Clinical trial NCT04177602: Evaluating Trifluridine/Tipiracil Based Chemoradiation in Locally Advanced Rectal Cancer - The Phase I/II TARC Trial
Official title: Evaluating Trifluridine/Tipiracil Based Chemoradiation in Locally Advanced Rectal Cancer - The Phase I/II TARC Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Locally Advanced Rectal Cancer
Keywords: trifluridine tipiracil chemoradiation
locally advanced rectal cancer
neoadjuvant
adenocarcinoma of the rectum
Lead sponsor: Universitätsklinikum Hamburg-Eppendorf
Sponsor class: OTHER
Collaborators: name: Clinical Trial Center North (CTC North GmbH & Co. KG)
name: Servier Affaires Médicales
First posted: 2019-11-26
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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
Primary purpose: TREATMENT

Brief summary: 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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Maximum tolerated dose (MTD)/Phase 1 part
timeFrame: 8 weeks
measure: Rate of pathological complete remissions (pCR)/Phase 2 part
timeFrame: 3 months
Secondary outcomes:
measure: Disease free survival (DFS)
timeFrame: 4 years
measure: Overall survival (OS)
timeFrame: 4 years
measure: Loco-regional failure
timeFrame: 4 years
measure: Histopathological R0 resection rate
timeFrame: 3 months
measure: Tumour regression grades
timeFrame: 3 months
measure: Pathological down-staging (ypT0-2N0) rate
timeFrame: 3 months
measure: Neoadjuvant rectal score (NAR)
timeFrame: 3 months
measure: Adverse event rate
timeFrame: 3 months
measure: Rate of perioperative complications
timeFrame: 3 months
Other outcomes:
Locations:
city: Flensburg
country: Germany
facility: Malteser Krankenhaus St. Franziskus Hospital
state: Schleswig-Holstein
city: Luebeck
country: Germany
facility: Lübecker Onkologische Schwerpunktpraxis Dres. med. Uthgenannt, Kirso, Weber
state: Schleswig-Holstein
city: Stade
country: Germany
facility: Klinik Dr. Hancken / MVZ Onkologie
state: Schleswig-Holstein
city: Halle/Saale
country: Germany
facility: University Medical Center Halle
city: Hamburg
country: Germany
facility: Hämatologisch- Onkologische Praxis Eppendorf (HOPE)
city: Hamburg
country: Germany
facility: II. Medizinische Klinik und Poliklinik Hubertus Wald Tumorzentrum - UCCH
city: Hamburg
country: Germany
facility: Überörtliche Gemeinschaftspraxis für Innere Medizin Schwerpunkt Hämatologie, Onkologie und Palliativmedizin Dres. Verpoort, Wierecky & Zeller
city: Hamburg
country: Germany
facility: Hämatologisch- Onkologische Praxis Altona (HOPA)
Study officials:
affiliation: University Cancer Center Hamburg
name: Alexander Stein
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.