RecruitingPhase 3NCT03875781

Non Inferiority Study of Preoperative Chemotherapy Without Pelvic Irradiation for Rectal Cancer

Non Inferiority Multicenter Phase III Randomized Trial Comparing Preoperative Chemotherapy Only to Chemotherapy Followed by Chemoradiotherapy for Locally Advanced Resectable Rectal Cancer (Intergroup FRENCH-GRECCAR- PRODIGE)

Sponsor

Assistance Publique - Hôpitaux de Paris

Enrollment

540 participants

Start Date

Jun 5, 2019

Study Type

INTERVENTIONAL

Conditions

Advanced Cancer Rectal Cancer

Summary

This study is a non-inferiority phase III randomised trial comparing preoperative chemotherapy alone (modified FOLFIRINOX) to chemotherapy followed by 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 chemotherapy followed by chemoradiotherapy arm is 75%. This hazard rate, in an exponential survival model, corresponds to a decrease in the 3-year PFS rate on the preoperative chemotherapy arm to 67%. The study will randomize 540 patients (270 in the chemotherapy group and 270 in the chemoradiotherapy group) in 42 french academic centers.

Eligibility

Min Age: 18 Years

Inclusion Criteria7

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 Criteria23

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.
Recent or concomitant treatment with brivudine is contraindicated
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), complete and permanent insufficiency in dihydropyrimidine dehydrogenase
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.

Interventions

DRUGChemotherapy

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.

DRUGRadiochemotherapy

Arm B: Active comparator * Intervention Name : modified FOLFIRINOX followed by preoperative standardized radiochemotherapy (control 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.followed by 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 25 fractions in pelvic volume and 50 Gy in 25 fractions to the tumor.