Colorectal Cancer Clinical Trial
— CARCINOSISOfficial title:
Assessment of Histopathological Response to Combination Chemotherapy With Oxaliplatin, Irinotecan, Fluorouracil and Bevacizumab in Patients With Peritoneal Metastasis From Colorectal Cancer
There is a paucity of data on the histopathological response of peritoneal tumor deposits
from colorectal cancer to neoadjuvant chemotherapy. Particularly, no prospective assessment
of chemotherapy-associated histopathological response within the peritoneum has been
performed so far. Therefore, there is an urgent need to conduct a clinical trial aimed at
prospectively assessing the histopathological response within the peritoneum in patients
with peritoneal metastasis from colorectal cancer.
Recently, Loupakis et al. reported that the triplet regimen of 5-fluorouracil, oxaliplatin
and irinotecan (FOLFOXIRI) in combination with bevacizumab significantly improved median
progression-free survival in metastatic colorectal cancer patients from 9.7 to 12.1 months
as compared with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab. In view
of these data, it is likely that FOLFOXIRI + bevacizumab will also lead to a significant
improvement of the histopathological response within the peritoneum of patients with
peritoneal metastasis from colorectal cancer (pcCRC) as compared with previous standard
chemotherapy.
The investigators hypothesize that FOLFOXIRI + bevacizumab will induce a pCR or major
response in peritoneal tumor deposits in >30% of patients (taking the response rate to
FOLFOX- or FOLFIRI-based neoadjuvant chemotherapy from the published literature as a
reference).
Status | Recruiting |
Enrollment | 30 |
Est. completion date | February 2020 |
Est. primary completion date | February 2019 |
Accepts healthy volunteers | No |
Gender | Both |
Age group | 18 Years and older |
Eligibility |
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. Eastern Cooperative Oncology Group (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. Aspartate aminotransferase (AST) and Alanine transaminase (ALT) = 88 U/l (= 175 U/l if liver metastases are present). 10. Alkaline phosphatase = 325 U/l (= 650 U/l if liver metastases are present). 11. Calculated creatinine clearance > 50 mL/min OR serum creatinine = 1.5 mg/dl. 12. Proteinuria < 2+ by dipstick or urine protein <1 g by 24-hr urine collection. 13. Not pregnant or nursing. 14. Negative pregnancy test (for females of childbearing potential). 15. Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last study treatment. 16. Written informed consent. 17. General condition considered feasible for major abdominal surgery after systemic chemotherapy. 18. =3 liver metastases amenable to curative resection using a minor liver resection. 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. 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. 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. 9. History or evidence upon physical/neurological examination of central nervous system (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 cerebrovascular accident (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 Common Toxicity Criteria for Adverse Effects (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. |
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Country | Name | City | State |
---|---|---|---|
Austria | Medical University of Vienna, Department of Internal Medicine I | Vienna | |
Austria | Medical University of Vienna, Department of Surgery | Vienna |
Lead Sponsor | Collaborator |
---|---|
Medical University of Vienna |
Austria,
Cremolini C, Loupakis F, Antoniotti C, Lonardi S, Masi G, Salvatore L, Cortesi E, Tomasello G, Spadi R, Zaniboni A, Tonini G, Barone C, Vitello S, Longarini R, Bonetti A, D'Amico M, Di Donato S, Granetto C, Boni L, Falcone A. Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann Oncol. 2015 Jun;26(6):1188-94. doi: 10.1093/annonc/mdv112. Epub 2015 Feb 23. — View Citation
Elias D, Gilly F, Boutitie F, Quenet F, Bereder JM, Mansvelt B, Lorimier G, Dubè P, Glehen O. Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study. J Clin Oncol. 2010 Jan 1;28(1):63-8. doi: 10.1200/JCO.2009.23.9285. Epub 2009 Nov 16. Erratum in: J Clin Oncol. 2010 Apr 1;28(10):1808. — View Citation
Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. doi: 10.1056/NEJMoa1403108. — View Citation
Passot G, You B, Boschetti G, Fontaine J, Isaac S, Decullier E, Maurice C, Vaudoyer D, Gilly FN, Cotte E, Glehen O. Pathological response to neoadjuvant chemotherapy: a new prognosis tool for the curative management of peritoneal colorectal carcinomatosis. Ann Surg Oncol. 2014 Aug;21(8):2608-14. doi: 10.1245/s10434-014-3647-0. Epub 2014 Mar 26. — View Citation
Verwaal VJ, van Ruth S, de Bree E, van Sloothen GW, van Tinteren H, Boot H, Zoetmulder FA. Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer. J Clin Oncol. 2003 Oct 15;21(20):3737-43. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Percentage of viable cells within the resected peritoneal deposits after completion of neoadjuvant chemotherapy with FOLFOXIRI + bevacizumab. | The percentage of viable cells within the resected specimen after completion of neoadjuvant chemotherapy will be determined. For patients with multiple peritoneal specimens, the median percentage of viable cells in all specimens will be calculated. Patients with 0-49 % of viable cells will be considered as responders. | at the time of surgical re-exploration (days 78 to 106) | No |
Secondary | Change in the percentage of viable cells in peritoneal tumor deposits before and after completion of neoadjuvant chemotherapy. | In case of multiple specimens, the change in the median percentages of viable cells in peritoneal tumor deposits between baseline and after completion of neoadjuvant chemotherapy will be compared. | at the time of surgical re-exploration (days 78 to 106) | No |
Secondary | Change in Peritoneal Cancer Index (PCI) between baseline and after completion of neoadjuvant chemotherapy with FOLFOXIRI + bevacizumab. | at the time of surgical re-exploration (days 78 to 106) | No | |
Secondary | Change in resectability (the ability to achieve a complete surgical cytoreduction) between initial surgical exploration and surgical re-exploration after administration of combination chemotherapy with FOLFOXIRI + bevacizumab. | at the time of surgical re-exploration (days 78 to 106) | No | |
Secondary | Radiologic response to combination chemotherapy with FOLFOXIRI + bevacizumab as assessed by 18F-2-fluoro-2-deoxy-D-glucose (FDG)-PET CT/MRI. | days 71 to 106 | No | |
Secondary | Incidence of treatment-emergent adverse events. | through study completion, an average of 12 months | Yes | |
Secondary | Relapse-free survival (RFS) | from date of complete surgical cytoreduction until the date of first documented relapse, assessed up to 60 months | No | |
Secondary | Progression-free survival (PFS) | from date of study enrolment until metastatic tumor progression or death from any cause, assessed up to 60 months | No | |
Secondary | Overall survival (OS) | through study completion, assessed up to 60 months | No |
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