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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

NCT03653507

Description:

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, 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.

Related Conditions:
  • Adenocarcinoma of the Gastroesophageal Junction
  • Gastric Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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 IDs

  • ORG STUDY ID: 8951-CL-0302
  • SECONDARY ID: 2018-000519-26
  • NCT ID: NCT03653507

Conditions

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

Interventions

DrugSynonymsArms
zolbetuximabIMAB362Arm A (zolbetuximab plus CAPOX)
oxaliplatinArm B (placebo plus CAPOX)
capecitabineArm B (placebo plus CAPOX)
placeboArm B (placebo plus CAPOX)

Purpose

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, 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.

Detailed Description

      The study consists of the following periods: screening; treatment; post-treatment follow up,
      safety follow up, long term and survival follow-up.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (zolbetuximab plus CAPOX)ExperimentalParticipants will receive a loading dose of zolbetuximab at Cycle 1 Day 1 followed by a lower dose in subsequent cycles every 3 weeks. Additionally, participants will receive CAPOX (capecitabine/oxaliplatin) treatment until IRC confirmed disease progression or a total of 8 cycles (each cycle is defined as 3 weeks = 21 days). Oxaliplatin is administered on day 1 of each cycle, whereas capecitabine is taken twice daily on days 1 through 14. After 8 cycles of CAPOX, subjects may continue to receive capecitabine twice daily on days 1 through 14 of each cycle at the investigator's discretion until the subject meets study treatment discontinuation criteria.
  • zolbetuximab
  • oxaliplatin
  • capecitabine
Arm B (placebo plus CAPOX)Placebo ComparatorParticipants will receive placebo starting at Cycle 1 Day 1 and every 3 weeks thereafter. Additionally, participants will receive CAPOX (capecitabine/oxaliplatin) treatment until IRC confirmed disease progression or a total of 8 cycles (each cycle is defined as 3 weeks = 21 days). Oxaliplatin is administered on day 1 of each cycle, whereas capecitabine is taken twice daily on days 1 through 14. After 8 cycles of CAPOX, subjects may continue to receive capecitabine twice daily on days 1 through 14 of each cycle at the investigator's discretion until the subject meets study treatment discontinuation criteria.
  • oxaliplatin
  • capecitabine
  • placebo

Eligibility Criteria

        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 (βhCG) 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)

               -  WOCBP who agrees to follow the contraceptive guidance throughout the treatment
                  period and for 6 months after the final study treatment administration

          -  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 6 months after the final study treatment administration.

          -  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 the first dose of study treatment.

          -  Subject has measurable disease according to RECIST 1.1 within 28 days prior to the
             first dose of study treatment. For subjects with only 1 measurable lesion and prior
             radiotherapy, the lesion must be outside the field of prior radiotherapy or must 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.

          -  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 analyzed
             laboratory tests within 14 days prior to the first dose of study treatment. In case of
             multiple central laboratory data within this period, the most recent data should be
             used to determine eligibility.

               -  Hemoglobin (Hb) ≥ 9 g/dl. NOTE: subject must not have received any growth factor
                  or blood transfusions within 14 days prior to the hematology values obtained at
                  screening. Subjects requiring transfusions to meet eligibility criteria are not
                  eligible.

               -  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)

               -  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 as long as it was completed at least 6 months
             prior to the first dose of study treatment.

          -  Subject has received radiotherapy for locally advanced unresectable or metastatic
             gastric or GEJ adenocarcinoma unless the radiotherapy was completed > 28 days prior to
             the first dose of study treatment. Subject who received palliative radiotherapy to
             peripheral bone metastases ≥ 14 days prior to first dose of study treatment and has
             recovered from all acute toxicities is eligible.

          -  Subject has received treatment with herbal medications or other treatments that have
             known antitumor activity within 28 days prior to first dose of study treatment.

          -  Subject has received systemic immunosuppressive therapy, including systemic
             corticosteroids within 14 days prior to first dose of study treatment. Subject 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) or a single dose of
             systemic corticosteroids is eligible.

          -  Subject has received other investigational agents or devices within 28 days prior to
             first dose of study treatment.

          -  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 gastric outlet syndrome or persistent/recurrent vomiting.

          -  Subject had recent gastric bleeding and/or is symptomatic with proven gastric ulcers
             that excludes 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 hepatitis C infection. 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
             serology but negative hepatitis C virus (HCV) ribonucleic acid (RNA) test results are
             eligible.

          -  Subject has an active autoimmune disease that has required systemic treatment within
             the past 2 years.

          -  Subject has active infection requiring systemic therapy that has not completely
             resolved within 14 days prior to first dose of study treatment.

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

               -  Congestive heart failure (defined as New York Heart Association [NYHA] Class III
                  or IV), myocardial infarction, unstable angina, coronary angioplasty, coronary
                  stenting, coronary artery bypass graft, cerebrovascular accident (CVA), or
                  hypertensive crisis within 6 months prior to administration of first dose of
                  study treatment;

               -  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 (Subjects with rate
                  controlled atrial fibrillation for > 1 month prior to first dose of study
                  treatment are eligible.)

          -  Subject has known central nervous system (CNS) metastases and/or carcinomatous
             meningitis.

          -  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 the first dose of study
             treatment.

               -  Subject is without complete recovery from a major surgical procedure ≤ 14 days
                  prior to the first dose of study treatment.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free Survival (PFS)
Time Frame:up to 13 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:up to 23 months
Safety Issue:
Description:OS is defined as the time from the date of randomization until the date of death from any cause.
Measure:Objective Response Rate (ORR)
Time Frame:up to 13 months
Safety Issue:
Description: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.
Measure:Duration Of Response (DOR)
Time Frame:up to 13 months
Safety Issue:
Description: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.
Measure:Safety and tolerability assessed by adverse events (AEs)
Time Frame:up to 16 months
Safety Issue:
Description: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.
Measure:Number of participants with laboratory assessments abnormalities and or adverse events
Time Frame:up to 14 months
Safety Issue:
Description:Number of participants with potentially clinically significant laboratory values.
Measure:Number of participants with vital signs abnormalities and or adverse events
Time Frame:up to 14 months
Safety Issue:
Description:Number of participants with potentially clinically significant vital sign values.
Measure:Number of participants with electrocardiograms (ECG) abnormalities and or adverse events
Time Frame:up to 14 months
Safety Issue:
Description:Number of participants with potentially clinically significant ECG values.
Measure:Number of participants with Eastern Cooperative Oncology Group (ECOG) performance status abnormalities and or adverse events
Time Frame:up to 13 months
Safety Issue:
Description: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.
Measure: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)
Time Frame:up to 16 months
Safety Issue:
Description: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.
Measure: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
Time Frame:up to 16 months
Safety Issue:
Description: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.
Measure:Health Related Quality of Life (HRQoL) measured by the Global Pain (GP) questionnaire
Time Frame:up to 16 months
Safety Issue:
Description: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.
Measure:Health Related Quality of Life (HRQoL) measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) questionnaire
Time Frame:up to 16 months
Safety Issue:
Description: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.
Measure:Pharmacokinetics (PK) of zolbetuximab: Concentration Immediately Prior to Dosing at multiple dosing (Ctrough)
Time Frame:up to 16 months
Safety Issue:
Description:Ctrough will be derived from the PK serum samples collected.
Measure:Number of anti-drug antibody (ADA) Positive Participants
Time Frame:up to 16 months
Safety Issue:
Description:Immunogenicity will be measured by the number of participants that are ADA positive.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Astellas Pharma Global Development, Inc.

Trial Keywords

  • CLDN 18.2
  • gastroesophageal junction cancer
  • adenocarcinoma
  • IMAB362
  • oxaliplatin
  • HER2
  • claudiximab
  • capecitabine
  • gastric cancer
  • HER2 Negative
  • zolbetuximab

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