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A Study to Assess the Efficacy of Zolbetuximab (IMAB362) Plus mFOLFOX6 Compared With Placebo Plus mFOLFOX6 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 (Spotlight)

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ClinicalTrials.gov Identifier: NCT03504397
Recruitment Status : Recruiting
First Posted : April 20, 2018
Last Update Posted : September 24, 2018
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Brief Summary:

The purpose of this study is to evaluate the efficacy of zolbetuximab plus mFOLFOX6 compared with placebo plus mFOLFOX6 (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.


Condition or disease Intervention/treatment Phase
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 Drug: zolbetuximab Drug: placebo Drug: oxaliplatin Drug: leucovorin Drug: fluorouracil Phase 3

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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 550 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of Zolbetuximab (IMAB362) Plus mFOLFOX6 Compared With Placebo Plus mFOLFOX6 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
Actual Study Start Date : June 21, 2018
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : September 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A (zolbetuximab plus mFOLFOX6)
Participants 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 12 treatments of mFOLFOX6 (or components of mFOLFOX6 if some components are discontinued due to toxicity) over 4 cycles (each cycle has 42 days) in which mFOLFOX6 is administered on Days 1, 15 and 29. Participants may continue to receive fluorouracil (5-FU) and leucovorin at the investigator's discretion until the subject meets study treatment discontinuation criteria.
Drug: zolbetuximab
Zolbetuximab will be administered as a 2-hour IV infusion.
Other Name: IMAB362

Drug: oxaliplatin
Oxaliplatin will be administered as a 2-hour IV infusion

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

Drug: fluorouracil
Fluorouracil will be administered as IV bolus over 5-15 minutes and continuous IV infusion over 46-48 hours.

Placebo Comparator: Arm B (Placebo plus mFOLFOX6)
Participants will receive placebo starting at Cycle 1 Day 1 and every 3 weeks thereafter. Additionally, participants will receive 12 treatments of mFOLFOX6 (or components of mFOLFOX6 if some components are discontinued due to toxicity) over 4 cycles (each cycle has 42 days) in which mFOLFOX6 is administered on Days 1, 15 and 29. Participants may continue to receive fluorouracil (5-FU) and leucovorin at the investigator's discretion until the subject meets study treatment discontinuation criteria.
Drug: placebo
Placebo will be administered as a 2-hour IV infusion.

Drug: oxaliplatin
Oxaliplatin will be administered as a 2-hour IV infusion

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

Drug: fluorouracil
Fluorouracil will be administered as IV bolus over 5-15 minutes and continuous IV infusion over 46-48 hours.




Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: Up to 13 months ]
    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 :
  1. Overall Survival (OS) [ Time Frame: Up to 23 months ]
    OS is defined as the time from the date of randomization until the date of death from any cause.

  2. Objective Response Rate (ORR) [ Time Frame: Up to 13 months ]
    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.

  3. Duration Of Response (DOR) [ Time Frame: Up to 13 months ]
    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.

  4. Safety and tolerability assessed by adverse events (AEs) [ Time Frame: Up to 16 months ]
    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.

  5. Number of participants with laboratory assessments abnormalities and or adverse events [ Time Frame: Up to 14 months ]
    Number of participants with potentially clinically significant laboratory values.

  6. Number of participants with vital signs abnormalities and or adverse events [ Time Frame: Up to 14 months ]
    Number of participants with potentially clinically significant vital sign values.

  7. Number of participants with electrocardiograms (ECG) abnormalities and or adverse events [ Time Frame: Up to 14 months ]
    Number of participants with potentially clinically significant ECG values.

  8. Number of participants with Eastern Cooperative Oncology Group (ECOG) performance status abnormalities and or adverse events [ Time Frame: Up to 13 months ]
    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.

  9. Health Related Quality of Life (HRQoL) measured by the European Organization for Research and Treatment of Cancer (EORTC-QLQ-C30) questionnaire [ Time Frame: Up to 16 months ]
    The EORTC-QLQ-C30 is a cancer-specific instrument consisting of 5 functional domain scales: physical, role, emotional, social and cognitive.

  10. HRQoL measured by the QLQ-OG25 questionnaire [ Time Frame: Up to 16 months ]
    The EORTC-QLQ-OG25 instrument evaluates Gastric and GEJ cancer-specific symptoms such as stomach discomfort, difficulties eating and swallowing and indigestion.

  11. HRQoL measured by the Global Pain (GP) questionnaire [ Time Frame: Up to 16 months ]
    The GP instrument is a single assessment of overall pain.

  12. HRQoL measured by the EuroQOL Five Dimensions Questionnaire 5L (EQ-5D-5L) questionnaire [ Time Frame: Up to 16 months ]
    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.

  13. PK of zolbetuximab: Concentration Immediately Prior to Dosing at multiple dosing (Ctrough) [ Time Frame: Up to 16 months ]
    Ctrough will be derived from the PK serum samples collected.

  14. Number of anti-drug antibody (ADA) Positive Participants [ Time Frame: Up to 16 months ]
    Immunogenicity will be measured by the number of participants that are ADA positive.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

    • Not a woman of child-bearing potential (WOCBP) OR
    • WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 6 months after the final study drug administration
  • Female subject must agree not to breastfeed starting at screening and throughout the study period, and for 6 months after the final study drug administration.
  • Female subject must agree not to donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration.
  • A sexually active male subject with a female partner(s) who is of child-bearing potential must agree to use contraception during the treatment period and for at least 6 months after the final study drug administration.
  • Male subject must agree not to donate sperm starting at screening and throughout the study period, and for 6 months after the final study drug 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 drug 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 immunohistochemistry (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 to 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 laboratory data within this period, the most recent data should be used to determine eligibility.

    • Hemoglobin (Hgb) ≥ 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) ≥ 1.5 x 10^9/L
    • Platelets ≥ 100 x 10^9/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 (PT)/international normalized ratio (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 may have received treatment with herbal medications that have known anti-tumor activity >28 days prior to 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 start of study treatment. Subject who received palliative radiotherapy to peripheral bone metastases ≥14 days prior to start of study treatment and has recovered from all acute toxicities is allowed.
  • Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to first dose of study treatment. 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) or a single dose of systemic corticosteroids are allowed.
  • 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 mFOLFOX6.
  • Subject has known dihydropyrimidine dehydrogenase deficiency.
  • Subject has gastric outlet syndrome or persistent/recurrent vomiting.
  • Subject with recent gastric bleeding or symptomatic subjects with proven gastric ulcers that would 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 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 start of study treatment.
  • Subject has significant cardiovascular disease, including:

    • 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 or hypertensive crisis within 6 months prior to administration of first dose of study drug.
    • History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
    • QTc interval > 450 msec
    • Cardiac arrhythmias requiring anti-arrhythmic medications (Subject with rate controlled atrial fibrillation for > 1 month prior to first dose of study drugs are eligible)
  • Subject has known active central nervous system 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 before the start of study treatment.

    • Subject without complete recovery from a major surgical procedure ≤ 14 days before start 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 comorbid 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03504397


Contacts
Contact: Astellas Pharma Global Development 800-888-7704 astellas.registration@astellas.com

Locations
United States, Arizona
Western Regional Medical Center, Inc Recruiting
Goodyear, Arizona, United States, 85338
United States, California
University of California Davis Recruiting
Sacramento, California, United States, 95817
United States, Georgia
Southeastern Regional Medical Center Recruiting
Newnan, Georgia, United States, 30265
United States, Minnesota
Health Partners Institute Recruiting
Saint Louis Park, Minnesota, United States, 55426
United States, New York
Stony Brook University Cancer Center Recruiting
Stony Brook, New York, United States, 11794
United States, Ohio
Toledo Clinic Cancer Center Recruiting
Toledo, Ohio, United States, 43623
United States, Pennsylvania
Lancaster General Hospital Recruiting
Lancaster, Pennsylvania, United States, 17602
Thomas Jefferson - Sidney Kimmel Cancer Center Recruiting
Philadelphia, Pennsylvania, United States, 19107
Eastern Regional Medical Center Inc Recruiting
Philadelphia, Pennsylvania, United States, 19124
Sponsors and Collaborators
Astellas Pharma Global Development, Inc.
Investigators
Study Director: Global Medical Lead Astellas Pharma Global Development, Inc.

Responsible Party: Astellas Pharma Global Development, Inc.
ClinicalTrials.gov Identifier: NCT03504397     History of Changes
Other Study ID Numbers: 8951-CL-0301
2017-002567-17 ( EudraCT Number )
First Posted: April 20, 2018    Key Record Dates
Last Update Posted: September 24, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. ):
HER2
IMAB362
leucovorin
fluorouracil
Gastric cancer
claudiximab
zolbetuximab
oxaliplatin
adenocarcinoma
Gastro-Esophageal Junction cancer
HER2 Negative mFOLFOX6

Additional relevant MeSH terms:
Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Oxaliplatin
Fluorouracil
Antibodies, Monoclonal
Antineoplastic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs