Multicenter Phase 2 Trial: a Tailored Strategy for Locally Advanced Rectal Carcinoma (GRECCAR4)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Centre Val d'Aurelle - Paul Lamarque
Sponsor:
Information provided by (Responsible Party):
Centre Val d'Aurelle - Paul Lamarque
ClinicalTrials.gov Identifier:
NCT01333709
First received: April 8, 2011
Last updated: May 7, 2014
Last verified: May 2014
  Purpose

The purpose of this study is to determine whether the tailored management of locally advanced rectal carcinoma can improve the oncologic and functional outcome.


Condition Intervention Phase
Locally Advanced Malignant Neoplasm
Rectal Carcinoma
Drug: Induction trichemotherapy - FOLFIRINOX regimen
Other: Early tumor response evaluation by MRI volumetry
Radiation: Radiochemotherapy Cap 50
Radiation: Radiochemotherapy Cap 60
Procedure: Radical proctectomy with total mesorectal excision
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Multicenter Phase 2 Study: a Tailored Strategy for Locally Advanced Rectal Carcinoma

Resource links provided by NLM:


Further study details as provided by Centre Val d'Aurelle - Paul Lamarque:

Primary Outcome Measures:
  • Ro resection rate [ Time Frame: Within 15 days after surgery ] [ Designated as safety issue: Yes ]
    To confirm the feasibility of a tailored management with a 90% R0 resection rate achieved for all arms.


Secondary Outcome Measures:
  • Efficiency of MRI for prognosis [ Time Frame: Within 15 days after the surgery ] [ Designated as safety issue: Yes ]
    To specify the efficiency of MRI for prognosis in terms of volumetry, downstaging, downsizing and CRM measurement after completion of the induction trichemotherapy.

  • Compliance rate with neoadjuvant treatment schedule [ Time Frame: Within 4 months after the start of treatment ] [ Designated as safety issue: Yes ]
    To measure the compliance rate to the whole neoadjuvant schedule (induction CT + radiochemotherapy)

  • Acute and late toxicity of neoadjuvant treatments [ Time Frame: For the duration of treatment, as expexcted to be up to 4 months and within the 5-year follow-up ] [ Designated as safety issue: Yes ]
    To evaluate overall toxicity of neoadjuvant treatments (induction trichemotherapy + radiochemotherapy) according to the Common Terminology Criteria for Adverse Events v4.0 (NCI CTC v4.0).

  • Pathological complete response rate [ Time Frame: Within 15 days after surgery ] [ Designated as safety issue: No ]
    To assess the pathological complete response rate (ypT0N0)

  • Tumor regression grade (TRG) [ Time Frame: Within 15 days after surgery ] [ Designated as safety issue: No ]
    To assess at pathologic examination the tumor regression grade (TRG) according to the Dworak classification.

  • Perioperative and postoperative morbidity [ Time Frame: Within 6 weeks after surgery and during the 5-year follow-up ] [ Designated as safety issue: Yes ]
    To assess the impact of the therapeutic strategy on perioperative and postoperative morbidity.

  • Sphincter-saving surgery rate [ Time Frame: Up to 2 months after the end of the neoadjuvant treatment ] [ Designated as safety issue: No ]
    To assess the impact of the therapeutic strategy on the rate of sphincter-saving surgery.

  • Functional outcome [ Time Frame: For a 5-year follow-up ] [ Designated as safety issue: No ]
    To assess the long-term digestive,urinary and sexual functional results of tailored strategy

  • Quality of life [ Time Frame: For a 5-year follow-up ] [ Designated as safety issue: No ]
    To assess the impact of treatments on quality of life according to the EORTC QLQ-C30.

  • Local recurrence rate [ Time Frame: For a 5-year follow-up ] [ Designated as safety issue: No ]
    To measure the local recurrence rate in each treatment arm.

  • Incidence of metastases [ Time Frame: For a 5-year follow-up ] [ Designated as safety issue: No ]
    To measure the incidence of distant metastases (liver, pulmonary, peritoneal, ganglionnary or any others) in each treatment arm.


Estimated Enrollment: 150
Study Start Date: May 2011
Estimated Study Completion Date: September 2019
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A: immediate rectal surgery
"Very good" responder patients will be randomly assigned to proctectomy within 2-4 weeks after the end of the induction chemotherapy.
Drug: Induction trichemotherapy - FOLFIRINOX regimen
A short (4 cycles) and intensive trichemotherapy combinig irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2, 5-Fu (bolus 400 mg/m2, followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered for 8 weeks (D1=D15).
Other: Early tumor response evaluation by MRI volumetry
Two weeks after the CT completion, the tumor volume will be measured by MRI with specific software which automatically borders the tumor so as to determine the early tumor response. A centralized reassessment of all MRI exams will be systematically performed by two radiologists of the coordinator center.
Procedure: Radical proctectomy with total mesorectal excision
The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.
Arm B: RCT Cap 50 and then rectal surgery
"Very good" responder patients will be randomly assigned to receive chemoradiotherapy combining the administration of oral capecitabine (1600 mg/m2/day, BID) and radiotherapy at a total dose of 50 grays (2Gy/day, 5 days a week, 5 weeks, boost 6 Gy).
Drug: Induction trichemotherapy - FOLFIRINOX regimen
A short (4 cycles) and intensive trichemotherapy combinig irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2, 5-Fu (bolus 400 mg/m2, followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered for 8 weeks (D1=D15).
Other: Early tumor response evaluation by MRI volumetry
Two weeks after the CT completion, the tumor volume will be measured by MRI with specific software which automatically borders the tumor so as to determine the early tumor response. A centralized reassessment of all MRI exams will be systematically performed by two radiologists of the coordinator center.
Radiation: Radiochemotherapy Cap 50
RCT Cap 50 will combine radiotherapy at a dose of 50 Gy by either conventional 3D or IMRT (2 Gy per fraction, 5 fractions per week during 5 weeks / 44 Gy in mini pelvis, and boost 6 Gy on reduced peritumoral volume) with concomitant oral capecitabine at 1600 mg/m2 per day delivered the days of RT treatment (2 daily intake).
Procedure: Radical proctectomy with total mesorectal excision
The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.
Arm C: RCT Cap 50 and then rectal surgery
"Good or poor" responder patients will be randomly assigned to receive chemoradiotherapy combining the administration of oral capecitabine (1600 mg/m2/day, BID) and radiotherapy at a total dose of 50 grays (2Gy/day, 5 days a week, 5 weeks, boost 6 Gy).
Drug: Induction trichemotherapy - FOLFIRINOX regimen
A short (4 cycles) and intensive trichemotherapy combinig irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2, 5-Fu (bolus 400 mg/m2, followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered for 8 weeks (D1=D15).
Other: Early tumor response evaluation by MRI volumetry
Two weeks after the CT completion, the tumor volume will be measured by MRI with specific software which automatically borders the tumor so as to determine the early tumor response. A centralized reassessment of all MRI exams will be systematically performed by two radiologists of the coordinator center.
Radiation: Radiochemotherapy Cap 50
RCT Cap 50 will combine radiotherapy at a dose of 50 Gy by either conventional 3D or IMRT (2 Gy per fraction, 5 fractions per week during 5 weeks / 44 Gy in mini pelvis, and boost 6 Gy on reduced peritumoral volume) with concomitant oral capecitabine at 1600 mg/m2 per day delivered the days of RT treatment (2 daily intake).
Procedure: Radical proctectomy with total mesorectal excision
The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.
Experimental: Bras D: RCT Cap 60 and then rectal surgery
"Good or poor" responder patients will be randomly assigned to receive chemoradiotherapy combining the administration of oral capecitabine (1600 mg/m2/day, BID) and radiotherapy at a total dose of 60 grays (2Gy/day, 5 days a week, 6 weeks, boost 14 Gy).
Drug: Induction trichemotherapy - FOLFIRINOX regimen
A short (4 cycles) and intensive trichemotherapy combinig irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2, 5-Fu (bolus 400 mg/m2, followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered for 8 weeks (D1=D15).
Other: Early tumor response evaluation by MRI volumetry
Two weeks after the CT completion, the tumor volume will be measured by MRI with specific software which automatically borders the tumor so as to determine the early tumor response. A centralized reassessment of all MRI exams will be systematically performed by two radiologists of the coordinator center.
Radiation: Radiochemotherapy Cap 60
RCT Cap 60 will combine radiotherapy at a dose of 60 Gy by either conventional 3D or IMRT (2 Gy per fraction, 5 fractions per week during 6 weeks / 44 Gy in mini pelvis, and boost 16 Gy on reduced peritumoral volume) with concomitant oral capecitabine at 1600 mg/m2 per day delivered the days of RT treatment (2 daily intake)
Procedure: Radical proctectomy with total mesorectal excision
The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.

Detailed Description:

Locally advanced rectal carcinoma raise the issue of both the oncological control, local and general, and the therapeutic morbidity. Surgery alone can cure only one out of two patients, radiochemotherapy improves the local control but the metastatic risk remains about 30% with enhanced postoperative morbidity and poor functional results. The tumor response to preoperative treatment is the major prognostic factor which revealed the aggressiveness of the tumor. To this day, there are no biologic predictive markers for tumor response.

The purpose of this trial is to tailor the management according to the early tumoral response after short and intensive induction trichemotherapy. MRI volumetric tumor response will be used to distinguish between good responders and bad responders.

"Very good" responders will be randomized to either immediate surgery or radiochemotherapy followed by surgery (Standard arm: Cap 50). "Good or bad" responders will be randomized between two arms: intensive radiochemotherapy (Cap 60) or the standard arm (Cap 50).

This tailored management should result in a better oncologic prognosis with a lower rate of post therapeutic functional disorders.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed rectal carcinoma
  • Primary tumor evaluated by pelvic MR Imaging:

    i) iT3 ≥c tumors, with MRI showing a predictive CRM ≤ 2 mm or a EMS (Extra Mural Spread) ≥ 5 mm

ii) Resectable iT4 tumors (only randomized within the "poor responders" group)

iii) Any T tumors with MRI showing a predictive CRM ≤ 1 mm

  • No detectable metastases: Thorax-abdomen-pelvic CT-scan
  • Patient ≥ 18 years
  • ECOG Performance Status 0-1-2
  • Patient information and written informed consent form signed
  • Patient who can receive radiotherapy and chemotherapy
  • Negative pregnancy test in women of childbearing potential
  • Patient covered by a Social Security system
  • Hematology : Haemoglobin ≥ 9 g/dL, WBC ≥ 4000/mm3, neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L
  • Hepatic function : total bilirubin ≤ 1.5 x ULN, AST and ALT ≤ 3 x ULN, Alkaline phosphatases ≤ 3 x ULN
  • Renal function : creatinine ≤ 1.25 x ULN or creatinine clearance ≥ 60 ml/min

Exclusion Criteria:

  • Indication for immediate surgery
  • Primary tumor not measured at the MRI before inclusion
  • Previous pelvic radiotherapy
  • Contraindication to radiotherapy and/or chemotherapy
  • Severe renal or liver impairment
  • Cardiac and/or coronary disease which could contraindicate 5-Fu administration
  • Active infectious disease
  • Peripheral sensitive neuropathy
  • History of prior cancer (except if it was cured more than 5 years ago, and if complete remission)
  • Patient (male or female) of reproductive potential not using an effective contraceptive method during the whole treatment and up to 6 months after the completion of treatment
  • Concurrent participation in any other clinical trial likely to interfere with the therapeutic schedule
  • Fertile female patient not using adequate contraception, or breast-feeding woman
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01333709

Contacts
Contact: Philippe ROUANET, MD., Ph D +33 467 61 31 14 Philippe.Rouanet@valdorel.fnclcc.fr

Locations
France
CRLC Val d'Aurelle-Paul Lamarque Recruiting
Montpellier, France, 34298
Principal Investigator: Philippe ROUANET, MD, Ph D         
Sponsors and Collaborators
Centre Val d'Aurelle - Paul Lamarque
Investigators
Principal Investigator: Philippe ROUANET, MD, Ph D CRLC Val d'Aurelle-Paul Lamarque
  More Information

No publications provided

Responsible Party: Centre Val d'Aurelle - Paul Lamarque
ClinicalTrials.gov Identifier: NCT01333709     History of Changes
Other Study ID Numbers: GRECCAR 4, 2010-023546-73
Study First Received: April 8, 2011
Last Updated: May 7, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Centre Val d'Aurelle - Paul Lamarque:
locally advanced rectal carcinoma
Tailored treatment strategy
MRI volumetry
Early tumor response

Additional relevant MeSH terms:
Carcinoma
Neoplasms
Rectal Neoplasms
Colorectal Neoplasms
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Rectal Diseases
Capecitabine
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014