None listed
Conditions
Brief summary
This study aims to determine the maximum tolerated dose (MTD) and assess the efficacy of panitumumab, irinotecan and trifluridine/tipiracil when given in combination for participants with RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC). Who is it for? You may be eligible to join this study if you are aged 18 years or above and have a confirmed diagnosis of metastatic colorectal cancer that is RAS/BRAF wild type. Study details This study will be conducted in two parts: phase Ib and phase II. The study will commence with a phase Ib dose escalation phase, during which participants will be administered Irinotecan (180mg/m2) and Panitumumab (6mg/Kg) intravenously (IV) on Day 1 of every 14 day cycle, in combination with oral Trifluridine/tipiracil twice a day on Days 1-5 of every 14 day cycle. Dosing of trifluridine/Tipiracil will commence at 25 mg/m2 orally twice a day in the first group. If tolerated, the dose will be elevated for subsequent groups up to a maximum of 35 mg/m2 orally twice a day. Phase II of the study will enrol a separate group of participants who will receive the maximum tolerated dose determined in phase Ib. Treatment in both phases will continue until disease progression, unacceptable toxicity or participant withdrawal. Participants will be regularly assessed throughout the study in order to monitor safety and tumour response. Follow-up visits will occur every 12 weeks after the end of treatment visit until death or study closure. It is hoped that this study will provide evidence for further research into this combination, and improve health outcomes for patients with this disease.
Interventions
Irinotecan (180mg/m2), and Panitumumab (6mg/Kg), will be administered intravenously (IV) on Day 1 of every 14 day cycle.
Trifluridine/tipiracil will be administered orally (PO) twice a day (BD) on Days 1-5 of every 14 day cycle. Trifluridine/tipiracil will be supplied as 15 mg (comprising 15 mg trifluridine/6.14 mg tipiracil) and 20 mg (comprising 20 mg trifluridine/8.19mg tipiracil) immediate-release film-coated tablets and the number of tablets needed to achieve the assigned dose will be det
Irinotecan (180mg/m2), and Panitumumab (6mg/Kg), will be administered intravenously (IV) on Day 1 of every 14 day cycle. Trifluridine/tipiracil will be administered orally (PO) twice a day (BD) on Days 1-5 of every 14 day cycle. Trifluridine/tipiracil will be supplied as 15 mg (comprising 15 mg trifluridine/6.14 mg tipiracil) and 20 mg (comprising 20 mg trifluridine/8.19mg tipiracil) immediate-release film-coated tablets and the number of tablets needed to achieve the assigned dose will be determined according to the patient’s body surface area. Dosing of trifluridine/tipiracil in the dose escalation phase (phase Ib) will be as follows: Dose Level Trifluridine/tipiracil 1 (starting dose) 25 mg/m2 orally, BD 2 30 mg/m2 orally, BD 3 35 mg/m2 orally, BD The dose escalation phase (phase Ib) will recruit participants who have received and failed one prior chemotherapy regimen for metastatic colorectal cancer (mCRC). It is anticipated that this phase of the study will take 6 months to complete. The maximum (MTD) will be assessed during the dose escalation phase, where participants will be enrolled in cohorts. Each cohort will consist of a minimum of 3 newly enrolled evaluable patients. If there is no dose-limiting toxicities (DLT) in the first 3 patients within a cohort, a new cohort at the next dose level will commence. If safety data show one patient in a cohort experiencing a DLT, then the cohort will be increased to a maximum of six evaluable patients. If no more than one of the six patients experiences a DLT, then the next dose level may be evaluated. If two or more patients entered in any cohort experience a DLT, then the MTD has been exceeded, and the previous dose level will be considered the MTD. If no dose level has 2 or more DLT`s, then dose level 3 will be considered the MTD. A minimum of 6 evaluable patients will be treated at the dose level before the dose can be declared as the MTD and enrolment into the phase II component can begin. Cohorts may also be expanded at any dose level to further assess safety parameters as required. If a dose level is opened and patients in the previous cohort subsequently develop unexpected toxicities the cohort will be closed and the previous cohort will be re-assessed with further patients enrolled into the previous cohort as required. The maximum tolerated dose (MTD) of tipiracil/trifluridine will be the dose level administered in the expansion phase (phase II). The expansion phase (phase II) will recruit participants that have received no prior treatment for mCRC, and is anticipated to take up to 18 months to complete. Treatment will continue until disease progression or withdrawal criteria are met.
Sponsors
Central Adelaide Local Health Network Incorporated
Study design
Allocation
Non-randomised trial
Intervention model
Other
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion criteria • Provide a signed and dated Participant Information and Consent Sheet • Age greater than or equal to 18 years • Histological diagnosis of colorectal cancer that is RAS/BRAF wild type. • Metastatic disease not amenable to resection, including borderline resectable cases. • Measurable disease as assessed by CT scan in accordance with RECIST v1.1 criteria. • Phase Ib group only: Received and failed one, and only one, prior chemotherapy regimen for mCRC consisting of first-line fluoropyrimidine-based chemotherapy (Treatment failure is defined as radiological progression per RECIST v1.1 criteria after therapy for metastatic disease, prior adjuvant therapy completed <6 months prior to metastatic disease, or toxicity limiting further therapy). Phase II group only: previously untreated mCRC. • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 during screening.. • Adequate bone marrow function with haemoglobin >100 g/L, platelets >100 X 109/L; neutrophils >1.5 X 109/L within 7 days of enrolment. • Adequate renal function, with calculated creatinine clearance >40 ml/min (Cockcroft and Gault) within 7 days of enrolment. • Adequate hepatic function with serum total bilirubin greater than or equal to 1.25 x upper limit of normal (ULN) range and ALT or AST greater than or equal to 2.5xULN (or greater than or equal to 5xULN if liver metastases present) within 7 days of enrolment • Magnesium greater than or equal to lower limit of normal within 7 days of enrolment. • Life expectancy of at least 12 weeks. • Negative pregnancy test within 7 days before commencing study treatment (women of childbearing potential only).
Exclusion criteria
Exclusion criteria • Phase Ib group only: any history of prior pelvic radiotherapy • Phase Ib group only: history of prior systemic chemotherapy, immunotherapy, approved proteins/antibodies or any investigational agent within 4 weeks prior to commencing study treatment. • Radiotherapy within 14 days of commencing study treatment. • Unresolved toxicities greater than or equal to grade 2 resulting from prior systemic therapy or radiotherapy. • Any medical or psychiatric conditions that compromise the patient’s ability to give informed consent or to complete the protocol. • Prior treatment with EGFR targeting therapies such as cetuximab, panitumumab or erlotinib. • Prior therapy with irinotecan. • History of interstitial pneumonitis, pulmonary fibrosis or evidence of interstitial pneumonitis, or pulmonary fibrosis on baseline chest CT scan. • History of Gilbert syndrome. • Known cirrhosis, chronic active hepatitis, or chronic persistent hepatitis. • Patients with active bleeding diathesis. • Any uncontrolled clinically significant cardiac disease, arrhythmias or angina pectoris • Active inflammatory bowel disease or other bowel disease causing chronic diarrhoea (defined as Common Terminology Criteria for Adverse Events (CTCAE) greater than or equal to grade 2 [version 4.03]) • Chronic treatment with immunosuppressives. • Patients with a known history of HIV seropositivity. • Patients who have any severe and/or uncontrolled medical conditions or infections • Patients who have a history of another primary malignant disease apart from non-melanotic skin cancer or carcinoma in situ of the uterine cervix or any other cancer treated with curative intent >2 years previously without evidence of relapse. • Known brain metastasis. • Pregnancy or lactation. • Women and partners of women of childbearing potential who are not using effective contraception. Highly effective contraception must be used throughout study treatment and for 6 months following the completion of all study treatment. • Patients with history of serious drug adverse reactions.
Outcome results
None listed