Efficacy and Safety of IMAB362 in Combination With the EOX Regimen for CLDN18.2-positive Gastric Cancer
- Conditions
- CLDN18.2-positive Adenocarcinoma of the Gastroesophageal JunctionCLDN18.2-positive Gastric AdenocarcinomaCLDN18.2-positive Adenocarcinoma of Esophagus
- Interventions
- Registration Number
- NCT01630083
- Lead Sponsor
- Astellas Pharma Global Development, Inc.
- 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 available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 252
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description EOX+zolbetuximab 1000 mg/m^2 oxaliplatin 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. EOX Treatment epirubicin 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. EOX Treatment oxaliplatin 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. EOX Treatment capecitabine 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. EOX+zolbetuximab 800/600 mg/m^2 oxaliplatin 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. EOX+zolbetuximab 800/600 mg/m^2 epirubicin 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. EOX+zolbetuximab 800/600 mg/m^2 capecitabine 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. EOX+zolbetuximab 800/600 mg/m^2 zolbetuximab 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. EOX+zolbetuximab 1000 mg/m^2 epirubicin 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. EOX+zolbetuximab 1000 mg/m^2 zolbetuximab 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. EOX+zolbetuximab 1000 mg/m^2 capecitabine 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.
- Primary Outcome Measures
Name Time Method Progression-free survival (PFS) 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) 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.
- Secondary Outcome Measures
Name Time Method Time to Progression (TTP) 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) 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.
Duration of Response (DOR) 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).
Clinical PFS 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 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) 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).
Disease Control Rate (DCR) 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.
Trial Locations
- Locations (48)
Site RUS009
🇷🇺Kursk, Russian Federation
Site UKR003
🇺🇦Dnipropetrovsk, Ukraine
Site UKR007
🇺🇦Kyiv, Ukraine
Site RUS015
🇷🇺St.Petersburg, Russian Federation
Site RUS013
🇷🇺Yaroslavl, Russian Federation
Site UKR002
🇺🇦Donetsk, Ukraine
Site UKR009
🇺🇦Zaporizhia, Ukraine
Site CZE002
🇨🇿Olomouc, Czechia
Site GER001
🇩🇪Essen, Germany
Site GER010
🇩🇪Dresden, Germany
Site GER029
🇩🇪Bochum, Germany
Site RUS005
🇷🇺Pyatigorsk, Russian Federation
Site UKR005
🇺🇦Kharkiv, Ukraine
Site UKR001
🇺🇦Donetsk, Ukraine
Site UKR004
🇺🇦Simferopol, Ukraine
Site UKR011
🇺🇦Sumy, Ukraine
Site CZE001
🇨🇿Znojmo, Czechia
Site BUL001
🇧🇬Sofia, Bulgaria
Site BUL005
🇧🇬Sofia, Bulgaria
Site RUS002
🇷🇺Obninsk, Russian Federation
Site UKR008
🇺🇦Ivano-Frankivsk, Ukraine
Site UKR015
🇺🇦Poltava, Ukraine
Site GER012
🇩🇪Bielefeld, Germany
Site GER013
🇩🇪Pinneberg, Germany
Site LAT002
🇱🇻Riga, Latvia
Site RUS016
🇷🇺Bryansk, Russian Federation
Site GER017
🇩🇪Frankfurt, Germany
Site GER005
🇩🇪Halle/Saale, Germany
Site GER020
🇩🇪Leipzig, Germany
Site RUS007
🇷🇺Ivanovo, Russian Federation
Site RUS017
🇷🇺Novgorod, Russian Federation
Site RUS012
🇷🇺Orel, Russian Federation
Site GER029-01
🇩🇪Bochum, Germany
Site LAT001
🇱🇻Liepaja, Latvia
Site RUS023
🇷🇺Omsk, Russian Federation
Site RUS011
🇷🇺Arkhangelsk, Russian Federation
Site RUS003
🇷🇺St.Petersburg, Russian Federation
Site UKR010
🇺🇦Uzhhorod, Ukraine
Site BUL003
🇧🇬Sofia, Bulgaria
Site GER016
🇩🇪Münster, Germany
Site RUS019
🇷🇺Ryazan, Russian Federation
Site BUL002
🇧🇬Varna, Bulgaria
Site RUS001
🇷🇺Moscow, Russian Federation
Site BUL004
🇧🇬Plovdiv, Bulgaria
Site RUS006
🇷🇺Chelyabinsk, Russian Federation
Site RUS014
🇷🇺Orenburg, Russian Federation
Site RUS010
🇷🇺St.Petersburg, Russian Federation
Site UKR006
🇺🇦Lviv, Ukraine