Brazilian Total Neoadjuvant Therapy Trial (BRAZIL-TNT)

A Prospective Randomized Controlled Trial of Total Neo-adjuvant Therapy vs Conventional Chemo-radiation Aiming at Increasing Rates of Clinical Complete Response in Locally Advanced Rectal Cancer

Standard therapy for localized rectal cancer includes chemotherapy and radiation therapy, followed by a "recovery" period of 7-12 weeks, surgery and adjuvant chemotherapy for 3-6 months. Even though this protocol achieves high cure rates, many patients need a rectal amputation with placement of definitive colostomies. About 10-20% of patients have a complete clinical response to chemo-radiation and no tumor can be found in the surgical specimen. These patients can be followed with close surveillance and avid surgery. The aim of this study is to evaluate if a strategy including the use of a highly active chemotherapy called "FOLFIRINOX" during the 12 weeks between the end of radiation therapy and evaluation for surgery increases the rates of complete response and, therefore, allows more patients to undergo non-surgical management.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Neoplasms
• Intervention / Treatment: Drug: Folfirinox

Detailed Description

Adult patients with locally advanced rectal cancer who have completed conventional long-course chemo-radiation of 54Gy with capecitabine will be randomized 1:1 to a total neo-adjuvant therapy (TNT) protocol or to a control group. Patients in the TNT arm will receive 4 cycles of interval chemotherapy with FOLFIRINOX (5-FU, irinotecan, oxaliplatin) between the end of chemo-radiation and re-staging and those in the control group will undergo standard post-radiation care during this period. All patients will be re-staged with colonoscopy and pelvic MRI 12 weeks after the end of chemo-radiation. Those with a complete clinical response will be placed under a watch-and-wait protocol with digital rectal examinations every 2 months and pelvic MRI and sigmoidoscopy every 6 months. Those wih residual tumors will undergo resection with total mesorectal excision (TME). Patients with a "near complete response", as defined by a multidisciplinary tumor board, will be re-staged at week 16 or 18 after chemo-radiation before undergoing surgery. Adjuvant chemotherapy will be done following the local standard of care.

• Study Type: Interventional
• Enrollment (Estimated): 150
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Diogo Gomes, MD; Phone Number: +55-11-2151-8056; Email: diogo.gomes@einstein.br
• Study Contact Backup: Name: Leticia Brito, MD; Phone Number: +55-11-2151-8056; Email: leticia.brito@einstein.br

Study Locations

• Brazil
  • São Paulo, Brazil, 04378-500
    • Recruiting
    • Hospital Municipal Vila Santa Catarina
    • Contact: Diogo Gomes, MD; Phone Number: +55-11-2151-8056; Email: diogo.gomes@einstein.br
    • Contact: Leticia Brito; Phone Number: +55-11-2151-8056; Email: leticia.brito@einstein.br

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >= 18 y/o
• Biopsy-confirmed rectal adenocarcinoma
• Tumor Stage T3+ or N+ M0
• Adequate liver function (total bilirubin < = 4.0)
• Adequate kidney function (calculate creatinine-clearance >=30ml/m2/min)
• Adequate bone marrow function (Platelet counts >=90.000, hemoglobin >=8mg/dl, neutrophile count >= 1.500/cm3)
• Completed chemo-radiation with at least 54Gy and capecitabine 1650mg/m2/d

Exclusion Criteria:

• Prior tumor resection
• Prior radiation to the pelvis
• Prior chemotherapy for rectal cancer
• Life expectancy < 6 months
• Unfit for surgery
• Need for urgent/ immediate surgery

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Total neoadjuvant therapy (TNT); 4 cycles of mFOLFIRINOX every 14 days: Oxaliplatin 85 mg/m2; Irinotecan 150mg/m2; 5-FU 2.400mg/m2; Dexamethasone 12mg; Atropine 0.5mg; Netupitant/palonosetron	Drug: Folfirinox; 5-FU 2400mg/m2; Oxaliplatin 85 mg/m2, Irinotecan 150mg/m2; Other Names: mFOLFIRINOX; FOLFOXIRI; 5-FU, oxaliplatin, irinotecan
No Intervention: Standard of care; Standard post-radiation care

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cCR + PathCR	Complete clinical response or pathological response	12 weeks after the end of chemoradiation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of R0 resection	Rate of tumor resection with negative margins	12 weeks
Rate of organ preservation	Rate of patients who remain colostomy-free	6 months after surgery
Overall toxicity	Grade 3-4 toxicities according to CTCAE 4.0	12 weeks

Collaborators and Investigators

• Sponsor: Hospital Israelita Albert Einstein
• Collaborators: Ministry of Health, Brazil
• Investigators: Principal Investigator: Diogo Gomes, MD, Hospital Israelita Albert Einstein

Publications and helpful links

Helpful Links

• Program of the Brazilian Ministry of Health that us sponsoring the trial

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2020
• Primary Completion (Estimated): November 30, 2023
• Study Completion (Estimated): December 30, 2023

Study Registration Dates

• First Submitted: October 5, 2021
• First Submitted That Met QC Criteria: October 5, 2021
• First Posted (Actual): October 18, 2021

Study Record Updates

• Last Update Posted (Actual): October 11, 2023
• Last Update Submitted That Met QC Criteria: October 10, 2023
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Rectal cancer; Total neoadjuvant therapy; Neoadjuvant chemo-radiation; Watch-and-wait
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Oxaliplatin; Irinotecan; Folfirinox
• Other Study ID Numbers: 4015-20

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No