CLDN18.2-positive Adenocarcinoma of the Gastroesophageal Junction, CLDN18.2-positive Adenocarcinoma of Esophagus, CLDN18.2-positive Gastric Adenocarcinoma
Conditions
Keywords
IMAB362, ASP8951, zolbetuximab
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.
Interventions
DRUGepirubicin
Epirubicin will be administered at a dose of 50 mg/m\^2 as a 15-minute intravenous infusion on day 1 of each cycle.
DRUGoxaliplatin
Oxaliplatin will be administered at a dose of 130 mg/m\^2 as a 2-hour intravenous infusion on day 1 of each cycle.
DRUGcapecitabine
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.
DRUGzolbetuximab
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.
Sponsors
Astellas Pharma Global Development, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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. |
| 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). |
Countries
Bulgaria, Czechia, Germany, Latvia, Russia, Ukraine
Outcome results
None listed