Aflibercept or Bevacizumab as Second-line Treatment of RAS Mutated Metastatic Colorectal Cancer (ARBITRATION)

AflibeRcept or Bevacizumab In Combination With Folfiri as Second-line Treatment of RAS Mutated metastaTIc cOlorectal Cancer patieNts

Colorectal cancer is the third most frequent neoplasm after prostate and lung in man and breast and lung cancers in woman from Western Countries. The intensive study of predictive factors has strongly ameliorated the therapeutic flow-chart of metastatic colorectal cancer (mCRC) by allowing the selection of patients who benefit from specific therapies. In this context, the assessment of RAS (N- and K-) oncogene mutations is able to predict the response to anti-EGFR agents being mutated RAS mCRC patients resistant to these drugs. In this group of patients the use of anti-angiogenic drugs (bevacizumab and aflibercept) is predominant. Still to date there are no studies to guide oncologists in the selection of the best anti-angiogenic drug (bevacizumab beyond progression vs aflibercept) after failure of the first-line chemotherapy in RAS-M mCRC patients. The present is the first observational, pragmatic, prospective study aimed to report outcomes of mCRC patients treated with folfiri plus bevacizumab versus folfiri plus aflibercept in second-line treatment of mRAS mCRC. Furthermore, the serum levels of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), vascular endothelial growth factor-A and C (VEGF-A and C), stromal cell-derived factor-1 (SDF-1), platelet-derived growth factor beta (PDGF-β), basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), chemokine (C-C motif) ligand 2 (CCL2), and chemokine (C-C motif) ligand 5 (CCL5) and Placental Growth Factor (PlGF), will be evaluated before starting second-line chemotherapy with bevacizumab or aflibercept in order to evidence any pattern related to response and/or prognosis. The hypothesis is that knowledge of eventual unbalance of these factors could help to select the best anti-angiogenic drug in second-line treatment of mRAS mCRC patients.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Folfiri/Bevacizumab; Drug: Folfiri/Aflibercept

• Study Type: Observational
• Enrollment (Anticipated): 220

Contacts and Locations

• Study Contact: Name: Alessandro Ottaiano, MD; Phone Number: 0815903510; Email: a.ottaiano@istitutotumori.na.it

Study Locations

• Italy
  • Naples, Italy, 80131
    • Recruiting
    • SSD-Terapie Innovative Metastasi Addominali, Dipartimento di Oncologia Addominale, Istituto Nazionale Tumori di Napoli, IRCCS "G. Pascale".
    • Contact: Guglielmo Nasti, MD; Phone Number: 0815903510; Email: g.nasti@istitutotumori.na.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

mCRC RAS mutated patients progressing at with first-line chemotherapy with at first-line chemotherapy based on fluoropyrimidines, oxaliplatin and bevacizumab.

Description

Inclusion Criteria:

• Cytological or histological diagnosis of RAS mutated mCRC;
• progression at first-line chemotherapy with fluoropyrimidines, oxaliplatin and bevacizumab;
• stage IV;
• age <75 years;
• ECOG Performance Status 0 or 1;
• life expectancy> 3 months;
• negative pregnancy test for all potentially childbearing women.

Exclusion Criteria:

• presence of primary non-treated stenosing colorectal neoplasm;
• active or uncontrolled infections or bleedings;
• other concomitant uncontrolled diseases or blood laboratory values contraindicating the study drugs at clinician evaluation;
• presence of brain metastases;
• refusal or inability to provide informed consent;
• impossibility to guarantee follow-up.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
A; mCRC RAS mutated patients progressing to first-line chemotherapy with fluoropyrimidines, oxaliplatin and bevacizumab.	Drug: Folfiri/Bevacizumab; Irinotecan (180 mg/m2), leucovorin (400 mg/m2), fluorouracil as an intravenous bolus of 400 mg/m2, and fluorouracil as a continuous 46-h infusion of 2400 mg/m2 in combination with bevacizumab (5 mg/kg) on day 1 of each 14-day cycle.
B; mCRC RAS mutated patients progressing to first-line chemotherapy with fluoropyrimidines, oxaliplatin and bevacizumab.	Drug: Folfiri/Aflibercept; Irinotecan (180 mg/m2), leucovorin (400 mg/m2), fluorouracil as an intravenous bolus of 400 mg/m2, and fluorouracil as a continuous 46-h infusion of 2400 mg/m2 in combination with aflibercept (4 mg/kg) on day 1 of each 14-day cycle.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS).	OS will be measured from treatment start until death from any cause.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxic effects.	Toxic effects will be assessed by CTCAE of the National Cancer Institute, version 4.0, June 14, 2010.	3 years
Responses' duration.	Time elapsed from date of response to progression occurrence.	3 years
Progression-free survival (PFS).	PFS will be determined from the date of treatment start until progression.	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum level of VEGF-A (Vascular Endothelial Growth Factor-A).	The molecule will be measured through ELISA test.	3 years
Serum level of PlGF (Placental Growth Factor).	The molecule will be measured through ELISA test.	3 years

Collaborators and Investigators

• Sponsor: National Cancer Institute, Naples
• Investigators: Principal Investigator: Alessandro Ottaiano, MD, SSD-Innovative Therapies for Abdominal Metastases

Publications and helpful links

General Publications

• Ottaiano A, Capozzi M, Tafuto S, De Stefano A, De Divitiis C, Romano C, Avallone A, Nasti G. Folfiri-Aflibercept vs. Folfiri-Bevacizumab as Second Line Treatment of RAS Mutated Metastatic Colorectal Cancer in Real Practice. Front Oncol. 2019 Aug 13;9:766. doi: 10.3389/fonc.2019.00766. eCollection 2019.
• Ottaiano A, Scala S, Santorsola M, Trotta AM, D'Alterio C, Portella L, Clemente O, Nappi A, Zanaletti N, De Stefano A, Avallone A, Granata V, Notariello C, Luce A, Lombardi A, Picone C, Petrillo A, Perri F, Tatangelo F, Di Mauro A, Albino V, Izzo F, Rega D, Pace U, Di Marzo M, Chiodini P, De Feo G, Del Prete P, Botti G, Delrio P, Caraglia M, Nasti G. Aflibercept or bevacizumab in combination with FOLFIRI as second-line treatment of mRAS metastatic colorectal cancer patients: the ARBITRATION study protocol. Ther Adv Med Oncol. 2021 Mar 24;13:1758835921989223. doi: 10.1177/1758835921989223. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2020
• Primary Completion (Anticipated): May 11, 2023
• Study Completion (Anticipated): May 11, 2024

Study Registration Dates

• First Submitted: May 13, 2020
• First Submitted That Met QC Criteria: May 20, 2020
• First Posted (Actual): May 21, 2020

Study Record Updates

• Last Update Posted (Actual): May 21, 2020
• Last Update Submitted That Met QC Criteria: May 20, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab; Aflibercept
• Other Study ID Numbers: 04/20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Complete study protocol will be published.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No