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Bevacizumab With Pelvic Radiotherapy And Primary Chemotherapy in Patients With Poor-Risk Rectal Cancer (BRANCH)

Primary Purpose

Rectal Cancer

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Radiation therapy
Oxaliplatin
Raltitrexed
levofolinic acid
5-fluorouracil
Bevacizumab
Sponsored by
National Cancer Institute, Naples
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rectal Cancer focused on measuring locally advanced, high risk, preoperative therapy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients with histologically or cytologically confirmed diagnosis of locally advanced rectal cancer (LARC) at high risk of recurrence (T4, N+, T3N0 with tumor located in the lower third of the rectum and/or circumferential resection margin (CRM) £5 mm), or LARC with resectable organ metastasis (M1).
  • Age 18 years or older
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
  • Life expectancy of at least 12 weeks
  • Measurable and/or evaluable (resectable organ metastasis)lesions according to RECIST criteria
  • Neutrophils > 1500 and Platelets > 100,000 /L
  • Total bilirubin < or = 1.5 time the upper-normal limits (UNL) of the Institutional normal values and ASAT (SGOT) and/or ALAT (SGPT) < or = 2.5 x UNL, or < or = 5 x UNL in case of liver metastases, alkaline phosphatase < or = 2.5 x UNL, or < or = 5 x UNL in case of liver metastases.
  • Creatinine clearance > 50 mL/min or serum creatinine < or = 1.5 x UNL
  • Urine dipstick of proteinuria < 2+. Patients discovered to have > or = 2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate < or = 1 g of protein/24 hr.
  • Written informed consent.
  • Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating Center

Exclusion Criteria:

  • Prior radiotherapy or chemotherapy for rectal cancer.
  • Untreated brain metastases or spinal cord compression or primary brain tumours
  • History or evidence upon physical examination of CNS disease unless adequately treated (e.g., seizure not controlled with standard medical therapy or history of stroke).
  • History of inflammatory bowel disease and/or acute/subacute bowel occlusion
  • Serious, non-healing wound, ulcer, or bone fracture
  • Evidence of bleeding diathesis or coagulopathy.
  • Uncontrolled hypertension
  • Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular accidents (≤ 6 months), myocardial infarction (≤ 6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication
  • Current or recent (within 10 days prior to study treatment start) ongoing treatment with anticoagulants for therapeutic purposes.
  • Chronic, daily treatment with high-dose aspirin (>325 mg/day) or other medications known to predispose to gastrointestinal ulceration.
  • Treatment with any investigational drug within 30 days prior to enrolment.
  • Patients with known allergy to Chinese hamster ovary cell proteins, or any of the components of the study medications
  • Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of basal and squamous cell carcinoma or cervical cancer in situ
  • Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study.
  • Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    preoperative chemoradiotherapy

    Arm Description

    Preoperative radiation therapy and combination chemotherapy plus bevacizumab

    Outcomes

    Primary Outcome Measures

    Percentage of Patients With Complete Tumor Regression Rate (TRG1)
    Complete tumor regression rate (TRG1) was the ratio of patients with TRG1, graded at surgical resection, and total patients included in the study, expressed in percentage. Tumor regression grade (TRG) was misured according to the Mandard Scale. Briefly,TRG1 was a complete tumor regression (regardless of the presence of acellular mucine lakes), and TRG2 was a nearly complete tumor regression with extensive fibrosis; TRG3 presented with clear evidence of residual cancer cells but with predominant fibrosis;TRG4 was a residual of cancer cells outgrowing fibrosis; TRG5 was the absence of regressive changes.

    Secondary Outcome Measures

    Number of Participants With Adverse Events
    Number of Participants with Adverse Events as a Measure of Safety and Tolerability
    Number of Patients With Sphincter Preservation
    Sphincter preservation in patients with tumor < 5 cm from anal verge in 8 weeks after chemoradiation therapy
    Progression Free Survival (PFS)
    PFS was calculated from the date of the initial treatment until tumor progression or relapse, death for any cause or last follow up. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
    Overall Survival (OS)
    OS was calculated from the date of initial treatment to the date of death for any cause or last follow up.
    Clinical Response Rate
    Clinical response was assessed before surgery with the same imaging modalities that were used for the inclusion in the study. Clinical response rate was the ratio between complete and partial response, evaluated by RECIST CRITERIA, and total of patients evaluated, expressed in percentage of patients. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    Patients With Metastatic Lymphnodes at Pathology Exam After Surgery
    Number of patients with metastatic lymphnodes at pathology exam after surgery.

    Full Information

    First Posted
    November 11, 2011
    Last Updated
    January 13, 2021
    Sponsor
    National Cancer Institute, Naples
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    1. Study Identification

    Unique Protocol Identification Number
    NCT01481545
    Brief Title
    Bevacizumab With Pelvic Radiotherapy And Primary Chemotherapy in Patients With Poor-Risk Rectal Cancer
    Acronym
    BRANCH
    Official Title
    Bevacizumab With Pelvic Radiotherapy And Primary Chemotherapy in Patients With Poor-Risk Rectal Cancer: the BRANCH Trial
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    September 2020
    Overall Recruitment Status
    Completed
    Study Start Date
    December 2006 (Actual)
    Primary Completion Date
    July 2011 (Actual)
    Study Completion Date
    December 2016 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    National Cancer Institute, Naples

    4. Oversight

    Data Monitoring Committee
    No

    5. Study Description

    Brief Summary
    The purpose of this study is to evaluate the use of chemotherapy, radiation therapy and bevacizumab before surgery in patients with locally advanced rectal cancer (LARC).
    Detailed Description
    To determine the pathological complete response (pCR-TRG1) rate in patients treated with 2 different schedule of bevacizumab plus primary chemotherapy and radiotherapy of the pelvic region when optimal surgery is applied. Bevacizumab will be given by intravenous infusion at the dose of 5 mg/kg concurrent with chemotherapy and radiotherapy every 2 weeks for 4 cycles from -14 days to start chemo-radiotherapy (classical schedule) or 4 days before the concurrent administration of chemotherapy and radiation therapy for 2 cycles if the number of TRG1 was not reached in the first stage with the classical schedule Simon's methods will be used to calculate sample size.Setting a and b errors as 0.05 and 0.20, respectively, and defining as minimum activity of interest (p0) a TRG1 rate=30%. In order to demonstrate a TRG1 rate ≥50% (p1), at least 6 TRG1 on the first 15 patients, and at least 19 TRG1 on a total of 46 patients should be reported in the first and second stage, respectively.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Rectal Cancer
    Keywords
    locally advanced, high risk, preoperative therapy

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    62 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    preoperative chemoradiotherapy
    Arm Type
    Experimental
    Arm Description
    Preoperative radiation therapy and combination chemotherapy plus bevacizumab
    Intervention Type
    Radiation
    Intervention Name(s)
    Radiation therapy
    Intervention Description
    Radiation therapy will be administered at the total dose of 45 Gy, given with five weekly fractions over a period of 5 weeks. The daily fraction dose will be 1.8 Gy
    Intervention Type
    Drug
    Intervention Name(s)
    Oxaliplatin
    Intervention Description
    100 mg/m2 on day 1 every 2 weeks for 3 cycles (for patients with resectable organ metastases (M1), an additional 2 cycles of chemotherapy will be given after radiation therapy)
    Intervention Type
    Drug
    Intervention Name(s)
    Raltitrexed
    Intervention Description
    2.5 mg/m2 on day 1 every 2 weeks for 3 cycles (for patients with resectable organ metastases (M1) , an additional 2 cycles of chemotherapy will be given after radiation therapy)
    Intervention Type
    Drug
    Intervention Name(s)
    levofolinic acid
    Intervention Description
    250 mg/m2 on day 2 every 2 weeks for 3 cycles (for patients with resectable organ metastases (M1), an additional 2 cycles of chemotherapy will be given after radiation therapy)
    Intervention Type
    Drug
    Intervention Name(s)
    5-fluorouracil
    Intervention Description
    800 mg/m2 on day 2 every 2 weeks for 3 cycles (for patients with resectable organ metastases (M1), an additional 2 cycles of chemotherapy will be given after radiation therapy)
    Intervention Type
    Drug
    Intervention Name(s)
    Bevacizumab
    Intervention Description
    will be given by intravenous infusion at the dose of 5 mg/kg concurrent with chemotherapy and radiotherapy every 2 weeks for 4 cycles from -14 days to start chemo-radiotherapy (classical schedule) or 4 days before the concurrent administration of chemotherapy and radiation therapy for 2 cycles if the number of TRG1 was not reached in the first stage (statistical design) with the classical schedule (for patients with resectable organ metastases (M1), one additional administration of bevacizumab will be given after radiation therapy)
    Primary Outcome Measure Information:
    Title
    Percentage of Patients With Complete Tumor Regression Rate (TRG1)
    Description
    Complete tumor regression rate (TRG1) was the ratio of patients with TRG1, graded at surgical resection, and total patients included in the study, expressed in percentage. Tumor regression grade (TRG) was misured according to the Mandard Scale. Briefly,TRG1 was a complete tumor regression (regardless of the presence of acellular mucine lakes), and TRG2 was a nearly complete tumor regression with extensive fibrosis; TRG3 presented with clear evidence of residual cancer cells but with predominant fibrosis;TRG4 was a residual of cancer cells outgrowing fibrosis; TRG5 was the absence of regressive changes.
    Time Frame
    In 8 weeks after completion of chemoradiotherapy
    Secondary Outcome Measure Information:
    Title
    Number of Participants With Adverse Events
    Description
    Number of Participants with Adverse Events as a Measure of Safety and Tolerability
    Time Frame
    Up to 8 weeks after surgery
    Title
    Number of Patients With Sphincter Preservation
    Description
    Sphincter preservation in patients with tumor < 5 cm from anal verge in 8 weeks after chemoradiation therapy
    Time Frame
    In 8 weeks after chemoradiation therapy
    Title
    Progression Free Survival (PFS)
    Description
    PFS was calculated from the date of the initial treatment until tumor progression or relapse, death for any cause or last follow up. Progression was defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
    Time Frame
    10 years
    Title
    Overall Survival (OS)
    Description
    OS was calculated from the date of initial treatment to the date of death for any cause or last follow up.
    Time Frame
    10 years
    Title
    Clinical Response Rate
    Description
    Clinical response was assessed before surgery with the same imaging modalities that were used for the inclusion in the study. Clinical response rate was the ratio between complete and partial response, evaluated by RECIST CRITERIA, and total of patients evaluated, expressed in percentage of patients. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    Time Frame
    7 weeks after chemoradiation therapy up to 11 weeks
    Title
    Patients With Metastatic Lymphnodes at Pathology Exam After Surgery
    Description
    Number of patients with metastatic lymphnodes at pathology exam after surgery.
    Time Frame
    In 8 weeks after chemoradiation therapy completion

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Patients with histologically or cytologically confirmed diagnosis of locally advanced rectal cancer (LARC) at high risk of recurrence (T4, N+, T3N0 with tumor located in the lower third of the rectum and/or circumferential resection margin (CRM) £5 mm), or LARC with resectable organ metastasis (M1). Age 18 years or older Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 Life expectancy of at least 12 weeks Measurable and/or evaluable (resectable organ metastasis)lesions according to RECIST criteria Neutrophils > 1500 and Platelets > 100,000 /L Total bilirubin < or = 1.5 time the upper-normal limits (UNL) of the Institutional normal values and ASAT (SGOT) and/or ALAT (SGPT) < or = 2.5 x UNL, or < or = 5 x UNL in case of liver metastases, alkaline phosphatase < or = 2.5 x UNL, or < or = 5 x UNL in case of liver metastases. Creatinine clearance > 50 mL/min or serum creatinine < or = 1.5 x UNL Urine dipstick of proteinuria < 2+. Patients discovered to have > or = 2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate < or = 1 g of protein/24 hr. Written informed consent. Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating Center Exclusion Criteria: Prior radiotherapy or chemotherapy for rectal cancer. Untreated brain metastases or spinal cord compression or primary brain tumours History or evidence upon physical examination of CNS disease unless adequately treated (e.g., seizure not controlled with standard medical therapy or history of stroke). History of inflammatory bowel disease and/or acute/subacute bowel occlusion Serious, non-healing wound, ulcer, or bone fracture Evidence of bleeding diathesis or coagulopathy. Uncontrolled hypertension Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular accidents (≤ 6 months), myocardial infarction (≤ 6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication Current or recent (within 10 days prior to study treatment start) ongoing treatment with anticoagulants for therapeutic purposes. Chronic, daily treatment with high-dose aspirin (>325 mg/day) or other medications known to predispose to gastrointestinal ulceration. Treatment with any investigational drug within 30 days prior to enrolment. Patients with known allergy to Chinese hamster ovary cell proteins, or any of the components of the study medications Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of basal and squamous cell carcinoma or cervical cancer in situ Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study. Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Antonio Avallone, M.D.
    Organizational Affiliation
    National Cancer Institute, Naples
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Learn more about this trial

    Bevacizumab With Pelvic Radiotherapy And Primary Chemotherapy in Patients With Poor-Risk Rectal Cancer

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