Catumaxomab for Treatment of Peritoneal Carcinomatosis in Patients With Gastric Adenocarcinomas

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy of catumaxomab by determination of the rate of macroscopic complete remissions of peritoneal carcinomatosis after treatment with one cycle (four doses) of catumaxomab followed by six cycles of routine neoadjuvant chemotherapy.

Official Title
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Explorative Trial to Investigate Catumaxomab (Anti-EpCAM x Anti-CD3) for Treatment of Peritoneal Carcinomatosis in Patients With Gastric Adenocarcinomas Prior to Gastrectomy

Conditions
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Gastric Adenocarcinoma With Peritoneal Carcinomatosis, Siewert Type II Adenocarcinoma of Esophagogastric Junction With Peritoneal Carcinomatosis, Siewert Type III Adenocarcinoma of Esophagogastric Junction With Peritoneal Carcinomatosis

Intervention / Treatment
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* Drug: catumaxomab, Fluorouracil, leucovorin, oxaliplatin, docetaxel
* Drug: Fluorouracil, leucovorin, oxaliplatin, docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of resectable gastric adenocarcinoma or adenocarcinoma of the esophagogastric junction (type II and type III according to Siewerts classification) Macroscopic peritoneal carcinomatosis (stage P1-4 according to Gilly et al., appendix 1) Patients potentially eligible for gastrectomy after primary systemic (and intraperitoneal) treatment Signed and dated informed consent before the start of specific protocol procedures Age > 18 years ECOG Performance Status of 0 or 1 Life expectancy of at least 12 weeks Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening Hemoglobin > 10.0 g/dl Leukocyte count > 4.000/μl; absolute neutrophil count (ANC) > 2.000/μl Platelet count > = 100.000/µl Total bilirubin < 1,5 times the upper limit of normal ALT and AST < 3 x upper limit of normal Alkaline phosphatase < 5 x ULN Serum creatinine < 1.5 x upper limit of normal and creatinine clearance > 60 ml/min The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations Exclusion Criteria: Distant metastasis other than peritoneal seedings Prior diagnosis of any malignancy not cured by surgery alone less than 5 years before study entry Clinically significant cardiovascular disease (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) = < 1 year before enrolment History of HIV infection or chronic hepatitis B or C Active, clinically serious infections (> grade 2 NCI-CTC version 3.0) Pre-existing neuropathy > grade 1 (NCI CTCAE), except for loss of tendon reflex Patients with seizure disorder requiring medication (such as steroids or antiepileptics) History of organ allograft Patients undergoing renal dialysis Known hypersensitivity to any of the drugs given in the study; known hypersensitivity to murine (rat and/or mouse) proteins Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study Excluded therapies and medications, previous and concomitant: Prior anti-cancer chemotherapy or immunotherapy. Investigational drug therapy outside of this trial during or within 4 weeks of study entry Major surgery within 4 weeks of starting the study, and patients must have recovered from effects of major surgery Pregnant or breast-feeding patients, or planning to become pregnant within 6 months after the end of treatment. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and for 6 months after the end of treatment Substance abuse, medical, psychological or social conditions that may interfere with the patient's understanding of the informed consent procedure, participation in the study or evaluation of the study results

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: catumaxomab<br>this arm was stopped. the antibody previously used as a study drug is not available at this time. patients will be randomized only into the standard arm [Catumaxomab: 4 intraperitoneal infusions of catumaxomab at an escalating dose of 10µg (d0), 20µg (d3), 50µg (d7), and 150µg (d10) and 7 days after the last catumaxomab infusion FLOT; 6 cycles q2w: Fluorouracil 2600 mg/m² as 24h infusion (d1) , leucovorin 200mg/m² (d1), oxaliplatin 85 mg{m² (d1), docetaxel 50 mg/m² (d1)) | Drug: catumaxomab, Fluorouracil, leucovorin, oxaliplatin, docetaxel<br>* Catumaxomab: 4 intraperitoneal infusions of catumaxomab at an escalating dose of 10µg (d0), 20µg (d3), 50µg (d7), and 150µg (d10) and 7 days after the last catumaxomab infusion FLOT; 6 cycles q2w: Fluorouracil 2600 mg/m² as 24h infusion (d1) , leucovorin 200mg/m² (d1), oxaliplatin 85 mg{m² (d1), docetaxel 50 mg/m² (d1)<br>* Other names: Catumaxomab + FLOT;|
| Active Comparator: standard therapy<br>FLOT; 6 cycles q2w: Fluorouracil 2600 mg/m² as 24h infusion (d1) leucovorin 200mg/m² (d1) oxaliplatin 85 mg{m² (d1) docetaxel 50 mg/m² (d1) | Drug: Fluorouracil, leucovorin, oxaliplatin, docetaxel<br>* FLOT; 6 cycles q2w: Fluorouracil 2600 mg/m² as 24h infusion (d1) leucovorin 200mg/m² (d1) oxaliplatin 85 mg{m² (d1) docetaxel 50 mg/m² (d1)<br>* Other names: FLOT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of macroscopic complete remissions of peritoneal carcinomatosis | Macroscopic complete response (mCR) rate of the peritoneal lesions, as resulting from the second diagnostic laparoscopy or laparotomy performed after chemotherapy. | Assessment after 14 - 18 weeks after start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surgical resection rate (R0, R1, R2) | All tumor evaluation is performed according to RECIST | Assessment after 14 - 18 weeks after start of treatment | 
| Overall survival (OS) | The duration of overall survival (OS) will be determined by measuring the time interval from randomization to the date of death or last observation (censored). | Assessment over minimum 16 months up to 3 years | 
| Disease-free survival (DFS) | Disease-free survival (DFS) will be defined as the time from surgery, resulting in a R0 finding and macroscopic complete remission of PC, to the time of disease progression or relapse (according to RECIST) or death, or to the date of last assessment without any such event (censored observation). Patients with evidence of disease at surgery are counted as having the event at time = 0. | Assessment over minimum 16 months up to 3 years | 
| Progression-free survival (PFS) | Progression-free survival (PFS) will be defined as the time from randomization to the time of disease progression or relapse (according to RECIST) or death, or to the date of last assessment without any such event (censored observation). | Assessment over minimum 16 months up to 3 years | 
| Frequency, relationship, and severity of AEs |  | Assessment over minimum 16 months up to 3 years | 
| Immunoreaction against tumor in tissue samples | blood and tumor tissue from every patient assed at 2time points. the first Laparoscopy (before randomization)and the second Laparoscopy (after chemotherapy) | 14 - 18 weeks | 
| Detection of disseminated tumor cells via PCR | blood and tumor tissue from every patient assessed at 2time points. the first Laparoscopy (before randomization) and the second Laparoscopy (after chemotherapy) | 14 - 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adenocarcinoma, Esophagogastric Junction, Peritoneal Carcinomatosis, Catumaxomab, AIO-STO-0110