant laboratory values.	up to 14 months
Secondary	Number of participants with vital signs abnormalities and or adverse events	Number of participants with potentially clinically significant vital sign values.	up to 14 months
Secondary	Number of participants with electrocardiograms (ECG) abnormalities and or adverse events	Number of participants with potentially clinically significant ECG values.	up to 14 months
Secondary	Number of participants with Eastern Cooperative Oncology Group (ECOG) performance status abnormalities and or adverse events	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.	up to 13 months
Secondary	Health Related Quality of Life (HRQoL) measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core Questionnaire (EORTC-QLQ-C30)	EORTC-QLQ-C30 is a cancer-specific 30-item questionnaire. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much." A change of 5 - 10 points is considered a small change. A change of 10 - 20 points is considered a moderate change.	up to 16 months
Secondary	Health Related Quality of Life (HRQoL) measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Oesophago-Gastric Module 25 (QLQ-OG25) questionnaire plus EORTC-QLQ-STO22 Belching subscale	The EORTC-QLQ-OG25 instrument evaluates Gastric and Gastroesophageal Junction (GEJ) cancer-specific symptoms such as stomach discomfort, difficulties eating and swallowing and indigestion. It is a 25-item questionnaire. Participants rate items on a four-point scale, with 1 as "not at all" and 4 as "very much". To ensure relevant symptoms are adequately covered two questions from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Stomach (EORTC-QLQ-STO22) instrument related to belching and bile or acid coming in your mouth will be asked following the OG25 questionnaire. Participants rate items on a 4 point scale, with 1 as "not at all" and 4 as "very much". The total and subscale scores from the OG25 and item scores from the STO22 items will be reported.	up to 16 months
Secondary	Health Related Quality of Life (HRQoL) measured by the Global Pain (GP) questionnaire	The GP instrument is a single assessment of overall pain where 0 equals no pain and 10 equals extreme pain. Low pain scores are considered a better outcome than a high pain score.	up to 16 months
Secondary	Health Related Quality of Life (HRQoL) measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) questionnaire	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.	up to 16 months
Secondary	Pharmacokinetics (PK) of zolbetuximab: Concentration Immediately Prior to Dosing at multiple dosing (Ctrough)	Ctrough will be derived from the PK serum samples collected.	up to 16 months
Secondary	Number of anti-drug antibody (ADA) Positive Participants	Immunogenicity will be measured by the number of participants that are ADA positive.	up to 16 months