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

• ClinicalTrials.gov Identifier: NCT01630083
• Recruitment Status: Completed
• First Posted: June 28, 2012
• Last Update Posted: January 18, 2020
• Sponsor: Astellas Pharma Global Development, Inc.
• Information provided by (Responsible Party): Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )

Tracking Information

• First Submitted Date: June 19, 2012
• First Posted Date: June 28, 2012
• Last Update Posted Date: January 18, 2020
• Actual Study Start Date: July 19, 2012
• Actual Primary Completion Date: January 31, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 14, 2020)

• Progression-free survival (PFS) [ 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. ]
  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.
• Number of Participants with Adverse Events (AEs) [ Time Frame: From the first dose of study drug administration up to 30 days after the last study medication administration (up to 1791 days). ]
  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.

Original Primary Outcome Measures (submitted: June 26, 2012)

• Progression-free survival (PFS) [ Time Frame: at least 33 months ]
  PFS is defined as the time from randomization of therapy to the first observation of disease progression or death from any cause or last tumor evaluation if free of progression. For patients who have not progressed either clinically or on the last scan, they will be censured as of the last tumor evaluation.
• Safety and Tolerability [ Time Frame: at least 33 months ]
  Descriptive statistics for treatments will be given on the number of patients whose treatment had to be reduced, delayed or permanently stopped.

Current Secondary Outcome Measures (submitted: January 14, 2020)

• Clinical PFS [ 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. ]
  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 [ Time Frame: Up to 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.
• Overall Survival (OS) [ 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. ]
  OS is defined as the time from randomization to death from any cause or last contact (if alive).
• Time to Progression (TTP) [ 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. ]
  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) [ Time Frame: Up to week 94 ]
  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.
• Disease Control Rate (DCR) [ Time Frame: Up to week 94 ]
  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.
• Duration of Response (DOR) [ 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. ]
  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).

Original Secondary Outcome Measures (submitted: June 26, 2012)

• Survival rate at 12 months [ Time Frame: at least 33 months ]
  To determine survival status at 12 months following initiation of therapy each patient will be classified as alive or dead (irrespective of cause of death). For this purpose, upon completion of the last cycle, all patients will continue to be followed until death or loss to follow up. Patients who discontinue treatment due to progression will be followed in the same manner.
• Overall survival (OS) [ Time Frame: at least 33 months ]
  Overall survival is defined as the time from randomization to death from any cause or last contact if alive.
• Time to progression (TTP) [ Time Frame: at least 33 months ]
  TTP is defined as the time from randomization of therapy to the first observation of confirmed disease progression. For patients who have not progressed either clinically or on the last scan, they will be censured as of the last tumor evaluation.
• Objective tumor response rate (ORR) [ Time Frame: at least 33 months ]
  ORR comprises the fraction of patients with CR, PR according to RECIST v1.1. It is set in relation to the ITT population and PP population (see section 8).
• Disease control rate (DCR) [ Time Frame: at least 33 months ]
  DCR is defined as the fraction of patients with CR or PR or SD according to RECIST v1.1. It is set in relation to the ITT population and PP population
• Duration of response (DOR) [ Time Frame: at least 33 months ]
  Duration of response is determined as the time when criteria for CR, PR, and SD are first met until the first date that recurrent or progressive disease or death occurs.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of IMAB362 in Combination With the EOX Regimen for CLDN18.2-positive Gastric Cancer
• Official Title: A Randomized Phase II Multicenter, Open-Label Study Evaluating the Efficacy and Safety of IMAB362 in Combination With the EOX (Epirubicin, Oxaliplatin, Capecitabine) Regimen as First-Line Treatment of Patients With CLDN18.2-Positive Advanced Adenocarcinomas of the Stomach, the Esophagus or the Gastroesophageal Junction

Brief Summary

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Primary Purpose: Treatment

Condition

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

Intervention

• Drug: epirubicin
  Epirubicin will be administered at a dose of 50 mg/m^2 as a 15-minute intravenous infusion on day 1 of each cycle.
• Drug: oxaliplatin
  Oxaliplatin will be administered at a dose of 130 mg/m^2 as a 2-hour intravenous infusion on day 1 of each cycle.
• Drug: capecitabine
  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.
• Drug: zolbetuximab
  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.
  Other Name: IMAB362

Study Arms

• Active Comparator: EOX Treatment
  Participants will receive up to 8 cycles of epirubicin, oxaliplatin and capecitabine (EOX) chemotherapy treatment alone (50 mg/m^2 epirubicin intravenously on day 1 of each cycle, 130 mg/m^2 oxaliplatin intravenously on day 1 of each cycle, 625 mg/m^2 capecitabine orally twice daily on days 1 to 21 of each cycle). The first dose of capecitabine to be taken in the evening of day 1.
  Interventions:

  • Drug: epirubicin
  • Drug: oxaliplatin
  • Drug: capecitabine
• Experimental: EOX+zolbetuximab 800/600 mg/m^2
  Participants will received up to 8 cycles of EOX chemotherapy treatment in combination with zolbetuximab administered as loading dose of 800 mg/m^2 intravenously on day 1 of cycle 1 followed by 600 mg/m^2 intravenously on day 1 of each subsequent cycle. Zolbetuximab to be administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants will be permitted to continue zolbetuximab monotherapy (600 mg/m^2 every 3 weeks to be administered intravenously as a 2-hour infusion) until progressive disease (PD), withdrawal of consent or unacceptable toxicity. PD per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 is defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study, an absolute increase of at least 5mm must also be demonstrated, unequivocal progression of existing non-target lesions and appearance of one or more new lesions is considered progression.
  Interventions:

  • Drug: epirubicin
  • Drug: oxaliplatin
  • Drug: capecitabine
  • Drug: zolbetuximab
• Experimental: EOX+zolbetuximab 1000 mg/m^2
  Participants will receive up to 8 cycles of EOX chemotherapy treatment in combination with zolbetuximab 1000 mg/m^2 intravenously on day 1 of each cycle. Zolbetuximab to be administered prior to EOX chemotherapy. After completion of the EOX treatment phase, participants will be permitted to continue zolbetuximab monotherapy (1000 mg/m^2 every 3 weeks administered intravenously as a 2-hour infusion ) until PD, withdrawal of consent or unacceptable toxicity.
  Interventions:

  • Drug: epirubicin
  • Drug: oxaliplatin
  • Drug: capecitabine
  • Drug: zolbetuximab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 8, 2016): 252
• Original Estimated Enrollment (submitted: June 26, 2012): 140
• Actual Study Completion Date: January 31, 2019
• Actual Primary Completion Date: January 31, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Bulgaria, Czechia, Germany, Latvia, Russian Federation, Ukraine
• Removed Location Countries: Czech Republic

Administrative Information

• NCT Number: NCT01630083
• Other Study ID Numbers: GM-IMAB-001-03; 2011-005285-38 ( EudraCT Number ); 8951-CL-0202 ( Other Identifier: Astellas )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: 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.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• URL: https://www.clinicalstudydatarequest.com/

• Current Responsible Party: Astellas Pharma Inc ( Astellas Pharma Global Development, Inc. )
• Original Responsible Party: Ganymed Pharmaceuticals AG
• Current Study Sponsor: Astellas Pharma Global Development, Inc.
• Original Study Sponsor: Ganymed Pharmaceuticals AG
• Collaborators: Not Provided

Investigators

• Study Director: Executive Director; Astellas Pharma Global Development, Inc.

• PRS Account: Astellas Pharma Inc
• Verification Date: January 2020