Clinical trial NCT04749108: Study Evaluating the Tailored Management of Locally-advanced Rectal Carcinoma
Official title: Multicentric Phase II-III Study Evaluating the Tailored Management of Locally-advanced Rectal Carcinoma After a Favorable Response to Induction Chemotherapy
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Locally Advanced Malignant Neoplasm
Rectal Carcinoma
Lead sponsor: Institut du Cancer de Montpellier - Val d'Aurelle
Sponsor class: OTHER
First posted: 2021-02-11
Enrollment: 1075
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Drug: Induction chemotherapy - modified FOLFIRINOX regimen Other: Early tumor response evaluation by MRI volumetry Radiation: Radiochemotherapy Cap 50 Procedure: Radical proctectomy with total mesorectal excision
Primary purpose: TREATMENT

Brief summary: 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 chemotherapy. 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).

Detailed description: Cancer of the rectum is a common disease. It affects nearly 15,000 new people each year, with more men (53%) than women (47%).

In more than 9 out of 10 cases, it occurs after 50 years. Three types of treatments are used to treat rectal cancer: surgery, radiotherapy and drug treatments.

The standard treatment for Locally Advanced Rectal Cancers (LARC) is multidisciplinary, combining chemotherapy, radiotherapy and surgery. The usual treatment in this situation is called induction chemotherapy administrated before radiochemotherapy. This phase of treatment taking place before surgery is called neoadjuvant therapy.

However, treating all cancers of the locally advanced rectum with the same neoadjuvant treatment exposes patients who are good responders to neoadjuvant chemotherapy with possible toxicity to radiotherapy and patients who are poor responders to ineffectiveness of conventional radiotherapy with surgery and so to a mutilating ineffective treatment.

The short- and long-term toxicity of pelvic radiation may be the most compelling reason to reconsider reflexive neoadjuvant radiochemotherapy (NA-RCT) and to move toward a more individualized approach.

A large North American trial is currently evaluating the suppression of preoperative radiation therapy in patients selected as a good responder to induction chemotherapy.

A first trial called GRECCAR-4 (Surgical Research Group on Rectum CAncer) with induction chemotherapy by 5 Fluorouracil + Irinotecan + Oxaliplatin and personalized radiochemotherapy reported the following results:

* High-dose induction chemotherapy is well tolerated and reproducible
* Early assessment after neo-adjuvant chemotherapy makes it possible to discriminate between good and bad responders without a negative impact on surgery.
* Personalized management of LARC according to the early tumor response to chemotherapy is possible.
* In good responder patients, a resection rate of 100% was achieved (even in the arm without radiotherapy), but due to poor recruitment, it is not possible to draw a formal conclusion regarding these promising results.
* The oncological results at 5 years show a local recurrence rate of 0% for the good responders and 4.8% for the poor responders. The 5-year overall survival was 86.7% with a 5-year progression-free survival of 75.0%.

GRECCAR 14 is the only French trial to question the feasibility of appropriate management of non-metastatic LARC. Its main objective is to evaluate, in good responder patients, personalized management after preoperative CT treatment.

GRECCAR-14 will try to confirm this strategy taking into account the 1st results of GRECCAR 4.

The study will initially focus on 200 patients to assess the surgical quality of this therapeutic strategy and then on 230 additional patients to assess the effectiveness of this personalized treatment on survival without recurrence.

Eligibility criteria: INCLUSION CRITERIA FOR SCREENING

1. Written consent,
2. Patient who receive Folfirinox,
3. Patient aged over 18 years old,
4. World Health Organization (WHO) performance status ≥ 1,
5. Histologically confirmed diagnosis of adenocarcinoma of the rectum,
6. Distal part of the tumor from 1 to 12 cm from the upper part of the levator ani (dynamic rectal examination),
7. No unequivocal evidence on CT-Scan of established metastatic disease,
8. MRI evaluation of the locally advanced tumor before neoadjuvant chemotherapy:

   1. Predictive CRM \< 2 mm
   2. Or T3c-d (extending ≥ 5 mm beyond the muscularis propria) with extra mural venous invasion (EMVI)
   3. Or T4a-b (except bone and sphincteric invasion).

NON INCLUSION CRITERIA FOR SCREENING

1. Non measurable rectal tumor or not assessed by MRI before inclusion,
2. Ultra-low rectal tumor at diagnosis which imposes radiotherapy administration (inferior tumor pole less than 1 cm from the upper part of the levator ani).
3. Active cardiac disease including any of the following: a. Congestive heart failure ≥ New York Heart Association (NYHA) class 2 (appendix 4), b. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months), c. Myocardial infarction less than 6 months before first dose of treatment, d. Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted),
4. Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to study inclusion, except for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors \[Ta (non invasive tumor), Tis (carcinoma in situ) and T1 (lamina propria invasion)\],
5. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 6 months before start of treatment.

INCLUSION CRITERIA FOR EXPERIMENTAL TREATMENT

1. WHO performance status 0-1,
2. Patient with tumoral regression ≥ 60% and CRM ≥ 1mm,
3. No unequivocal evidence on CT-Scan of established metastatic disease,
4. General condition considered suitable for radical pelvic surgery and a systemic therapy with Capecitabine
5. Adequate hematologic, hepatic, renal and ionogram function assessed within 7 days prior to study treatment a. Platelet count ≥ 100,000/mm3; Hemoglobin (Hb) ≥ 9 g/dL; Absolute neutrophil count (ANC) ≥ 1,500/ mm3 b. Total bilirubin ≤ 1.5 x Upper Limit Normal (ULN), Alkaline phosphatases ≤ 3 x ULN and ASpartate aminoTransferase (AST) and ALanine aminoTransferase (ALT) ≤ 3 x ULN, c. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 ml/min according to Modification of Diet in Renal Disease (MDRD),
6. For women of reproductive potential, negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test obtained within 7 days before the start of study treatment. Women not of reproductive potential are female patients who are postmenopausal or permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy),
7. For women of childbearing potential and men, agreement to use an adequate contraception for the duration of study participation and up to 6 months following completion of therapy. Females of childbearing potential who are sexually active with a non-sterilized male partner must use 2 methods, of effective contraception. The investigator or a designated associate is requested to advise the patient on how to achieve an adequate birth control. Adequate contraception is defined in the study as any medically recommended method (or combination of methods) as per standard of care,
8. No evidence of chronic or acute ischemic heart disease,
9. Willing to participate to the study, and able to give informed consent and to comply with the treatment and follow-up schedules,
10. Affiliation to the French Social Security System.

NON-INCLUSION CRITERIA FOR EXPERIMENTAL TREATMENT

1. Patient with a history of pelvic radiotherapy,
2. Contraindication to chemotherapy and/or radiotherapy,
3. Complete or partial Dihydropyrimidine deshydrogenase (DPD) deficiency (uracilemia ≥ 16 ng/mL),
4. Any infection that could jeopardize treatment administration,
5. Any other serious concomitant disease or disorder that may interfere with the patient's participation in the study and safety during the study (e.g., severe liver, heart, kidney, lung, metabolic, or psychiatric disorders),
6. History of inflammatory bowel disease,
7. Patients with a history of pulmonary fibrosis or interstitial pneumonia,
8. Patients using antivitamin K (Coumadin etc...) but it's possible to substitute the antivitamin K treatment with low molecular weight heparins (LMWHs) before starting chemotherapy,
9. Known hypersensitivity to Capecitabine drug, study drug classes, or any constituent of the products,
10. Patient who received live attenuated vaccine within 10 days of inclusion,
11. Pregnant or breastfeeding woman. If a patient is of childbearing age, she must have a negative pregnancy test (serum β-hCG) documented 72 hours prior to inclusion,
12. Patient treated with an investigational drug within the last 30 days,
13. Patient under curatorship or guardianship or safeguard justice,
14. Inability to submit to medical monitoring of the trial for geographical, social or psychological reasons.

Primary outcomes:
measure: R0 resection rate (R0 is defined as Circumferential resection margin (CRM ≥ 1 mm) for Phase II
timeFrame: Within 15 days after surgery
measure: 3-year Disease free survival (DFS) for Phase III
timeFrame: 3 years
Secondary outcomes:
measure: Compliance rate with neoadjuvant treatment schedule
timeFrame: Within 4.5 months after the start of treatment
measure: Pathological complete response rate
timeFrame: Within 15 days after surgery
measure: Sphincter-saving surgery rate
timeFrame: Up to 2 months after the end of the neoadjuvant treatment
measure: Quality of life by using the quality of life questionnaire score (QLQ-C30)
timeFrame: For a 1-year follow-up
measure: Bowel function, Low anterior resection syndrome (LARS)
timeFrame: For a 1-year follow-up
measure: Quality of life by using the quality of life questionnaire score (QLQ-CR29)
timeFrame: For a 1-year follow-up
measure: 3-year local recurrence free survival rate (L-RFS)
timeFrame: 3 years
measure: 3-year metastasis recurrence free survival rate (M-RFS)
timeFrame: 3 years
measure: 3-year Overall survival (OS)
timeFrame: 3 years
measure: 5-year Overall survival (OS)
timeFrame: 5 years
measure: Local recurrence rate
timeFrame: For a 2-3-year follow-up
measure: Clavien-Dindo grade
timeFrame: Within 1 month after surgery
measure: Neoadjuvant rectal Score by Fokas
timeFrame: Within 15 days after surgery
measure: Rates of Total mesorectal excision (TME) grading according to Quirke
timeFrame: Within 15 days after surgery
measure: Distal margin to the tumor
timeFrame: Within 15 days after surgery
measure: Definitive stoma rate
timeFrame: 36 MONTHS
measure: Second surgery rate
timeFrame: 36 MONTHS
measure: Rehospitalization rate
timeFrame: Within 1 month after surgery
measure: Dworak Classification
timeFrame: Approximately 6 weeks after randomization
measure: Metastasis recurrence rate
timeFrame: For a 2-3-year follow-up
measure: Disease Fee Survival rate (DFS)
timeFrame: For a 3-year follow-up
measure: Assessment of adverse events by using the NCI-CTCAE version 5 scale
timeFrame: Approximately 72 months for all patients
measure: Evaluation of urinary function by International Prostate Symptom Score (IPSS) questionnaire score
timeFrame: For a 1-year follow-up
measure: Evaluation of sexual function in men by International Index of Erectile Function (IIEFS) questionnaire score
timeFrame: For a 1-year follow-up
measure: Evaluation of sexual function in women by Female Sexual Function Index (FSFI) questionnaire score
timeFrame: For a 1-year follow-up
Other outcomes:
Locations:
city: Marseille
country: France
facility: Hôpital Nord de Marseille
state: Bouches Du Rhône
city: Marseille
country: France
facility: Hôpital Européen de MARSEILLE
state: Bouches-du-rhône
city: Besançon
country: France
facility: CHU Besançon
state: Doubs
city: Bordeaux
country: France
facility: CHU de Bordeaux
state: Gironde
city: Montpellier
country: France
facility: Insitut Régional du Cancer de Montpellier
state: Hérault
city: Vandœuvre-lès-Nancy
country: France
facility: CHU de Nancy
state: Lorraine
city: Nancy
country: France
facility: Centre Alexis Vautrin
state: Meurthe Et Moselle
city: Lille
country: France
facility: Centre Oscart Lambret
state: Nord
city: Amiens
country: France
facility: CHU Amiens
state: Picardie
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
state: Puy De Dôme
city: Pau
country: France
facility: CH PAU
state: Pyrénées-atlantiques
city: Lyon
country: France
facility: CHU de Lyon
state: Rhône
city: Annecy
country: France
facility: Ch Annecy
state: Savoie
city: Rouen
country: France
facility: CHU Rouen
state: Seine-Maritime
city: Le Kremlin-Bicêtre
country: France
facility: Hôpital Bicêtre
state: Val De Marne
city: Bordeaux
country: France
facility: Bordeaux Colorectal Institute
city: Dijon
country: France
facility: Centre Georges-François Leclerc
city: Grenoble
country: France
facility: Chu Grenoble
city: Lille
country: France
facility: Chu Lille
city: Lyon
country: France
facility: CAC Léon Bérard
city: Marseille
country: France
facility: Hôpital La Timone
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Nîmes
country: France
facility: CHU de Nîmes
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Paris
country: France
facility: Hôpital Saint-Antoine
city: Paris
country: France
facility: Hôpital Européen Georges-Pompidou
city: Paris
country: France
facility: Hôpital Diaconesses
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest
city: Toulouse
country: France
facility: CHU de Toulouse
Study officials:
affiliation: Philippe.Rouanet@icm.unicancer.fr
name: Philippe Rouanet, MD
role: STUDY_CHAIR
References:
citation: Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, Wittekind C, Beissbarth T, Rodel C. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012 Jun 1;30(16):1926-33. doi: 10.1200/JCO.2011.40.1836. Epub 2012 Apr 23.
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citation: Kang JH, Kim YC, Kim H, Kim YW, Hur H, Kim JS, Min BS, Kim H, Lim JS, Seong J, Keum KC, Kim NK. Tumor volume changes assessed by three-dimensional magnetic resonance volumetry in rectal cancer patients after preoperative chemoradiation: the impact of the volume reduction ratio on the prediction of pathologic complete response. Int J Radiat Oncol Biol Phys. 2010 Mar 15;76(4):1018-25. doi: 10.1016/j.ijrobp.2009.03.066. Epub 2009 Aug 3.
citation: Rouanet P. Which Trial to Demonstrate the Truthfulness of a Tailored Strategy in Rectal Carcinoma? Dis Colon Rectum. 2018 Jan;61(1):e1-e2. doi: 10.1097/DCR.0000000000000977. No abstract available.
citation: Nougaret S, Castan F, de Forges H, Vargas HA, Gallix B, Gourgou S, Rouanet P; GRECCAR Study Group. Early MRI predictors of disease-free survival in locally advanced rectal cancer from the GRECCAR 4 trial. Br J Surg. 2019 Oct;106(11):1530-1541. doi: 10.1002/bjs.11233. Epub 2019 Aug 22.
citation: Fokas E, Glynne-Jones R, Appelt A, Beets-Tan R, Beets G, Haustermans K, Marijnen C, Minsky BD, Ludmir E, Quirke P, Sebag-Montefiore D, Garcia-Aguilar J, Gambacorta MA, Valentini V, Buyse M, Rodel C. Outcome measures in multimodal rectal cancer trials. Lancet Oncol. 2020 May;21(5):e252-e264. doi: 10.1016/S1470-2045(20)30024-3.