Phase II Trial Comparing Trifluridine/Tipiracil with Panitumumab Versus Trifluridine/Tipiracil with Bevacizumab in Metastatic Colorectal Cancer
- Trial ID
- 2024-513723-16-00
- Protocol
- FIRE-8
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to compare the **efficacy** of treatment with trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab in patients with metastatic colorectal cancer. This comparison is clinically relevant as it aims to determine the most effective first-line treatment option for this condition, potentially improving patient outcomes and guiding therapeutic decisions.
Secondary objectives include:
- Comparing the **safety** profiles of the two treatment regimens.
- Evaluating patient-reported quality of life (QoL) during treatment with trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab.
Participants
The clinical trial involves participants diagnosed with **metastatic colorectal cancer**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a histologically confirmed adenocarcinoma of the colon or rectum, with metastatic disease characterized by at least one measurable lesion. The trial does not include vulnerable populations. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are fully active or capable of self-care. Adequate bone marrow, hepatic, and renal function are necessary, as defined by specific laboratory criteria. The trial population was selected based on these health criteria, and the sponsor has not provided the total number of participants. Lifestyle considerations such as diet and physical activity are not specified, but participants must adhere to specific contraceptive measures if applicable. The selection process ensures that participants are not eligible or unwilling to undergo combination chemotherapy, and they must have RAS wild-type status confirmed through validated testing methods.
Plans and Procedures
The clinical trial is a **randomized**, open-label, multicenter Phase II study designed to evaluate the efficacy of **trifluridine/tipiracil** in combination with either **panitumumab** or **bevacizumab** as a first-line treatment for patients with **metastatic colorectal cancer**. The trial aims to compare the efficacy of these treatment regimens, with the primary endpoint being the objective response rate (ORR) according to RECIST 1.1, assessed at local trial centers. Secondary endpoints include overall survival (OS), progression-free survival (PFS), and quality of life (QoL) assessments, among others. The trial is expected to conclude by December 31, 2029, with recruitment having commenced on December 21, 2021.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of adenocarcinoma, and RAS wild-type status. Following randomization, participants will receive treatment over a maximum period of six months, with regular follow-up visits to monitor treatment efficacy and safety. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants are expected to be involved in the study for the duration of the treatment period, with conditions for early termination including adverse events, disease progression, or withdrawal of consent.
The trial involves the administration of **trifluridine/tipiracil** orally, while **panitumumab** and **bevacizumab** are administered via intravenous infusion. The study is not classified as low-intervention and adheres to rigorous scientific and ethical standards to ensure the safety and well-being of participants. The trial's design and methodology are structured to provide robust data on the comparative efficacy of the treatment regimens, contributing valuable insights into the management of metastatic colorectal cancer.
Treatment
The clinical trial involves the administration of **Bevacizumab**, a concentrate for solution for infusion. Bevacizumab is administered via **intravenous infusion**. The dosage is calculated based on the participant's body weight, with a maximum daily dose of 5 mg/kg and a total maximum dose of 60 mg/kg over the treatment period. The treatment duration is set for a maximum of 6 months. Participant compliance with the dosing schedule will be monitored throughout the trial.
Another experimental medication used in the trial is **Lonsurf**, which contains the active substances **trifluridine** and **tipiracil hydrochloride**. Lonsurf is available in two formulations: 20 mg/8.19 mg and 15 mg/6.14 mg film-coated tablets. The medication is administered orally, with a maximum daily dose of 70 mg/m² and a total maximum dose of 4200 mg/m² over the treatment period. The treatment duration is also set for a maximum of 6 months. Compliance with the oral dosing schedule will be closely monitored.
**Panitumumab** is another investigational product used in this trial, provided as a concentrate for solution for infusion. It is administered via **intravenous use**. The dosage is determined based on the participant's body weight, with a maximum daily dose of 6 mg/kg and a total maximum dose of 72 mg/kg over the treatment period. The treatment duration is set for a maximum of 6 months. Participant adherence to the dosing regimen will be assessed throughout the study.
The trial aims to compare the efficacy of the combination of trifluridine/tipiracil with either panitumumab or bevacizumab as a first-line treatment for metastatic colorectal cancer. The study is designed to ensure rigorous monitoring of participant compliance and adherence to the specified dosing schedules for each investigational product.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the **Objective Response Rate (ORR)**, evaluated according to RECIST 1.1 criteria at the local trial center. Secondary endpoints include overall survival (OS), progression-free survival (PFS), and ORR assessed by central review. Additional secondary endpoints involve the depth of response (DpR) and early tumor shrinkage (ETS), both assessed by central review. Quality of life (QoL) will be measured using the EQ-5D-5L questionnaire. The trial will also monitor the type, incidence, severity, and causal relationship of non-serious and serious adverse events, with severity evaluated according to CTCAE version 5.0. Furthermore, subsequent anti-tumor treatment lines and the identification of biomarkers for treatment efficacy and toxicity will be explored.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient’s signed informed consent
- Patients ≥ 18 years at the time of signing the informed consent
- Histologically confirmed adenocarcinoma of the colon or rectum (appendix carcinoma is excluded)
- Metastatic colorectal cancer (mCRC) with at least one measurable lesion according to RECIST 1.1 in a computed tomography (CT) or magnetic resonance imaging (MRI) scan performed within 5 weeks prior to randomisation
- Metastases are primarily unresectable or patient is unable/unwilling to undergo surgery
- RAS wild-type (KRAS, exons 2, 3, 4 and NRAS, exons 2, 3, 4) mCRC, proven in the primary tumor or metastasis. The RAS mutational status must be determined by means of a validated test method.
- Patient is not eligible to undergo combination chemotherapy according to investigator’s assessment or unwilling to undergo combination chemotherapy.
- ECOG performance status 0-2
- Adequate bone marrow, hepatic and renal organ function, defined by the following laboratory test results: • Absolute neutrophil count ≥1.5 x 109/L (1500/µL) • Hemoglobin ≥ 80 g/L (8 g/dL) • Platelet count ≥ 75 x109/L (75,000/µL) without transfusion • Total serum bilirubin of ≤ 1.5 x upper limit of normal (ULN) • Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) ≤ 2.5 × ULN; if liver function abnormalities are due to underlying liver metastasis, AST and ALT ≤ 5 × ULN • Calculated glomerular filtration rate (GFR) according to Cockcroft –Gault formula or according to MDRD ≥ 30 mL/min or serum creatinine ≤ 1.5 x ULN • Urine dipstick for proteinuria < 2+ (within 14 days prior to randomisation), unless a subsequent 24-hour urine collection demonstrates < 1 g of protein in 24 hours.
- Patients without anticoagulation need to present with an INR <1.5 x ULN and PTT <1.5 x ULN. Patients with anticoagulation may be enrolled if the patient receives the medication at a stable dose for at least 2 weeks before randomisation and provided that INR and PTT are <1.5 x ULN.
- For females of childbearing potential (FCBP): negative pregnancy test within 14 days before randomisation and agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of <1% per year during the treatment period and for at least 6 months after the last dose of study treatment. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male partner’s sterilization, hormonal contraceptives that inhibit ovulation supplemented with a barrier method, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below: With female partners of childbearing potential, men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of <1% per year during the treatment period and for 6 months after the last dose of study treatment. In this regard, double barrier methods are not considered to have a failure rate of < 1%. Men must refrain from donating sperm during this same period. With pregnant female partners, men must remain abstinent or use a condom during the treatment period and for 6 months after the last dose of study medication to avoid exposing the embryo. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
Exclusion Criteria
- Prior systemic therapy of metastatic disease. Note: Prior adjuvant chemotherapy is permitted, if completed > 3 months prior to randomisation. Multimodal treatment of rectal cancer is not considered anti-metastatic therapy and does not preclude study participation
- Known brain metastasis. In case of symptoms that are suggestive of brain metastasis, brain metastasis has to be ruled out by means of cranial CT/MRI.
- Significant cardiovascular disease such as: New York Heart Association Class III or greater heart failure; myocardial infarction within 6 months prior to randomisation; balloon angioplasty (PTCA) with or without stenting within 6 months prior to randomisation; despite anti-arrhythmic therapy unstable cardiac arrhythmia > grade 2 NCI CTCAE; unstable angina pectoris
- Transient ischaemic attack or cerebrovascular accident within 6 months prior to randomization, history of cerebral or aortic aneurysm or dissection
- Medical history of deep vein thrombosis or pulmonary embolism within 6 months prior to randomisation or medical history of recurrent thromboembolic events (> 1 episode of deep vein thrombosis, pulmonary embolism, peripheral embolism) within the last 2 years.
- Severe bleeding event within the last 6 months before randomisation (except tumor bleeding surgically treated by tumor resection)
- Evidence of bleeding diathesis or significant coagulopathy
- Uncontrolled hypertension defined as systolic blood pressure ≥160 mm Hg and/or diastolic ≥ 100 mm Hg under antihypertensive medication
- Severe chronic non-healing wounds, ulcerous lesions or untreated bone fracture.
- History of abdominal or tracheoesophageal fistula or gastrointestinal perforation, or intra-abdominal abscess -unrelated to surgery- within 6 months prior to randomisation.
- Acute or subacute bowel obstruction, active chronic inflammatory bowel disease or chronic diarrhea
- History of keratitis, ulcerative keratitis or severe dry eye.
- Hypersensitivity to trifluridine/tipiracil or panitumumab or bevacizumab or any of the excipients, known hypersensitivity to Chinese hamster ovary cell products, known hypersensitivity to human or humanized antibodies
- Current or recent (within 10 days of randomisation) use of or anticipated need for continuous treatment during study treatment with acetylsalicylic acid > 325 mg/day or treatment with dipyramidole, ticlopidine > 2 x 250 mg/day, clopidogrel > 75 mg/day, and cilostazol. Combination of these drugs are not allowed.
- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomisation, or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 28 days prior to randomisation or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure
- Core biopsy or other minor surgical procedure, excluding placement of a vascular access devices, within 3 days prior to the first dose of bevacizumab
- History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis/interstitial pneumonia, or idiopathic pneumonitis/interstitial pneumonia, or evidence of active pneumonitis or pulmonary fibrosis on screening chest imaging
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.
- Medical history of other malignant disease than mCRC with the following exceptions: - patients who have been disease-free for at least three years before randomisation - patients with adequately treated and completely resected basal cell or squamous cell skin cancer, in situ cervical, breast or prostate cancer, stage I uterine cancer – patients with any treated or untreated malignant disease that is associated with a 5 year survival prognosis of ≥90% and does not require active therapy
- Known alcohol or drug abuse
- Pregnant or breastfeeding females
- Participation in a clinical trial or experimental drug treatment within 28 days prior to inclusion in the clinical trial or within a period of 5 half-lives of the substances administered in a clinical trial or during an experimental drug treatment prior to inclusion in the clinical trial, depending on which period is longest, or simultaneous participation in another clinical trial while taking part in this clinical trial.
- Patient committed to an institution by virtue of an order issued either by the judicial or the administrative authorities
- Patient possibly dependent from the investigator including the spouse, children and close relatives of any investigator
- Limited legal capacity
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 21 Dec 2021 | 153 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Lonsurf 15 mg/6.14 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 70 | 6 | PRD4021653 |
BEVACIZUMAB | Test | — | INTRAVENOUS INFUSION | 5 | 6 | SUB16402MIG |
Vectibix 20 mg/ml concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 6 | 6 | PRD3606042 |
Lonsurf 20 mg/8.19 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 70 | 6 | PRD4021877 |
BEVACIZUMAB | Test | — | INTRAVENIOUS INFUSION | 5 | 6 | SUB16402MIG |