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

NCT03875781 | Recruiting Phase 3 DMC

• 1 other identifier: P170920J
• Study Type: interventional
• Target: 540
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Rectal Cancer; Advanced Cancer

Keywords

Rectal cancer; FOLFIRINOX,; chemotherapy; radiochemotherapy; surgery

Outcome Measures

Primary Outcomes (1)

• Survival

  3-year progression-free survival

  3 years

Secondary Outcomes (30)

• Acute treatment toxicity

  Up to 1 month after the end of preoperative treatment

• Late toxicity related to treatment

  3 years after surgery

• Compliance to treatment

  Up to 1 month after the end of preoperative treatment

• Radiological response

  28±5 days after the end of preoperative treatment

• The rate of R0 resection

  4 weeks after surgery

Study Arms (2)

A: Modified Folfirinox

EXPERIMENTAL

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.

Drug: Chemotherapy

B: Modified Folfirinox followed by Radiochemotherapy

ACTIVE COMPARATOR

Active comparator: 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

Drug: Radiochemotherapy

Interventions

Radiochemotherapy DRUG

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.

B: Modified Folfirinox followed by Radiochemotherapy

Chemotherapy DRUG

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.

A: Modified Folfirinox

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

BENOIST

Le Kremlin-Bicêtre, Île-de-France Region, 94275, France

RECRUITING

Related Publications (6)

• Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC; EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med. 2006 Sep 14;355(11):1114-23. doi: 10.1056/NEJMoa060829.

  PMID: 16971718 BACKGROUND

• Wiltink LM, Chen TY, Nout RA, Kranenbarg EM, Fiocco M, Laurberg S, van de Velde CJ, Marijnen CA. Health-related quality of life 14 years after preoperative short-term radiotherapy and total mesorectal excision for rectal cancer: report of a multicenter randomised trial. Eur J Cancer. 2014 Sep;50(14):2390-8. doi: 10.1016/j.ejca.2014.06.020. Epub 2014 Jul 21.

  PMID: 25060825 BACKGROUND

• Schrag D, Weiser MR, Goodman KA, Gonen M, Hollywood E, Cercek A, Reidy-Lagunes DL, Gollub MJ, Shia J, Guillem JG, Temple LK, Paty PB, Saltz LB. Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol. 2014 Feb 20;32(6):513-8. doi: 10.1200/JCO.2013.51.7904. Epub 2014 Jan 13.

  PMID: 24419115 BACKGROUND

• Bensignor T, Brouquet A, Dariane C, Thirot-Bidault A, Lazure T, Julie C, Nordlinger B, Penna C, Benoist S. Pathological response of locally advanced rectal cancer to preoperative chemotherapy without pelvic irradiation. Colorectal Dis. 2015 Jun;17(6):491-8. doi: 10.1111/codi.12879.

  PMID: 25524450 BACKGROUND

• Deng Y, Chi P, Lan P, Wang L, Chen W, Cui L, Chen D, Cao J, Wei H, Peng X, Huang Z, Cai G, Zhao R, Huang Z, Xu L, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Zhou Z, Cai Y, Kang L, Huang M, Peng J, Ren D, Wang J. Modified FOLFOX6 With or Without Radiation Versus Fluorouracil and Leucovorin With Radiation in Neoadjuvant Treatment of Locally Advanced Rectal Cancer: Initial Results of the Chinese FOWARC Multicenter, Open-Label, Randomized Three-Arm Phase III Trial. J Clin Oncol. 2016 Sep 20;34(27):3300-7. doi: 10.1200/JCO.2016.66.6198. Epub 2016 Aug 1.

  PMID: 27480145 BACKGROUND

• Brouquet A, Bachet JB, Huguet F, Karoui M, Artru P, Sabbagh C, Lefevre JH, Vernerey D, Mariette C, Vicaut E, Benoist S; on behalf the FRENCH , GRECCAR, PRODIGE study groups. NORAD01-GRECCAR16 multicenter phase III non-inferiority randomized trial comparing preoperative modified FOLFIRINOX without irradiation to radiochemotherapy for resectable locally advanced rectal cancer (intergroup FRENCH-GRECCAR- PRODIGE trial). BMC Cancer. 2020 May 29;20(1):485. doi: 10.1186/s12885-020-06968-1.

  PMID: 32471382 DERIVED

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

Drug Therapy; Chemoradiotherapy

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Combined Modality Therapy; Radiotherapy

Study Officials

• Stéphane BENOIST, MD,PHD

  Service de chirurgie digestive et oncologique Hôpital Bicêtre - 94275 LE KREMLIN BICETRE

  STUDY CHAIR

Central Study Contacts

Stéphane BENOIST, MD,PHD

CONTACT

+ 33 1 45 21 34 72; stephane.benoist@aphp.fr

Antoine BROUQUET, MD,PHD

CONTACT

+ 33 1 45 21 34 70; antoine.brouquet@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: To demonstrate the non inferiority of preoperative modified FOLFIRINOX chemotherapy compared to radiochemotherapy in primary resectable locally advanced rectal cancer

Study Record Dates

• First Submitted: February 18, 2019
• First Posted: March 15, 2019
• Study Start: June 5, 2019
• Primary Completion (Estimated): December 5, 2026
• Study Completion (Estimated): December 5, 2026
• Last Updated: January 15, 2026

Record last verified: 2026-01

Locations

FR (1)