A Study of Bevacizumab (Avastin) in Participants With Newly Diagnosed Locally Advanced Rectal Cancer (INOVA)

Efficacy and Safety of Two Neoadjuvant Strategies With Bevacizumab in Locally Advanced Resectable Rectal Cancer: A Randomized, Non-Comparative Phase II Study

This study will assess the efficacy and safety of two different neoadjuvant treatment approaches including bevacizumab in newly diagnosed participants with high risk locally advanced rectal cancer. Participants will be randomized into one of two treatment arms (Arm A or Arm B).

Study Overview

• Status: Completed
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: Bevacizumab; Drug: Oxaliplatin; Drug: Folinic Acid; Drug: 5-fluorouracil; Radiation: Preoperative Radiotherapy; Procedure: Surgery

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Angers, France, 49055
    • ICO Paul Papin; Oncologie Medicale.
  • Angers, France, 49055
  • Besancon, France, 25030
  • Besancon, France, 25030
    • HOPITAL JEAN MINJOZ; Oncologie
  • Bordeaux, France, 33075
  • Bordeaux, France, 33075
    • Hopital Saint Andre; Département de Radiothérapie Et D'Oncologie Médicale
  • Dijon, France, 21079
    • Centre Georges Francois Leclerc; Oncologie 3
  • Dijon, France, 21079
  • La Tronche, France, 38700
  • La Tronche, France, 38700
    • Hopital Albert Michallon; Radiotherapie
  • Lille, France, 59020
  • Lille, France, 59020
    • Centre Oscar Lambret; Radiotherapie
  • Montbeliard, France, 25209
  • Montbeliard, France, 25209
    • Centre Hospitalier Andre Boulloche; Departement D'Oncologie
  • Montpellier, France, 34928
  • Montpellier, France, 34928
    • Centre Val Aurelle Paul Lamarque; Radiotherapie
  • Nancy, France, 54100
  • Nancy, France, 54100
    • Polyclinique Gentilly; CHIMIOTHERAPIE AMBULATOIRE
  • Nice, France, 06189
    • Centre Antoine Lacassagne; Hopital De Jour A2
  • Nice, France, 06189
  • Paris, France, 75970
    • HOPITAL TENON; Cancerologie Medicale
  • Paris, France, 75970
  • Paris, France, 75651
  • Paris, France, 75475
  • Paris, France, 75651
    • Ch Pitie Salpetriere; Oncologie Medicale
  • Paris, France, 75475
    • Hopital Saint Louis; Radiotherapie Oncologie
  • Pierre Benite, France, 69495
  • Pierre Benite, France, 69495
    • Ch Lyon Sud; Radiotherapie Sct Jules Courmont
  • Poitiers, France, 86021
  • Poitiers, France, 86021
    • Chu La Miletrie; Radiotherapie
  • Saint Herblain, France, 44805
    • Ico Rene Gauducheau; Oncologie
  • Saint Herblain, France, 44805
  • Strasbourg, France, 67065
    • Centre Paul Strauss; Oncologie Medicale
  • Strasbourg, France, 67065
  • Toulouse, France, 31078
  • Toulouse, France, 31078
    • Polyclinique Du Parc; Centre De Hautes Energies
  • Tours, France, 37044
  • Tours, France, 37044
    • Hopital Bretonneau; Clinique D'Oncologie & de Radiotherapie
  • Vandoeuvre Les Nancy, France, 54511
  • Vandoeuvre Les Nancy, France, 54511
    • Centre Alexis Vautrin; Oncologie Medicale

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• histologically confirmed locally advanced rectal cancer;
• measurable disease;
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

Exclusion Criteria:

• prior treatment with bevacizumab;
• prior radiotherapy to pelvic region, or previous cytotoxic chemotherapy;
• previous history of malignancy (other than basal and squamous cell cancer of the skin, or in situ cancer of the cervix);
• history or evidence of central nervous system (CNS) disease;
• clinically significant cardiovascular disease;
• chronic treatment with high dose aspirin (more than [>] 325 milligrams per day [mg/day]) or non-steroidal anti-inflammatory drugs.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (Bevacizumab, Induction Chemotherapy, Chemoradiotherapy); In this arm, participants will undergo 3 phases of treatment. During the Phase 1, participants will receive induction chemotherapy with 6 two-week cycles of bevacizumab + Folfox-4 (5-FU + oxaliplatin + folinic acid) for 12 weeks followed by a treatment-free interval of 3 to 4 weeks. The Phase 2 will include 7 weeks of bevacizumab + chemoradiotherapy (intravenous [IV] infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy [5-FU + radiotherapy], with administration of bevacizumab every two weeks [Cycles 1, 3 and 5]) followed by a treatment-free interval of 6 to 8 weeks. The Phase 3 will be surgery involving a radical rectal excision using the total mesorectal excision (TME) technique.	Drug: Bevacizumab; Bevacizumab will be administered at the fixed dose of 5 milligrams per kilogram (mg/kg) as an IV infusion over 30 to 90 minutes.; Other Names: Avastin; Drug: Oxaliplatin; Oxaliplatin will be administered at a dose of 85 milligrams per square meter (mg/m^2) as a 2-hour IV infusion.; Drug: Folinic Acid; Folinic acid will be administered at a dose of 200 mg/m^2 as a 2-hour infusion.; Drug: 5-fluorouracil; 5-fluorouracil will be administered at a dose of 400 mg/m^2 as an IV bolus, then at a dose of 600 mg/m^2 as a continuous infusion for 22 hours in Phase 1, and will be administered at a dose of 225 mg/m^2 as a 24-hour infusion, 5 days a week, for 5 weeks in Phase 2.; Radiation: Preoperative Radiotherapy; Radiotherapy will be delivered in fraction of 1.8 gray per day (Gy/day), 5 days a week for 5 weeks, i.e., a total dose of 45 Gy will be administered in 25 fractions over a period of 33 days.; Procedure: Surgery; Radical rectal excision based on the TME technique.
Experimental: Arm B (Bevacizumab, Chemoradiotherapy); In this arm, participants will receive the Phase 2 and Phase 3 treatments only. The phase 2 will include 7 weeks of bevacizumab + chemoradiotherapy (IV infusion of bevacizumab alone, 2 weeks before administration of the first cycle of chemoradiotherapy, then 5 one-week cycles of chemoradiotherapy [5-FU + radiotherapy], with administration of bevacizumab every two weeks [Cycles 1, 3 and 5]) followed by a treatment-free interval of 6 to 8 weeks. The phase 3 will be surgery involving a radical rectal excision using the TME technique.	Drug: Bevacizumab; Bevacizumab will be administered at the fixed dose of 5 milligrams per kilogram (mg/kg) as an IV infusion over 30 to 90 minutes.; Other Names: Avastin; Drug: 5-fluorouracil; 5-fluorouracil will be administered at a dose of 400 mg/m^2 as an IV bolus, then at a dose of 600 mg/m^2 as a continuous infusion for 22 hours in Phase 1, and will be administered at a dose of 225 mg/m^2 as a 24-hour infusion, 5 days a week, for 5 weeks in Phase 2.; Radiation: Preoperative Radiotherapy; Radiotherapy will be delivered in fraction of 1.8 gray per day (Gy/day), 5 days a week for 5 weeks, i.e., a total dose of 45 Gy will be administered in 25 fractions over a period of 33 days.; Procedure: Surgery; Radical rectal excision based on the TME technique.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Tumor Sterilization Defined by ypT0-N0	Tumor sterilization was defined as the absence of residual tumor cells in the resected specimen including lymph nodes (ypT0-N0). The rate of sterilization of the tumoral specimen was assessed after surgery on the surgical specimen by local review. Analyses were performed for participants who have been operated as defined by the protocol (within the study and TME technique) and for all participants who have been operated. Reported is the percentage of participants with tumor sterilization.	After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Tumor Down-Staging (ypT0-pT2)	A participant with a downstaging was defined as a participant with T3 (T describes the size of the original [primary] tumor) at inclusion and T2 or T1 or T0 after surgery, or with N+ (N describes lymph nodes involvement) at inclusion and N- after surgery and if T is equal at inclusion and after surgery. The clinical tumor-node-metastasis (cTNM) classification was used at inclusion and the pathological staging tumor and nodes (ypTN) classification after surgery. Reported is the percentage of participants with tumor downstaging of the surgical specimen according to the local review and centralized review.	After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)
Percentage of Participants With Local and Distant Recurrences	The percentage of participants with a recurrence was described by type of recurrence (local and distant recurrence).	After surgery (Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment)
Percentage of Participants With Second Cancer, Local or Regional Recurrence, Distant Metastasis, or Death		Baseline up to approximately 6 years
Disease-Free Survival (DFS)	The DFS was defined as the time from the first treatment intake to disease recurrence assessed (second primary cancer, local or distant recurrence, distant metastases) or death from any cause. The DFS was analyzed using Kaplan-Meier method.	From first time of the treatment administration to the date of second cancer, local or regional recurrence, distant metastasis or death from any cause (up to approximately 6 years)
Percentage of Participants Who Died		Baseline up to approximately 6 years
Overall Survival	The overall survival was defined as the time from the first treatment intake to death from any cause.	From the first treatment administration to the date of death (up to approximately 6 years)
Number of Cycles of Induction Chemotherapy		6 cycles (12 weeks; cycle length = 14 days)
Number of Cycles of Chemotherapy		Arm A: Week 16 to Week 23; Arm B: Week 1 to Week 7
Number of Cycles of Radiotherapy		Arm A: Week 16 to Week 23; Arm B: Week 1 to Week 7
Percentage of Participants With Surgery	The surgery involving a radical rectal excision using the TME technique.	Arm A: approximately 28-31 weeks after initiation of treatment; Arm B: approximately 13-15 weeks after initiation of treatment

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Publications and helpful links

General Publications

• Borg C, Andre T, Mantion G, Boudghene F, Mornex F, Maingon P, Adenis A, Azria D, Piutti M, Morsli O, Bosset JF. Pathological response and safety of two neoadjuvant strategies with bevacizumab in MRI-defined locally advanced T3 resectable rectal cancer: a randomized, noncomparative phase II study. Ann Oncol. 2014 Nov;25(11):2205-2210. doi: 10.1093/annonc/mdu377. Epub 2014 Aug 13.

Study record dates

Study Major Dates

• Study Start (Actual): October 23, 2007
• Primary Completion (Actual): March 23, 2016
• Study Completion (Actual): March 23, 2016

Study Registration Dates

• First Submitted: March 18, 2009
• First Submitted That Met QC Criteria: March 18, 2009
• First Posted (Estimate): March 19, 2009

Study Record Updates

• Last Update Posted (Actual): August 4, 2017
• Last Update Submitted That Met QC Criteria: July 31, 2017
• Last Verified: July 1, 2017

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; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Hematinics; Fluorouracil; Oxaliplatin; Bevacizumab; Leucovorin; Levoleucovorin; Folic Acid
• Other Study ID Numbers: ML19202; 2006-003472-35 (EudraCT Number)