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Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer (GRECCAR 15)

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ClinicalTrials.gov Identifier: NCT03879109
Recruitment Status : Recruiting
First Posted : March 18, 2019
Last Update Posted : August 5, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital, Bordeaux

Tracking Information
First Submitted Date  ICMJE March 13, 2019
First Posted Date  ICMJE March 18, 2019
Last Update Posted Date August 5, 2019
Actual Study Start Date  ICMJE July 8, 2019
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 15, 2019)
Proportion of curative surgery [ Time Frame: At surgery, expected average 6 to 8 weeks after neoadjuvant treatment ]
To determine the rate of R0 resection
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03879109 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 15, 2019)
  • Disease Free Survival [ Time Frame: From surgery until 3 years of follow-up ]
    Rate of disease-free survival at 3 years
  • Overall Survival [ Time Frame: From surgery until 3 years of follow-up ]
    Rate of overall survival at 3 years
  • Surgical morbidity [ Time Frame: From surgery until 30 days after surgery ]
    To analyse surgical morbidity (Dindo classification) during first 30 days after the surgery
  • Surgical mortality [ Time Frame: From surgery until 30 days after surgery ]
    To analyse surgical mortality (Dindo classification) during first 30 days after the surgery
  • Compliance to treatment [ Time Frame: From beginning of neoadjuvant treatment until surgery, expected average 20 weeks after neoadjuvant treatment ]
    Proportion of patients receiving full allocated neoadjuvant treatment
  • Proportion of good tumor response [ Time Frame: At 6 weeks (Arm A) and 4 weeks (Arm B) after neoadjuvant treatment ]
    Rate of tumor with a decreasing size of 50% at least after preoperative treatment at MRI
  • Quality of life [ Time Frame: Before neoadjuvant treatment, before surgery, 4 months, one year and two years after surgery ]
    To examine score of questionnaires QLQ CR-30, QLQ CR-29
  • Tolerance to treatment [ Time Frame: From beginning of neoadjuvant treatment until 1 year after surgery ]
    Number of patients with adverse events
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 Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer
Official Title  ICMJE A Phase III Randomized Trial Evaluating Chemotherapy Followed by Pelvic Reirradiation Versus Chemotherapy Alone as Pre-operative Treatment for Locally Recurrent Rectal Cancer (GRECCAR - PRODIGE - FRENCH)
Brief Summary

GRECCAR 15 is focused on Locally Recurrent Rectal Cancer (LRRC) for patients with previous pelvic radiotherapy for the primary rectal cancer. This situation leads to a 20% higher risk of non-curative resection for the LRRC management (R1 status) impacting significantly the overall survival. The widespread use of neoadjuvant radiotherapy for primary rectal cancer introduces this new problem: the treatment of LRRC in previously irradiated area.

The objective of GRECCAR 15 is to assess the efficacy of neoadjuvant chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone on the rate of curative surgery (R0) in previously irradiated patients with LRRC.

Detailed Description

The incidence of rectal cancer in the European Union is 15-25/100 000 per year. There is a 5-10% rate of locally recurrent rectal cancer (LRRC), with an overall survival rate of 40% at 5 years after complete resection. Curative surgery of LRRC requires multi-visceral resections which are associated with significant post-operative morbidity of 60%. Despite the combination of a potential curability and the high post-operative morbidity, there are currently neither good data from prospective randomized studies regarding optimum preoperative treatments for LRRC nor is there data assessing the efficacy of response to any such treatments. Moreover, the widespread use of neoadjuvant radiotherapy for primary cancer introduced a new problem: the treatment of LRRC in previously irradiated area. Some studies investigated various modalities of reirradiation and showed acceptable late toxicity and encouraging outcome. GRECCAR 15 would be the first prospective randomized trial so far to evaluate the interest of pelvic reirradiation for LRRC, in previously irradiated patients.

The objective is to assess the efficacy of neoadjuvant chemotherapy followed by pelvic reirradiation versus neoadjuvant chemotherapy alone on the rate of curative surgery (R0) in previously irradiated patients with LRRC.

Patients will be followed every 4 months during 2 years, and every 6 months the last year with chest, abdominal and pelvic scan and tumour markers.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Rectal Cancer
Intervention  ICMJE
  • Drug: Chemotherapy FOLFIRINOX, 6 cycles
    • oxaliplatin: 85 mg/m2
    • irinotecan: 180 mg/m²
    • folinic acid: 400 mg/m2
    • 5FU : 400 mg/m2 (bolus)
    • 5FU : 2400 mg/m2 (continuous infusion)
  • Radiation: Radiochemotherapy
    Reirradiation consists in conformational intensity modulated external irradiation (Intensity-modulated radiotherapy Volumetric Modulated Arc Therapy or tomotherapy) delivering a 30.6 Gy dose with high-energy photons in fractions of 1.8 Gy per day (17 fractions) 5 days a week With Concomitant chemotherapy including Capecitabine 1600 mg/m²/day, five days a week.
  • Procedure: Surgery

    Surgery will be performed at:

    • Arm A: 8 weeks (±1) after the end of treatment
    • Arm B: 6 weeks (±1) after the end of treatment

    Surgical procedures are defined into three categories:

    • Total mesorectal excision (TME)
    • Extended-TEM (e-TME)
    • Pelvic exenteration (PE)
Study Arms  ICMJE
  • Experimental: Arm A: Induction Chemotherapy followed by Pelvic reirradiation

    Protocol of chemotherapy FOLFIRINOX*, 6 cycles :

    • oxaliplatin: 85 mg/m2
    • irinotecan: 180 mg/m²
    • folinic acid: 400 mg/m2
    • 5FU : 400 mg/m2 (bolus)
    • 5FU : 2400 mg/m2 (continuous infusion)

    Protocol of reirradiation consists in conformational intensity modulated external irradiation, delivering a 30.6 Gy dose (1.8 Gy/day), with concomitant chemotherapy including Capecitabine 1600 mg/m²/day, five days a week.

    Interventions:
    • Drug: Chemotherapy FOLFIRINOX, 6 cycles
    • Radiation: Radiochemotherapy
    • Procedure: Surgery
  • Active Comparator: Arm B: Chemotherapy alone

    Protocol of chemotherapy FOLFIRINOX*, 6 cycles :

    • oxaliplatin: 85 mg/m2
    • irinotecan: 180 mg/m²
    • folinic acid: 400 mg/m2
    • 5FU : 400 mg/m2 (bolus)
    • 5FU : 2400 mg/m2 (continuous infusion)
    Interventions:
    • Drug: Chemotherapy FOLFIRINOX, 6 cycles
    • Procedure: Surgery
Publications * Not Provided

*   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 15, 2019)
186
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2025
Estimated Primary Completion Date July 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Signed and dated informed consent
  • Age ≥18 years
  • LRRC (histologically proven) ≤ 15 cm from the anal verge
  • Previous pelvic irradiation for the primary rectal cancer
  • No distant metastasis
  • Resectable locally recurrent rectal cancer (according to the International consensus, absolute contraindications for resectabililty are bilateral sciatic nerve involvement, circumferential bone involvement, high sacral involvement requiring total sacrectomy; relative contraindications for resectabilty are sciatic notch involvement and encasement external iliac vessels)
  • Adequate hematologic function : Hemoglobin ≥ 9 g/dL, leukocytes ≥ 4000/mm3, neutrophil count ≥ 2000/mm3, blood platelets ≥ 100 000/mm3
  • Adequate hepatic function : total bilirubin ≤ 1,5 x ULN, ASAT et ALAT ≤ 3 x ULN, alkalin phosphatases ≤ 3 x ULN
  • Adequate renal function : creatinine clearance ≥ 60 ml/min
  • ECOG performance status < 2
  • Women not sterilized by the first treatment (ovarian transposition) and males (and their female partners) patients agree to use two methods of effective contraception (one of them being a barrier method) during the study, for at least 6 months for men and 4 months for women after the last administration of study treatment
  • Patient affiliated to a social security system or beneficiary of the same
  • Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures

Exclusion Criteria:

  • Recurrent rectal cancer after local excision
  • Concomitant cancer or medical history of cancer within 5 years other than cancers treated in situ (cervical carcinoma or basocellular carcinoma or spinocellular carcinoma)
  • Contraindication for chemotherapy Contraindication for chemotherapy (refer to Summary of characteristics of the products of the study drugs available at http://base-donnees-publique.medicaments.gouv.fr) or radiotherapy or surgery
  • Symptomatic cardiac or coronary insufficiency
  • Personal or family history of long QT syndrome congenital
  • ECG at screening or baseline (predose) with QT/QTc > 450 msec (male) or QT/QTc > 470 msec (female)
  • Chronic inflammatory bowel disease and/or bowel obstruction
  • Patients with hypocalcemia, hypokalemia, hypomagnesemia.
  • Progressive active infection (HIV or chronic hepatitis B or C) or any other severe medical condition that may preclude the delivery of treatment
  • Dihydropyrimidine deshydrogenase (DPD) deficiency
  • Peripheral neuropathy > grade 1 (CTCAE grading system v5.0)
  • Concomitant treatment with millepertuis, yellow fever vaccine, live attenuated vaccine, phenytoin, warfarin or sorivudine (or chemically equivalent)
  • Pregnant or breast-feeding woman
  • Persons deprived of liberty or under guardianship or incapable of giving consent
  • Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol or follow-up schedule, as assessed by investigator
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: Quentin DENOST (0)5 56 79 58 10 ext +33 quentin.denost@chu-bordeaux.fr
Contact: Eric RULLIER eric.rullier@chu-bordeaux.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03879109
Other Study ID Numbers  ICMJE CHUBX 2017/52
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
Plan to Share IPD: No
Responsible Party University Hospital, Bordeaux
Study Sponsor  ICMJE University Hospital, Bordeaux
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Quentin DENOST University Hospital, Bordeaux
PRS Account University Hospital, Bordeaux
Verification Date August 2019

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