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Trial record 1 of 1 for:    NORAD-01
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Non Inferiority Study of Preoperative Chemotherapy Without Pelvic Irradiation for Rectal Cancer (NORAD01)

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ClinicalTrials.gov Identifier: NCT03875781
Recruitment Status : Recruiting
First Posted : March 15, 2019
Last Update Posted : January 10, 2020
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE February 18, 2019
First Posted Date  ICMJE March 15, 2019
Last Update Posted Date January 10, 2020
Actual Study Start Date  ICMJE June 2, 2019
Estimated Primary Completion Date June 2, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 14, 2019)
Survival [ Time Frame: 3 years ]
3-year progression-free survival
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03875781 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 14, 2019)
  • Acute treatment toxicity [ Time Frame: Up to 1 month after the end of preoperative treatment ]
    Acute and late treatment related toxicity: the rates of treatment related toxicity grade II or more
  • Late toxicity related to treatment [ Time Frame: 3 years after surgery ]
    Late treatment related toxicity: the rates of treatment related toxicity grade II or more
  • Compliance to treatment [ Time Frame: Up to 1 month after the end of preoperative treatment ]
    The rate of patients that receive full dose treatment
  • Radiological response [ Time Frame: 30±8 days after the end of preoperative treatment ]
    Radiologic response on post-treatment MRI based on tumor size reduction and tumor regression grade (ymrTRG)
  • The rate of R0 resection [ Time Frame: 4 weeks after surgery ]
    Rate of complete resection with safe > 1mm circumferential and longitudinal margin
  • Quality of mesorectal excision: 3-grades Quirke scoring system [ Time Frame: 4 weeks after surgery ]
    3-grades Quirke scoring system of the quality of mesorectal excision
  • Number of lymph nodes harvested [ Time Frame: 4 weeks after surgery ]
    A count of number of lymph nodes harvested
  • Size of circumferential margin [ Time Frame: 4 weeks after surgery ]
    Mesurement of circumferential margin
  • Size of longitudinal margin [ Time Frame: 4 weeks after surgery ]
    Mesurement of longitudinal margin
  • Sphincter saving surgery rate [ Time Frame: 4 weeks after surgery ]
    The rate of surgery with intestinal continuity and anal sphincter preservation
  • Postoperative morbidity [ Time Frame: 30 days after resection ]
    Postoperative morbidity: 30 day or in-hospital postoperative morbidity rates
  • Postoperative mortality [ Time Frame: 30 days after resection ]
    Postoperative mortality: 30 day or in-hospital postoperative mortality rates
  • Pathologic response after chemotherapy [ Time Frame: 4 weeks after surgery ]
    Pathologic response on Rodel Tumor Regression Grade
  • Pathologic response after chemoradiotherapy [ Time Frame: 4 weeks after surgery ]
    Pathologic response after chemoradiotherapy: rate of major pathologic response base on Rodel Tumor Regression Grade
  • Loco-regional recurrence free survival [ Time Frame: At 3 years ]
    Loco-regional recurrence free survival: 3-year locoregional recurrence free survival rates
  • Uncontrolled local recurrence [ Time Frame: At 3 years ]
    Uncontrolled local recurrence: 3-year uncontrolled local recurrence free survival rates
  • Overall survival [ Time Frame: At 3 years ]
    Overall survival: 3 year overall survival rates
  • Overall survival [ Time Frame: At 5 years ]
    Overall survival: 5 year overall survival rates
  • EORTC QLQ-CR29 [ Time Frame: Diagnosis time ]
    Assessed by the validated scales of quality of life for Colorectal Cancer Patients (QLQ-CR29) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 25 to 104 (104 is the worst quality of life)
  • EORTC QLQ-CR29 [ Time Frame: 30±8 days after the end of preoperative treatment ]
    Assessed by the validated scales of quality of life for Colorectal Cancer Patients (QLQ-CR29) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 25 to 104 (104 is the worst quality of life)
  • EORTC QLQ-CR29 [ Time Frame: At 6 months after surgery ]
    Assessed by the validated scales of quality of life for Colorectal Cancer Patients (QLQ-CR29) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 25 to 104 (104 is the worst quality of life)
  • EORTC QLQ-CR29 [ Time Frame: 1 year after surgery ]
    Assessed by the validated scales of quality of life for Colorectal Cancer Patients (QLQ-CR29) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 25 to 104 (104 is the worst quality of life)
  • LARS Scores [ Time Frame: Diagnosis time ]
    Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)
  • LARS Scores [ Time Frame: 30±8 days after the end of preoperative treatment ]
    Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)
  • LARS Scores [ Time Frame: 6 months after surgery ]
    Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)
  • LARS Scores [ Time Frame: 1 year after surgery ]
    Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)
  • Quality of life - physical functioning: QLQ-C30 [ Time Frame: At diagnosis ]
    Health related physical functioning assessed by the validated scale for Cancer Patients (QLQ-C30) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 0 to 100 (100 is the worst physical functioning)
  • Quality of life - physical functioning: QLQ-C30 [ Time Frame: 30±8 days after the end of preoperative treatment ]
    Health related physical functioning assessed by the validated scale for Cancer Patients (QLQ-C30) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 0 to 100 (100 is the worst physical functioning)
  • Quality of life - physical functioning: QLQ-C30 [ Time Frame: 6 months after surgery ]
    Health related physical functioning assessed by the validated scale for Cancer Patients (QLQ-C30) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 0 to 100 (100 is the worst physical functioning)
  • Quality of life - physical functioning: QLQ-C30 [ Time Frame: 1 year after surgery ]
    Health related physical functioning assessed by the validated scale for Cancer Patients (QLQ-C30) of the European Organisation for Research and Treatment of Cancer (EORTC). The scales ranges from 0 to 100 (100 is the worst physical functioning)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Non Inferiority Study of Preoperative Chemotherapy Without Pelvic Irradiation for Rectal Cancer
Official Title  ICMJE Non Inferiority Multicenter Phase III Randomized Trial Comparing Preoperative Chemotherapy Only to Chemoradiotherapy for Locally Advanced Resectable Rectal Cancer (Intergroup FRENCH-GRECCAR- PRODIGE)
Brief Summary

This study is a non-inferiority phase III randomised trial comparing preoperative chemotherapy alone (modified FOLFIRINOX) to chemoradiotherapy in patients with primary resectable locally advanced rectal cancer. The primary endpoint of the study is 3-year progression free survival.

Expected 3 year PFS rate in the preoperative chemoradiotherapy arm is 70%. This hazard rate, in an exponential survival model, corresponds to a decrease in the 3-year PFS rate on the preoperative chemotherapy arm to 62%. The study will randomize 574 patients (287 in the chemotherapy group and 287 in the chemoradiotherapy group) in 39 french academic centers.

Detailed Description

This study is a national, multicenter, open-label randomized, 2-arm phase III non-inferiority trial.

Patients with mid or low LARC (cT3N0 or cT1-T3N+ with CRM > 2 mm on pretreatment MRI) will be randomized to two arms of treatment: one experimental arm with systemic FOLFIRINOX chemotherapy for 3 months and one control arm with conventional standardized radiochemotherapy (intensified-modulated radiotherapy 50Gy + capecitabine). The choice of FOLFIRINOX for preoperative chemotherapy is based on recent data regarding its safety and efficacy rectal cancer with or without metastatic disease. All patients will have reassessment MRI after preoperative treatment and before surgery.

Objectives and study endpoints

- primary endpoint : 3-year progression-free survival (PFS) from the time to randomization. In this trial, a modified definition of PFS will be used for the primary endpoint. The rationale for using this modified definition of PFS is to better assess time to failure of the whole treatment strategy (preoperative treatment and surgery).

Progression will be assessed as follows:

  • progression during preoperative treatment and before surgery: circumferential resection margin < 2mm at MRI reeassessemnt and diagnosis of any new distant lesion whatever the site (liver, lung, peritoneum, adrenal) are considered as progression events.
  • progression after surgery: recurrence/progression after surgery or death, whatever comes first.

    • Secondary endpoints: treatment related toxicity, treatment compliance, R0 resection rate, sphincter saving surgery rate, postoperative morbidity and mortality rates, loco-regional recurrence free survival, overall survival, bowel and sexual functions at diagnosis, quality of life, radiologic and pathologic response after preoperative treatment.

Statistical analysis A sample size of 551 patients, based on an expected accrual duration of 36 months, 60 months minimum follow-up, and an expected 3 year PFS rate in the preoperative chemoradiotherapy arm of 70%, is expected to provide 295 PFS events required to provide 80% power to declare non-inferiority of the preoperative chemotherapy arm when the true hazard ratio between arms is 1.0 (H1). This design has a type one-error rate of 0.05 if the true hazard ratio between arms is 1.34 (H0). This hazard rate, in an exponential survival model, corresponds to a decrease in the 3-year PFS rate on the preoperative chemotherapy arm to 62%. Two interim analyses for efficacy and futility for the primary end point are planned. By considering a rate of 4% for not informative or lost to follow-up patients the total number of patients to be included in this trial was 551*100/96=574 patients.

Ancillary studies Pronostic value of circulating cancer cells before and after preoperative treatment and after surgery in patients undergoing surgery for rectal cancer after chemotherapy or radiochemotherapy will be evaluated. After assessment of prognostic value of each rate on survival, recurrence and response to treatment, evaluation of prognostic impact of variation of the rate during differents phases of treatment will be carried out.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
To demonstrate the non inferiority of preoperative modified FOLFIRINOX chemotherapy compared to radiochemotherapy in primary resectable locally advanced rectal cancer
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Rectal Cancer
  • Advanced Cancer
Intervention  ICMJE
  • Drug: Chemotherapy

    Arm A : Experimental

    • Intervention Type : Drug
    • Intervention Name : Modified FOLFIRINOX (experimental arm)
    • Intervention Description : preoperative chemotherapy: Modified FOLFIRINOX regimen comprised oxaliplatin 85mg/m2 + irinotecan 180mg/m2 + Folinic acid 400 mg/m2 at day1, then 5-FU given as a continuous infusion over 46h every two weeks. Six cycles are planned preoperatively.
  • Drug: Radiochemotherapy

    Arm B: Active comparator

    • Intervention Name : preoperative standardized radiochemotherapy (control arm)
    • Intervention Description : preoperative radiochemotherapy with concurrent capecitabine 825 mg/m2/12h 5 days/week and intensity modulated radiation therapy using a simultaneous integrated boost technique with 45 Gy in 20 fractions in pelvic volume and 50 Gy in 20 fractions to the tumor.
Study Arms  ICMJE
  • Experimental: A: Modified Folfirinox

    Experimental : preoperative chemotherapy:

    Modified FOLFIRINOX regimen comprised oxaliplatin 85mg/m2 + irinotecan 180mg/m2 + Folinic acid 400 mg/m2 at day1, then 5-FU given as a continuous infusion over 46h every two weeks. Six cycles are planned preoperatively.

    Intervention: Drug: Chemotherapy
  • Active Comparator: B: Radiochemotherapy

    Active comparator: preoperative radiochemotherapy:

    Preoperative radiochemotherapy with concurrent capecitabine 825 mg/m2/12h 5 days/week and intensity modulated radiation therapy using a simultaneous integrated boost technique with 45 Gy in 20 fractions in pelvic volume and 50 Gy in 20 fractions to the tumor

    Intervention: Drug: Radiochemotherapy
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 14, 2019)
574
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2, 2024
Estimated Primary Completion Date June 2, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically proven middle or low rectal carcinoma, ≤ 10 cm from the anal verge on MRI (sagittal slide)
  • cT3N0 and/or cT1-T3N+ on pretreatment imaging work up (pelvic contrast enhanced MRI and/or endorectal ultrasound),
  • Pretreatment predictive circumferential margin > 2mm on pretreatment imaging work up (pelvic contrast enhanced MRI)
  • Patients must be 18 years old or older
  • A World Health Organization (WHO/ECOG) performance status of 0 or 1
  • Informed consent signed
  • Patients of childbearing / reproductive potential should use adequate birth control measures during the study treatment period and for at least 6 months after the last study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly.

Exclusion Criteria:

  • Rectal tumor > 10 cm from the anal verge on MRI (sagittal slide)
  • cT4 tumor on pretreatment imaging work up (pelvic contrast enhanced MRI and/or endorectal ultrasound) or involvement of external sphincter
  • Circumferential margin ≤ 2 mm on pretreatment imaging work up (pelvic contrast enhanced MRI)
  • Metastatic disease
  • Prior pelvic irradiation or any contraindication to pelvic irradiation
  • Contraindication to oxaliplatin or irinotecan or 5FU based chemotherapy
  • Concomitant treatment with warfarin is contraindicated and warafarin must be replaced whenever possible to allow for inclusion.
  • contraindications to 5-FU: complete and permanent insufficiency in dihydropyrimidine dehydrogenase, bone marrow insufficiency, chronic and severe infection
  • contraindication to irinotecan : inflammatory bowel disease, bilirubin serum level > 3 times the upper limit of the normal rate, severe bone marrow insufficiency, WHO/ECOG performence status > 2,
  • Concomitant treatment with millepertuis.
  • contraindication to oxaliplatin :

    *bone marrow insufficiency before treatment initiation (neutrophil count <2x109/L and/or platelet count <100x109/L), peripheral neuropathy with permanent invalidity before treatment initiation

  • severe renal insufficiency (Creatinin clearance <30 ml/min)
  • contraindications to folinic acid : Biermer anemia and other anemia related to B12 vitamin insufficiency
  • contraindications to capecitabin : severe renal insufficiency (Creatinin clearance <30 ml/min)
  • live attenuated vaccine should not be used during and 6 months after preoperative treatment.
  • Previous colorectal cancer
  • Other concomitant or previous malignancy, except: i/ adequately treated in-situ carcinoma of the uterine cervix, ii/ basal or squamous cell carcinoma of the skin, iii/ cancer in complete remission for >5 years
  • Presence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
  • protected adults
  • Pregnancy or breastfeeding
  • Patient with no national health or universal plan affiliation coverage.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Stéphane BENOIST, MD,PHD + 33 1 45 21 34 72 stephane.benoist@aphp.fr
Contact: Antoine BROUQUET, MD,PHD + 33 1 45 21 34 70 antoine.brouquet@aphp.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03875781
Other Study ID Numbers  ICMJE P170920J
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Stéphane BENOIST, MD,PHD Service de chirurgie digestive et oncologique Hôpital Bicêtre - 94275 LE KREMLIN BICETRE
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP