Patients with peritoneal carcinomatosis from colorectal cancer are treated with a combination chemotherapy (FOLFOXIRI+ Bevacizumab) MedDRA version: 20.0 Level: PT Classification code 10052358 Term: Colorectal cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: LLT Classificat
Conditions
Interventions
Trade Name: Fluorouracil Accord 50 mg/ml, Solution for Injection or Infusion
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: FLUOROURACIL
Sponsors
Medical University of Vienna
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: General inclusion criteria: 1. Histologically confirmed carcinoma of the colon or rectum with synchronous or metachronous peritoneal metastasis. 2. Male and female patients, aged = 18 years. 3. ECOG performance score of = 2. 4. Life expectancy = 26 weeks. 5. Neutrophils (absolute count) = 1.5 g/l. 6. Platelet count = 100 g/l. 7. Hemoglobin > 9 g/dL. 8. Total bilirubin = 1.8 mg/dl. 9. AST and ALT = 88 U/l (= 175 U/l if liver metastases present). 10. Alkaline phosphatase = 325 U/l (= 650 U/l if liver metastases present). 11. Calculated creatinine clearance > 50 mL/min OR serum creatinine = 1.5 mg/dl. 12. Proteinuria =65 years) yes F.1.3.1 Number of subjects for this age range 25
Exclusion criteria
Exclusion criteria: General exclusion criteria: 1. Major surgical procedure or significant traumatic injury within 28 days prior to study enrolment (surgical exploration with diagnostic biopsy/sampling of peritoneal tumor deposits but without bowel resection or comparable surgical procedure is allowed). 2. History of previous cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy. 3. Pregnancy or lactation. 4. Inability or unwillingness to comply with the protocol. Resectability: 5. Evidence of current extraabdominal metastatic disease. Prior extraabdominal metastatic disease is allowed, provided that it has been curatively resected =6 months before study entry and that current staging shows no evidence of disease recurrence. 6. >3 liver metastases or any liver metastases not amenable to upfront curative resection using a minor liver resection. Prior treatment: 7. Prior systemic chemotherapy completed =3 months before study inclusion. 8. Treatment with any other investigational agent, or participation in another clinical trial within 30 days prior to entering this study. Other disease or conditions: 9. History or evidence upon physical/neurological examination of CNS disease (unrelated to cancer) unless adequately treated with standard medical therapy (e.g. uncontrolled seizures) 10. Untreated brain metastases, spinal cord compression or primary brain tumors. 11. Past or current history (within the last 2 years prior to treatment start) of other malignancies except colorectal cancer (patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible). 12. Clinically significant cardiovascular disease, for example CVA, myocardial infarction (£ 12 months before treatment start), unstable angina, New York Heart Association (NYHA) > Class II congestive heart failure (CHF), arrhythmia requiring medication, or uncontrolled hypertension. 13. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment. 14. Any previous venous thromboembolism > NCI CTCAE Grade 3. 15. Prior history of hypertensive crisis or hypertensive encephalopathy. 16. Evidence of bleeding diathesis or significant coagulopathy. 17. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to the first study treatment. 18. Known hypersensitivity to any of the study drugs. 19. Serious, non-healing wound, ulcer or bone fracture. 20. Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that puts the patient at high risk for treatment-related complications. 21. Symptomatic peripheral neuropathy = grade 1 according to the NCI Common Toxicity Criteria.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: • During Re-exploratory/surgical cytoreduction (3 to 5 weeks after completion of chemotherapy (days 78 to 106)) ; Main Objective: The primary objective of the study is to prospectively assess the histopathological response to neoadjuvant chemotherapy with FOLFOXIRI + bevacizumab in peritoneal tumor deposits of 30 patients with pcCRC by determining the % of viable tumor cells (vtc) in the resected specimen after neoadjuvant chemotherapy using standard pathology. In case of multiple specimens, the median % of viable cells will be calculated and used for analysis. The timepoint of the assessment of the primary objective will be during re-exploratory surgery/surgical cytoreduction between days 78 and 106 of the treatment phase of the study. We hypothesize that there will be >30% responders after neoadjuvant FOLFOXIRI + bevacizumab treatment. Responders will be defined as patients with pCR (0% vtc) and major response (1-49% vtc) after FOLFOXIRI + bevacizumab chemotherapy. Non-responders will be defined as patients with minor/no response (=50% vtc) after FOLFOXIRI + bevacizumab chemotherapy. ; Secondary Objective: •%of viable tumor cells in peritoneal tumor deposits(ptd)before vs after neoadjuvant chemotherapy(NAC) •Peritoneal Cancer Index before/after FOLFOXIRI+bevacizumab(BV)treatment •resectability at initial surgical exploration vs surgical re-exploration after FOLFOXIRI+BV treatment •(FDG-PET) CT/MRI at baseline(BL)vs after NAC and before surgical re-exploration •Immuno-infiltrate(II)of ptd before vs after chemotherapy,II of primary tumors vs II in ptd at BL •PD-1/PD-L1 expression on immune/tumor cells within the microenvironment of ptd before/after FOLFOXIRI+BV treatment,comparison of PD-1/PD-L1 expression in primary tumors and ptd at BL • | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): - To determine the change in the percentage of viable cells in peritoneal tumor deposits by comparing the percentage of viable tumor cells in the specimens before and after neoadjuvant chemotherapy. In case of multiple specimens, the median percentages before and after chemotherapy will be compared. - To determine the clinical response to combination chemotherapy with FOLFOXIRI + bevacizumab within the peritoneum by assessing the Peritoneal Cancer Index (PCI) before and after combination chemotherapy with FOLFOXIRI + bevacizumab. - To compare resectability at the time of initial surgical exploration with resectability at surgical re-exploration after administration of combination chemotherapy with FOLFOXIRI + bevacizumab. - To asses the radiologic response to combination chemotherapy with FOLFOXIRI + bevacizumab by comparing the (FDG-PET) CT/MRI at baseline with the (FDG-PET) CT/MRI after completion of neoadjuvant chemotherapy/before surgical re-exploration. - To compare the immuno-infiltrate of peritoneal tumor deposits before and after combination chemotherapy with FOLFOXIRI + bevacizumab as well as to compare the immuno-infiltrate of primary tumors with that of peritoneal tumor deposits at baseline. - To assess the expression of PD-1/PD-L1 on immune and tumor cells within the microenvironment of peritoneal tumor deposits before and after combination chemotherapy with FOLFOXIRI + bevacizumab as well as to compare the expression of PD-1/PD-L1 in primary tumors with that of peritoneal tumor deposits at baseline. - To assess cancer stem cell distribution within peritoneal tumor deposits and its association with hypoxia before and after neoadjuvant anti-angiogenic therapy with FOLFOXIRI + bevacizumab. - To perform serial measurements of surrogate parameters for response, including but not limited to methylated septin-9, at baseline, d | — |
Countries
Austria
Contacts
Public ContactDepartment of Surgery
Medical University of Vienna
Outcome results
None listed