Histopathological Response to FOLFOXIRI + Bevacizumab in Peritoneal Metastasis From Colorectal Cancer

NCT02591667 | Unknown Phase 2

• 1 other identifier: 2015-002917-30
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 2

Brief Summary

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).

Conditions

Colorectal Cancer; Peritoneal Metastasis

Keywords

Colorectal cancer; Peritoneal metastasis; Neoadjuvant chemotherapy; 5-Fluorouracil; Oxaliplatin; Irinotecan; Bevacizumab; Histopathological response

Outcome Measures

Primary Outcomes (1)

• 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)

Secondary Outcomes (8)

• Change in the percentage of viable cells in peritoneal tumor deposits before and after completion of neoadjuvant chemotherapy.

  at the time of surgical re-exploration (days 78 to 106)

• 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)

• 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)

• 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

• Incidence of treatment-emergent adverse events.

  through study completion, an average of 12 months

Study Arms (1)

Active treatment

EXPERIMENTAL

Patients will first undergo upfront staging laparoscopy with retrieval of tumor tissue for standard pathology. Two to 4 weeks after initial surgical exploration, patients will receive 4 cycles of FOLFOXIRI + bevacizumab, q2w. The last chemotherapy cycle will be given without bevacizumab. Five to 7 weeks after the last administration of bevacizumab (i.e., 3 to 5 weeks after completion of chemotherapy), patients will undergo surgery with the intent to perform complete surgical cytoreduction of all peritoneal tumor deposits. Further chemotherapy according to the currently available treatment guidelines, including intraperitoneal hyperthermic chemotherapy in patients where complete surgical cytoreduction has been achieved, will be given at the discretion of the investigator.

Procedure: Upfront staging laparoscopy + peritoneal biopsy; Drug: Neoadjuvant chemotherapy with FOLFOXIRI + bevacizumab; Procedure: Surgical re-exploration

Interventions

Upfront staging laparoscopy + peritoneal biopsy PROCEDURE

Upfront staging laparoscopy with biopsy of peritoneal tumor deposits, assessment of peritoneal cancer index and resectability.

Active treatment

Neoadjuvant chemotherapy with FOLFOXIRI + bevacizumab DRUG

Patients will receive 4 cycles of FOLFOXIRI + bevacizumab; the last cycle will be given w/o bevacizumab Dosage: Bevacizumab: 5 mg/kg via 30 min. IV infusion, day 1; Oxaliplatin: 85 mg/m2 via 2-hour IV infusion, day 1; Irinotecan: 165 mg/m2 via 1-hour IV infusion, day 1; Leucovorin: 200 mg/m2 via 2-hour IV infusion, day 1; 5-Fluorouracil: 3200 mg/m2 via 48-hour IV infusion, day 1;

Active treatment

Surgical re-exploration PROCEDURE

Three to 5 weeks after completion of FOLFOXIRI + bevacizumab chemotherapy, patients will undergo surgical re-exploration with the intent to perform a complete surgical cytoreduction. Further chemotherapy according to the currently available treatment guidelines, including intraperitoneal hyperthermic chemotherapy in patients where complete surgical cytoreduction has been achieved, may be given at the discretion of the investigator. Systemic chemotherapy may be started beginning 4 weeks post-surgery and after complete wound healing.

Active treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed carcinoma of the colon or rectum with synchronous or metachronous peritoneal metastasis.
• Male and female patients, aged ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 2.
• Life expectancy ≥ 26 weeks.
• Neutrophils (absolute count) ≥ 1.5 g/l.
• Platelet count ≥ 100 g/l.
• Hemoglobin \> 9 g/dL.
• Total bilirubin ≤ 1.8 mg/dl.
• Aspartate aminotransferase (AST) and Alanine transaminase (ALT) ≤ 88 U/l (≤ 175 U/l if liver metastases are present).
• Alkaline phosphatase ≤ 325 U/l (≤ 650 U/l if liver metastases are present).
• Calculated creatinine clearance \> 50 mL/min OR serum creatinine ≤ 1.5 mg/dl.
• Proteinuria \< 2+ by dipstick or urine protein \<1 g by 24-hr urine collection.
• Not pregnant or nursing.
• Negative pregnancy test (for females of childbearing potential).
• 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.

You may not qualify if:

• 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).
• History of previous cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy.
• Pregnancy or lactation.
• Inability or unwillingness to comply with the protocol.
• 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.
• \>3 liver metastases or any liver metastases not amenable to upfront curative resection using a minor liver resection.
• Treatment with any other investigational agent, or participation in another clinical trial within 30 days prior to entering this study.
• 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).
• Untreated brain metastases, spinal cord compression or primary brain tumors.
• 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).
• 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.
• Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.
• Any previous venous thromboembolism \> NCI Common Toxicity Criteria for Adverse Effects (CTCAE) Grade 3.
• Prior history of hypertensive crisis or hypertensive encephalopathy.
• Evidence of bleeding diathesis or significant coagulopathy.

Sponsors & Collaborators

• Medical University of Vienna: lead

Study Sites (2)

Medical University of Vienna, Department of Internal Medicine I

Vienna, 1090, Austria

RECRUITING

Medical University of Vienna, Department of Surgery

Vienna, 1090, Austria

RECRUITING

Related Publications (5)

• 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.

  PMID: 24668148 BACKGROUND

• 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.

  PMID: 25337750 BACKGROUND

• 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):1188-1194. doi: 10.1093/annonc/mdv112. Epub 2015 Feb 23.

  PMID: 25712456 BACKGROUND

• 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. doi: 10.1200/JCO.2003.04.187.

  PMID: 14551293 BACKGROUND

• Elias D, Gilly F, Boutitie F, Quenet F, Bereder JM, Mansvelt B, Lorimier G, Dube 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.

  PMID: 19917863 BACKGROUND

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Neoadjuvant Therapy; Bevacizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Combined Modality Therapy; Therapeutics; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Thomas Bachleitner-Hofmann, MD

  Medical University of Vienna

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Thomas Bachleitner-Hofmann, MD

CONTACT

+43-1-40400; thomas.bachleitner-hofmann@meduniwien.ac.at

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: ao.Univ.-Prof.Dr.

Study Record Dates

• First Submitted: October 13, 2015
• First Posted: October 29, 2015
• Study Start: March 1, 2016
• Primary Completion: February 1, 2019
• Study Completion: February 1, 2020
• Last Updated: April 5, 2016

Record last verified: 2016-04

Locations

AU (2)