Evaluating Trifluridine/Tipiracil Based Chemoradiation in Locally Advanced Rectal Cancer - The Phase I/II TARC Trial

Seamless phase I/II trial with phase I part for determination of maximum tolerated dose (MTD) of Trifluridine/tipiracil, followed by a randomized phase II trial (randomization ratio 2:1) with an experimental arm with Trifluridine/tipiracil based chemoradiotherapy (CRT) and a standard - calibration arm (internal control) with capecitabine CRT flanked by translational research in patients with locally advanced rectal cancer

Study Overview

• Status: Terminated
• Conditions: Locally Advanced Rectal Cancer
• Intervention / Treatment: Combination product: Trifluridine/tipiracil chemoradiation; Combination product: Capecitabine based chemoradiation

Detailed Description

This is a multicenter randomized seamless phase I/II trial with a phase I for determination of maximum tolerated dose (MTD) of Trifluridine/tipiracil, followed by a randomized phase II trial (randomization ratio 2:1) with an experimental arm with Trifluridine/tipiracil in combination with standard radiotherapy and a standard - calibration arm (internal control) with capecitabine CRT flanked by translational research, designed to assess the clinical performance and efficacy of Trifluridine/tipiracil compared to current standard capecitabine chemoradiation in patients with locally advanced rectal cancer.

The primary clinical objective in phase I is to determine the dosage and feasibility of Trifluridine/tipiracil based chemoradiation and in phase II whether Trifluridine/tipiracil with preoperative chemoradiation improves pathological complete remissions in patients with locally advanced rectal cancer.

The secondary objectives are to evaluate Trifluridine/tipiracil chemoradiation with respect to disease free survival, overall survival, local regional failure, pathological down-staging (ypT0-2N0) rate, tumour regression grade, histopathological R0 resection rate, neoadjuvant rectal score (NAR), and perioperative complication rate. Safety and toxicity, according to NCI CTC AE v5, quality of life and feasibility of the regimen are further secondary objectives that are to be evaluated.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Alexander Stein; Phone Number: +49(0)403603522; Email: stein@hope-hamburg.de
• Study Contact Backup: Name: Marianne Sinn; Phone Number: +49(0)407410; Email: ma.sinn@uke.de

Study Locations

• Germany
  • Halle/Saale, Germany
    • University Medical Center Halle
  • Hamburg, Germany, 20249
    • Hämatologisch- Onkologische Praxis Eppendorf (HOPE)
  • Hamburg, Germany, 20251
    • II. Medizinische Klinik und Poliklinik Hubertus Wald Tumorzentrum - UCCH
  • Hamburg, Germany, 20259
    • Überörtliche Gemeinschaftspraxis für Innere Medizin Schwerpunkt Hämatologie, Onkologie und Palliativmedizin Dres. Verpoort, Wierecky & Zeller
  • Hamburg, Germany, 22767
    • Hämatologisch- Onkologische Praxis Altona (HOPA)
  • Schleswig-Holstein
    • Flensburg, Schleswig-Holstein, Germany, 24939
      • Malteser Krankenhaus St. Franziskus Hospital
    • Luebeck, Schleswig-Holstein, Germany, 23562
      • Lübecker Onkologische Schwerpunktpraxis Dres. med. Uthgenannt, Kirso, Weber
    • Stade, Schleswig-Holstein, Germany, 21680
      • Klinik Dr. Hancken / MVZ Onkologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patients with histologically proven adenocarcinoma of the rectum (tumour ≤ 12 cm from the anal verge)
2. Indication for neoadjuvant chemoradiation: clinical tumour stage T3/4 or any node-positive disease (clinical stage according the TNM classification system, based on MRI).
3. No evidence of metastatic disease (as evidenced by negative CT-scan of the chest and abdomen).
4. The disease must be considered either resectable at the time of entry or expected to become resectable after preoperative chemoradiation.
5. Age ≥ 18 years
6. WHO/ECOG Performance Status ≤ 2
7. No prior cytotoxic chemotherapy or radiotherapy for rectal cancer.
8. No prior radiotherapy to the pelvis, for any reason.
9. Presence of adequate contraception in fertile patients. Adequate methods of contraception are: intra-uterine device, hormonal contraception, condom use with spermicide. Pregnant or breastfeeding women are excluded from participation.
10. Adequate bone marrow, hepatic and renal function: Haemoglobin ≥9.0 g/dL (transfusions allowed to achieve or maintain levels), absolute neutrophil count ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L, ALAT, ASAT ≤ 2.5 x ULN, Alkaline phosphatase ≤ 2.5 x ULN, Total bilirubin ≤1.5 x ULN, Creatinine clearance > 50 mL/min (calculated according to Cockroft and Gault).
11. Ability to swallow tablets.
12. Written informed consent and patient's agreement to comply with the study protocol.

Exclusion Criteria:

1. Previous (within the last 3 years) or concurrent malignancies, with the exception of adequately treated cone-biopsied in situ carcinoma of the cervix or basal cell carcinoma of the skin.
2. Clinically significant (i.e. active) cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmia not well controlled with medication) or myocardial infarction within the last 12 months.
3. Known allergy or any other adverse reaction to any of the study drugs or to any related compound.
4. Known significant impairment of intestinal resorption (e.g. chronic diarrhea, inflammatory bowel disease).
5. Pre-existing condition which would deter chemoradiotherapy or radiotherapy, i.e. fistulas, severe ulcerative colitis (particularly patients currently taking sulphasalazine), Crohn's disease, prior adhesions.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Trifluridine/tipiracil based radiotherapy; Trifluridine/tipiracil based chemoradiotherapy (CRT)	Combination product: Trifluridine/tipiracil chemoradiation; Trifluridine/tipiracil based chemoradiation
Active Comparator: standard calibration arm (internal control); capecitabine based chemoradiotherapy	Combination product: Capecitabine based chemoradiation; Capecitabine based chemoradiation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD)/Phase 1 part	Toxicity	8 weeks
Rate of pathological complete remissions (pCR)/Phase 2 part	Pathohistological response	3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease free survival (DFS)	recurrence and survival	4 years
Overall survival (OS)	Survival	4 years
Loco-regional failure	Loco-regional recurrence	4 years
Histopathological R0 resection rate	Pathohistological response	3 months
Tumour regression grades	Pathohistological response	3 months
Pathological down-staging (ypT0-2N0) rate	Pathohistological response	3 months
Neoadjuvant rectal score (NAR)	Clinical stage and Pathohistological response (<8 low, 8-16 intermediate, >16 high risk)	3 months
Adverse event rate	Rate of adverse events according to NCI CTC AE v5	3 months
Rate of perioperative complications	Perioperative complications	3 months

Collaborators and Investigators

• Sponsor: Universitätsklinikum Hamburg-Eppendorf
• Collaborators: Servier Affaires Médicales; Clinical Trial Center North (CTC North GmbH & Co. KG)
• Investigators: Principal Investigator: Alexander Stein, University Cancer Center Hamburg

Publications and helpful links

General Publications

• Rothkamm K, Christiansen S, Rieckmann T, Horn M, Frenzel T, Brinker A, Schumacher U, Stein A, Petersen C, Burdak-Rothkamm S. Radiosensitisation and enhanced tumour growth delay of colorectal cancer cells by sustained treatment with trifluridine/tipiracil and X-rays. Cancer Lett. 2020 Nov 28;493:179-188. doi: 10.1016/j.canlet.2020.08.038. Epub 2020 Sep 4.

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2019
• Primary Completion (Actual): September 2, 2022
• Study Completion (Actual): September 2, 2022

Study Registration Dates

• First Submitted: November 20, 2019
• First Submitted That Met QC Criteria: November 22, 2019
• First Posted (Actual): November 26, 2019

Study Record Updates

• Last Update Posted (Estimate): February 22, 2023
• Last Update Submitted That Met QC Criteria: February 20, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: neoadjuvant; adenocarcinoma of the rectum; locally advanced rectal cancer; trifluridine tipiracil chemoradiation
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine; Trifluridine
• Other Study ID Numbers: TARC-01

Drug and device information, study documents

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