Trifluridine/Tipiracil in Combination With Capecitabine and Bevacizumab in Metastatic Colorectal Cancer Patients. (TriComB)

A Phase I/II Study Exploring the Safety and Activity of Trifluridine/Tipiracil in Combination With Capecitabine and Bevacizumab in Metastatic Colorectal Cancer Patients

The aim oh this study is to determine the safety and recommended dose of trifluridine/tipiracil plus capecitabine and bevacizumab combination (part 1, dose escalation phase) and to assess its activity in previously untreated mCRC patients who are deemed not eligible for intensive chemotherapy (part 2, expansion phase).

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer Metastatic
• Intervention / Treatment: Drug: Capecitabine; Drug: Bevacizumab; Drug: Trifluridine/Tipiracil

Detailed Description

This is an open-label, multicenter, phase 1/2 study evaluating the safety and activity of trifluridine/tipiracil in combination with capecitabine and bevacizumab in mCRC. The first part (Part 1) of the study will consist in a dose-escalation assessment of the safety of the treatment in subjects with previously untreated mCRC deemed not fit for irinotecan- and/or oxaliplatin- based regimens (i. e. FOLFOX/XELOX/FOLFIRI/FOLFOXIRI with or without targeted agents).

The second part (Part 2) will be an open-label phase 2 study with a Fleming's single-stage design to evaluate the ORR of the study treatment at the recommended dose established in the first part of the study in the same patients' population.

Trifluridine/tipiracil, capecitabine and bevacizumab will be administered in 28-days cycles until progressive disease, unacceptable toxicities, or patients' refusal.

• Study Type: Interventional
• Enrollment (Estimated): 48
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Chiara Cremolini, MD, PhD; Phone Number: +39.050.992192; Email: chiaracremolini@gmail.com
• Study Contact Backup: Name: Laura Delliponti, MD; Phone Number: +39.050.992192; Email: tricombstudy@gmail.com

Study Locations

• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Not yet recruiting
      • Fondazione IRCCS Istituto Nazionale Tumori
      • Principal Investigator: Filippo Pietrantonio
      • Contact: Filippo Pietrantonio, MD; Email: Filippo.Pietrantonio@istitutotumori.mi.it
  • PI
    • Pisa, PI, Italy, 56126
      • Recruiting
      • Azienda Ospedaliero Universitaria Pisana
      • Sub-Investigator: Chiara Cremolini, MD
      • Contact: Gianluca Masi, MD; Phone Number: +39050992466; Email: gianluca.masi@unipi.it
      • Contact: Chiara Cremolini, MD; Phone Number: +39050992192; Email: chiaracremolini@gmail.com
      • Principal Investigator: Gianluca Masi, MD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Written informed consent to study procedures.
• Histologically proven diagnosis of colorectal cancer.
• Metastatic colorectal cancer not previously treated with chemotherapy for metastatic disease.
• At least one measurable lesion according to RECIST1.1.
• Age ≥ 18 years.
• ECOG PS ≤ 1.
• Life expectancy of at least 12 weeks.
• Previous adjuvant fluoropyrimidine-based chemotherapy allowed only if more than 12 months elapsed between the end of adjuvant and first relapse.
• Availability of archival tumour tissue (primary tumour and metastases or at least one of the two) for biomarker analysis.
• Availability of blood sample for biomarker analysis.
• Previously not eligible for a chemotherapy doublet or triplet (oxaliplatin and/or irinotecan-based combination).
• Neutrophils ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hemoglobin ≥ 9 g/dl.
• Total bilirubin ≤1.5 fold the upper-normal limits (UNL), AST (SGOT) and/or ALT (SGPT) ≤ 2.5 x UNL (or <5 x UNL in the case of liver metastases), alkaline phosphatase ≤ 2.5 x UNL (or <5 x UNL in case of liver metastases).
• Creatinine clearance ≥ 50 mL/min or serum creatinine ≤1.5 x UNL.
• Male subjects with female partners of childbearing potential must be willing to use adequate contraception as approved by the investigator (barrier contraceptive measure or oral contraception).
• Women of childbearing potential must have a negative blood pregnancy test at the baseline visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive.
• Subjects and their partners must be willing to avoid pregnancy during the trial and until 6 months after the last trial treatment.
• Will and ability to comply with the protocol.

Exclusion Criteria:

• Radiotherapy to any site within 4 weeks before the study.
• Previous treatment with trifluridine/tipiracil, bevacizumab and capecitabine (previous treatment with capecitabine was permitted only in the adjuvant setting and if more than 12 months elapsed between the end of adjuvant and first relapse).
• Untreated brain metastases or spinal cord compression or primary brain tumors.
• History or evidence upon physical examination of CNS disease unless adequately treated.
• Clinical signs of malnutrition.
• Active uncontrolled infections or other clinically relevant concomitant illness contraindicating chemotherapy administration.
• Evidence of bleeding diathesis or coagulopathy.
• Uncontrolled hypertension and prior history of hypertensive crisis or hypertensive encephalopathy.
• Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication.
• Significant vascular disease (e.g. aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months of study enrolment.
• Any previous venous thromboembolism ≥ NCI CTCAE Grade 4.
• History of abdominal fistula, GI perforation, intra-abdominal abscess or active GI bleeding within 6 months prior to the first study treatment.
• Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer).
• Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ.
• Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
• Known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs.
• Any concomitant drugs contraindicated for use with the trial drugs according to the product information of the pharmaceutical companies.
• Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception (barrier contraceptive measure or oral contraception) during the study and until 6 months after the last trial treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: trifluridine/tipiracil plus capecitabine and bevacizumab

Drug: Capecitabine; Part 1 • Capecitabine, 1000 mg/sqm orally twice daily on days 1-14 each 28 days Part 2 • Capecitabine, 1000 mg/sqm orally twice daily on days 1-14 each 28 days; Drug: Bevacizumab; Part 1 • Bevacizumab, 5 mg/kg IV dose over 30 minutes on days 1 and 15 each 28 days Part 2 • Bevacizumab, 5 mg/kg IV dose over 30 minutes on days 1 and 15 each 28 days; Drug: Trifluridine/Tipiracil; Part 1 • Trifluridine/tipiracil, dose escalation from 25 mg/sqm to 35 mg/sqm orally twice daily on days 15-19 (and days 22-26) each 28 days Part 2 • Trifluridine/tipiracil, at the recommanded dose established during part 1 orally twice daily on days 15-19 (and days 22-26) each 28 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
recommended dose	recommended dose of the combination trifluridine/tipiracil plus capecitabine plus bevacizumab	2 years
activity	activity of the combination trifluridine/tipiracil plus capecitabine plus bevacizumab in terms of overaal response rate per RECIST v1.1.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
quality of life for cancer patients	quality of life as measured by EORTC QLQ-C30 questionnaire.	3 years
quality of life for colorectal cancer patients	quality of life as measured by EORTC QLQ-CR29 questionnaire.	3 years
quality of life for dimensions health	quality of life as measured by EuroQol EQ-5D questionnaire.	3 years
survival	efficacy of the combination trifluridine/tipiracil plus capecitabine plus bevacizumab in terms of progression-free survival and overall survival	3 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
bioavailability	Absolute and relative bioavailability of the combination trifluridine/tipiracil plus capecitabine plus bevacizumab.	2 years
Steady state concentration	Steady state concentration of the combination trifluridine/tipiracil plus capecitabine plus bevacizumab.	2 years
Therapeutic index	Therapeutic index of the combination trifluridine/tipiracil plus capecitabine plus bevacizumab.	2 years
Volume of distribution	Volume of distribution of the combination trifluridine/tipiracil plus capecitabine plus bevacizumab.	2 years
Half-life	Plasma half-life of the combination trifluridine/tipiracil plus capecitabine plus bevacizumab.	2 years
Clearance	Clearance of the combination trifluridine/tipiracil plus capecitabine plus bevacizumab.	2 years

Collaborators and Investigators

• Sponsor: Gruppo Oncologico del Nord-Ovest
• Investigators: Study Chair: Chiara Cremolini, MD, PhD, Fondazione GONO

Study record dates

Study Major Dates

• Study Start (Actual): January 25, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): March 1, 2025

Study Registration Dates

• First Submitted: September 12, 2020
• First Submitted That Met QC Criteria: September 21, 2020
• First Posted (Actual): September 25, 2020

Study Record Updates

• Last Update Posted (Actual): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Capecitabine; Bevacizumab; Trifluridine
• Other Study ID Numbers: EUDRACT 2020-000923-37

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
• product manufactured in and exported from the U.S.: No