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

Rectal Cancer Clinical Trial

— NORAD01  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03875781
• Other study ID #: P170920J
• Status: Recruiting
• Phase: Phase 3
• Start date: June 5, 2019
• Est. completion date: December 5, 2026

Study information

• Verified date: March 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Stéphane BENOIST, MD,PHD
• Phone: + 33 1 45 21 34 72
• Email: stephane.benoist[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 systemic FOLFIRINOX chemotherapy for 3 months followed by 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. Since the annual world meeting of ASCO 2020, a new standard of treatment has been adopted using the combination of chemotherapy followed by radiochemotherapy that has been show to improve disease free survival in phase III controlled randomized trial (Conroy et al, J Clin Oncol 38: 2020 (suppl; abstr 4007).

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 518 patients, based on an expected accrual duration of 36 months, 60 months follow-up, and an expected 3 year PFS rate in the preoperative chemotherapy followed by chemoradiotherapy arm of 75%, is expected to provide 239 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 global type one-error rate of 0.05 if the true hazard ratio between arms is 1.39 (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 67%. 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 518*100/96 = 540 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 540
• Est. completion date: December 5, 2026
• Est. primary completion date: December 5, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

• 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.

Related Conditions & MeSH terms

• Advanced Cancer
• Rectal Cancer
• Rectal Neoplasms

Intervention

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.
• Radiochemotherapy
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.

Locations

Country	Name	City	State
France	BENOIST	Le Kremlin-Bicêtre	Ile De France

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

References & Publications (5)

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. — View Citation

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. Erratum In: N Engl J Med. 2007 Aug 16;357(7):728. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival	3-year progression-free survival	3 years
Secondary	Acute treatment toxicity	Acute and late treatment related toxicity: the rates of treatment related toxicity grade II or more	Up to 1 month after the end of preoperative treatment
Secondary	Late toxicity related to treatment	Late treatment related toxicity: the rates of treatment related toxicity grade II or more	3 years after surgery
Secondary	Compliance to treatment	The rate of patients that receive full dose treatment	Up to 1 month after the end of preoperative treatment
Secondary	Radiological response	Radiologic response on post-treatment MRI based on tumor size reduction and tumor regression grade (ymrTRG)	28±5 days after the end of preoperative treatment
Secondary	The rate of R0 resection	Rate of complete resection with safe > 1mm circumferential and longitudinal margin	4 weeks after surgery
Secondary	Quality of mesorectal excision: 3-grades Quirke scoring system	3-grades Quirke scoring system of the quality of mesorectal excision	4 weeks after surgery
Secondary	Number of lymph nodes harvested	A count of number of lymph nodes harvested	4 weeks after surgery
Secondary	Size of circumferential margin	Mesurement of circumferential margin	4 weeks after surgery
Secondary	Size of longitudinal margin	Mesurement of longitudinal margin	4 weeks after surgery
Secondary	Sphincter saving surgery rate	The rate of surgery with intestinal continuity and anal sphincter preservation	4 weeks after surgery
Secondary	Postoperative morbidity	Postoperative morbidity: 30 day or in-hospital postoperative morbidity rates	30 days after resection
Secondary	Postoperative mortality	Postoperative mortality: 30 day or in-hospital postoperative mortality rates	30 days after resection
Secondary	Pathologic response after chemotherapy	Pathologic response on Rodel Tumor Regression Grade	4 weeks after surgery
Secondary	Pathologic response after chemoradiotherapy	Pathologic response after chemoradiotherapy: rate of major pathologic response base on Rodel Tumor Regression Grade	4 weeks after surgery
Secondary	Loco-regional recurrence free survival	Loco-regional recurrence free survival: 3-year locoregional recurrence free survival rates	At 3 years
Secondary	Uncontrolled local recurrence	Uncontrolled local recurrence: 3-year uncontrolled local recurrence free survival rates	At 3 years
Secondary	Overall survival	Overall survival: 3 year overall survival rates	At 3 years
Secondary	Overall survival	Overall survival: 5 year overall survival rates	At 5 years
Secondary	EORTC QLQ-CR29	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)	Diagnosis time
Secondary	EORTC QLQ-CR29	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)	28±5 days after the end of preoperative treatment
Secondary	EORTC QLQ-CR29	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)	At 6 months after surgery
Secondary	EORTC QLQ-CR29	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)	1 year after surgery
Secondary	LARS Scores	Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)	Diagnosis time
Secondary	LARS Scores	Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)	28±5 days after the end of preoperative treatment
Secondary	LARS Scores	Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)	6 months after surgery
Secondary	LARS Scores	Bowel function assessed by the Low Anterior Resection Syndrome (LARS) score. The score ranges from 0 to 42 (42 is the most severe LARS)	1 year after surgery
Secondary	Quality of life - physical functioning: QLQ-C30	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)	At diagnosis
Secondary	Quality of life - physical functioning: QLQ-C30	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)	28±5 days after the end of preoperative treatment
Secondary	Quality of life - physical functioning: QLQ-C30	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)	6 months after surgery
Secondary	Quality of life - physical functioning: QLQ-C30	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)	1 year after surgery