Trial Evaluating 3-year Disease Free Survival in Patients With Locally Advanced Rectal Cancer Treated With Chemoradiation Plus Induction or Consolidation Chemotherapy and Total Mesorectal Excision or Non-operative Management

• ClinicalTrials.gov Identifier: NCT02008656
• Recruitment Status: Active, not recruiting
• First Posted: December 11, 2013
• Last Update Posted: January 17, 2023
• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: Colon and Rectal Surgery Inc.; The Cleveland Clinic; John Muir Health; Oregon Health and Science University; St. Joseph Hospital of Orange; University of California, Irvine; University of California, San Francisco; University of Chicago; University of South Florida; University of Vermont; University of Washington; Medstar Health Research Institute; Washington University School of Medicine; Creighton University Medical Center; The Methodist Hospital Research Institute; University of Rochester; University of Virginia; St. Paul's Hospital; St. Joseph, Florida; Cleveland Clinic Florida; University of Colorado, Denver; University of Michigan
• Information provided by (Responsible Party): Memorial Sloan Kettering Cancer Center

Study Description

Brief Summary:

The study is designed to test the hypothesis that patients with Locally advanced rectal cancer ( LARC) treated with Total neoadjuvant therapy (TNT) and Total mesorectal excision (TME) or Non-operative management (NOM) will have an improved 3-year disease-free survival (DFS) compared to patients with similar tumors treated with Chemoradiation therapy (CRT), Total mesorectal excision (TME) and Adjuvant chemotherapy (ACT).

Condition or disease	Intervention/treatment	Phase
Rectal Cancer	Drug: Oxaliplatin (OXAL); Drug: 5-Fluorouracil (5-FU); Drug: Leucovorin; Drug: Capecitabine (Xeloda®); Radiation: intensity modulated radiotherapy (IMRT); Behavioral: Quality of Life Questionnaires; Procedure: DRE-Endoscopy	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 358 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Multicenter Randomized Trial Evaluating 3-year Disease Free Survival in Patients With Locally Advanced Rectal Cancer Treated With Chemoradiation Plus Induction or Consolidation Chemotherapy and Total Mesorectal Excision or Non-operative Management
• Actual Study Start Date: November 2013
• Estimated Primary Completion Date: November 2023
• Estimated Study Completion Date: November 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: INCT; Arm 1 will receive chemotherapy before chemoradiation. This is called induction neoadjuvant chemotherapy arm (INCT). The neoadjuvant chemotherapy regimen is prescribed specifically as 8 cycles of FOLFOX or 5 cycles of CapeOX over a period of approximately 15-16 weeks. Endoscopic exam (2-4 wks) after chemotherapy. If stable or response then pt will have radiation with either 5-FU or capecitabine.	Drug: Oxaliplatin (OXAL); Drug: 5-Fluorouracil (5-FU); Drug: Leucovorin; Drug: Capecitabine (Xeloda®); Radiation: intensity modulated radiotherapy (IMRT); Behavioral: Quality of Life Questionnaires; Procedure: DRE-Endoscopy
Experimental: CNCT; Arm 2 will receive chemoradiation before chemotherapy This is called the consolidation neoadjuvant chemotherapy arm (CNCT). Pt will have 6 weeks of chemoradiation therapy. Along with the radiation the pt will receive either 5-FU or capecitabine. 2-4 weeks after pt will have endoscopic exam and if stable or response pt will have will have 8 cycles of FOLFOX or 6 cycles of CapeOX.	Drug: Oxaliplatin (OXAL); Drug: 5-Fluorouracil (5-FU); Drug: Leucovorin; Drug: Capecitabine (Xeloda®); Radiation: intensity modulated radiotherapy (IMRT); Behavioral: Quality of Life Questionnaires; Procedure: DRE-Endoscopy

Outcome Measures

Primary Outcome Measures :

1. disease-free survival (DFS) [ Time Frame: 3 years ]
   3-year DFS will be defined as the percentage of patients alive without recurrence of disease at 3 years measured from the date of randomization

Secondary Outcome Measures :

1. major adverse events [ Time Frame: 3 years ]
   Adverse events will be graded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Histologically confirmed diagnosis of adenocarcinoma of the rectum
• Clinical Stage II (T3-4, N-) or Stage III (any T, N+) based on MRI
• Rectal tumor at baseline which would be considered to require complete TME
• No evidence of distant metastases
• No prior pelvic radiation therapy
• No prior chemotherapy or surgery for rectal cancer
• Age ≥ 18 years The minimum legal age of consent for select Canadian provinces is 19
• No active infections requiring systemic antibiotic treatment (oral antibiotics are acceptable at the discretion of the treating physician)
• ECOG Performance status 0-2
• Women with childbearing potential (WOCBP) who are negative for pregnancy test (urine or blood) and who agree to use effective contraceptive method. A woman of childbearing potential is defined of one who is biologically capable of becoming pregnant. Reliable contraception should be used from trial screening and must be continued throughout the study.
• Patients must read, agree to, and sign a statement of Informed Consent prior to participation in this study. Patients who do not read or understand English are eligible and may be consented according to institutional and federal regulations.
• ANC > 1.5 cells/mm3, HGB > 8.0 gm/dl, PLT > 150,000/mm3 total bilirubin ≤ 1.5 x ULN (except in patients with Gilbert's Syndrome who must have total bilirubin ≤ 3.0 x ULN), AST≤ 3 x ULN, ALT ≤ 3 x ULN.

Exclusion Criteria:

• Recurrent rectal cancer
• Primary unresectable rectal cancer. A tumor is considered unresectable when invading adjacent organs and an en block resection will not achieve negative margins.
• Creatinine level greater than 1.5 times the upper limit of normal.
• Patients who have received prior pelvic radiotherapy.
• Patients who are unable to undergo an MRI.
• Patients with a history of any arterial thrombotic event within the past 6 months. This includes angina (stable or unstable), MI, TIA, or CVA.
• Patients with a history of venous thrombotic episodes such as deep venous thrombosis, pulmonary embolus occurring more than 6 months prior to enrollment may be considered for protocol participation, provided they are on stable doses of anticoagulant therapy. Similarly, patients who are anticoagulated for atrial fibrillation or other conditions may participate, provided they are on stable doses of anticoagulant therapy.
• Other Anticancer or Experimental Therapy. No other experimental therapies (including chemotherapy, radiation, hormonal treatment, antibody therapy, immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, matrix metalloprotease inhibitors, thalidomide, anti-VEGF/Flk-1 monoclonal antibody or other experimental drugs) of any kind are permitted while the patient is receiving study treatment.
• WOCBP who are unwilling or unable to use an acceptable method of avoiding pregnancy for the entire study period.
• Women who are pregnant or breast-feeding.
• Patients with any other concurrent medical or psychiatric condition or disease which, in the investigator's judgment, would make them inappropriate candidates for entry into this study.
• Patients with a history of a prior malignancy within the past 5 years, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.

Contacts and Locations

Locations

United States, California

University of California, Irvine

Irvine, California, United States, 92697

St. Joseph Hospital

Orange, California, United States, 92868-3849

University of California San Francisco

San Francisco, California, United States, 94143

John Muir Health

Walnut Creek, California, United States, 94598

United States, Colorado

University of Colorado

Aurora, Colorado, United States, 80045

United States, District of Columbia

Washington Hospital Center

Washington, District of Columbia, United States, 20010

United States, Florida

University Of South Florida

Tampa, Florida, United States, 33620

Cleveland Clinic Florida

Weston, Florida, United States, 33331

United States, Illinois

University of Chicago

Chicago, Illinois, United States, 60637

United States, Michigan

University of Michigan

Northville, Michigan, United States, 48168

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, Nebraska

CHI Heath Bergan Mercy

Omaha, Nebraska, United States, 68114

Colon and Rectal Surgery, Incorporated

Omaha, Nebraska, United States, 68114

United States, New Jersey

Memorial Sloan Kettering Basking Ridge

Basking Ridge, New Jersey, United States, 07920

Memorial Sloan Kettering Bergen

Montvale, New Jersey, United States, 07645

United States, New York

Memorial Sloan Kettering Commack

Commack, New York, United States, 11725

Memorial Sloan Kettering Westchester

Harrison, New York, United States, 10604

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

University of Rochester Medical Center

Rochester, New York, United States, 14642

Memorial Sloan Kettering Cancer Center at Phelps

Sleepy Hollow, New York, United States, 10591

Memorial Sloan Kettering Nassau

Uniondale, New York, United States, 11553

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

United States, Oregon

Oregon Health & Science University

Portland, Oregon, United States, 97239

United States, Vermont

University of Vermont Medical Center

Burlington, Vermont, United States, 05401

United States, Virginia

University of Virginia

Charlottesville, Virginia, United States, 22908

United States, Washington

University of Washington School of Medicine

Seattle, Washington, United States, 98109

Sponsors and Collaborators

Memorial Sloan Kettering Cancer Center

Colon and Rectal Surgery Inc.

The Cleveland Clinic

John Muir Health

Oregon Health and Science University

St. Joseph Hospital of Orange

University of California, Irvine

University of California, San Francisco

University of Chicago

University of South Florida

University of Vermont

University of Washington

Medstar Health Research Institute

Washington University School of Medicine

Creighton University Medical Center

The Methodist Hospital Research Institute

University of Rochester

University of Virginia

St. Paul's Hospital

St. Joseph, Florida

Cleveland Clinic Florida

University of Colorado, Denver

University of Michigan

Investigators

• Principal Investigator: Julio Garcia Aguilar, MD, PhD; Memorial Sloan Kettering Cancer Center

More Information

Additional Information:

Memorial Sloan Kettering Cancer Center 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Garcia-Aguilar J, Patil S, Gollub MJ, Kim JK, Yuval JB, Thompson HM, Verheij FS, Omer DM, Lee M, Dunne RF, Marcet J, Cataldo P, Polite B, Herzig DO, Liska D, Oommen S, Friel CM, Ternent C, Coveler AL, Hunt S, Gregory A, Varma MG, Bello BL, Carmichael JC, Krauss J, Gleisner A, Paty PB, Weiser MR, Nash GM, Pappou E, Guillem JG, Temple L, Wei IH, Widmar M, Lin S, Segal NH, Cercek A, Yaeger R, Smith JJ, Goodman KA, Wu AJ, Saltz LB. Organ Preservation in Patients With Rectal Adenocarcinoma Treated With Total Neoadjuvant Therapy. J Clin Oncol. 2022 Aug 10;40(23):2546-2556. doi: 10.1200/JCO.22.00032. Epub 2022 Apr 28.

Shi DD, Mamon HJ. Playing With Dynamite? A Cautious Assessment of TNT. J Clin Oncol. 2021 Jan 10;39(2):103-106. doi: 10.1200/JCO.20.02199. Epub 2020 Oct 14. No abstract available.

Smith JJ, Chow OS, Gollub MJ, Nash GM, Temple LK, Weiser MR, Guillem JG, Paty PB, Avila K, Garcia-Aguilar J; Rectal Cancer Consortium. Organ Preservation in Rectal Adenocarcinoma: a phase II randomized controlled trial evaluating 3-year disease-free survival in patients with locally advanced rectal cancer treated with chemoradiation plus induction or consolidation chemotherapy, and total mesorectal excision or nonoperative management. BMC Cancer. 2015 Oct 23;15:767. doi: 10.1186/s12885-015-1632-z.

Garcia-Aguilar J, Chow OS, Smith DD, Marcet JE, Cataldo PA, Varma MG, Kumar AS, Oommen S, Coutsoftides T, Hunt SR, Stamos MJ, Ternent CA, Herzig DO, Fichera A, Polite BN, Dietz DW, Patil S, Avila K; Timing of Rectal Cancer Response to Chemoradiation Consortium. Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol. 2015 Aug;16(8):957-66. doi: 10.1016/S1470-2045(15)00004-2. Epub 2015 Jul 14.

• Responsible Party: Memorial Sloan Kettering Cancer Center
• ClinicalTrials.gov Identifier: NCT02008656
• Other Study ID Numbers: 13-213
• First Posted: December 11, 2013
• Last Update Posted: January 17, 2023
• Last Verified: January 2023

Keywords provided by Memorial Sloan Kettering Cancer Center:

CAPECITABINE (ORAL); FLUOROURACIL; LEUCOVORIN; OXALIPLATIN; Total mesorectal excision; Chemoradiation therapy; Total neoadjuvant therapy; 13-213

Additional relevant MeSH terms:

Rectal Neoplasms; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases; Leucovorin; Fluorouracil; Capecitabine; Oxaliplatin; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antidotes; Protective Agents; Vitamin B Complex; Vitamins; Micronutrients