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Trial registered on ANZCTR


Registration number
ACTRN12617001190392
Ethics application status
Approved
Date submitted
8/08/2017
Date registered
15/08/2017
Date last updated
17/07/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
An open label dose-finding, safety and tolerability study of Panitumumab, Irinotecan, Trifluridine/Tipiracil in RAS wild-type patients with metastatic colorectal cancer.
Scientific title
An open label phase IB/II, non-randomised, dose-finding, safety and tolerability study of Panitumumab, Irinotecan, Trifluridine/Tipiracil in RAS wild-type patients with metastatic colorectal cancer
Secondary ID [1] 292615 0
None
Universal Trial Number (UTN)
U1111-1200-3961
Trial acronym
PIT Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
colorectal cancer 304296 0
Condition category
Condition code
Cancer 303645 303645 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 298828 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 303006 0
Phase IB: To determine the maximum tolerated dose (MTD) of trifluridine/tipiracil when given in combination with panitumumab, irinotecan.

Dose-limiting toxicity (DLT) will be assessed to determine the MTD. DLTs will be defined as the occurrence of specific drug related adverse events (AEs) during cycle 1 or 2.
Timepoint [1] 303006 0
During dose escalation phase (Phase Ib) the MTD will be assessed, where participants will be enrolled in cohorts in order to establish the maximum tolerated dose of trifluridine/tipiracil when given in combination with panitumumab, irinotecan. Safety monitoring of DLT's will be conducted at least 4-weekly, or more
frequently if required.
Primary outcome [2] 303007 0
Progression Free Survival (PFS)
Timepoint [2] 303007 0
PFS, as assessed by CT scan in accordance with RECIST 1.1, will be assessed at 6 months post enrolment for participants treated at the MTD during the dose expansion phase (Phase II).
Secondary outcome [1] 337681 0
Safety and toxicity: Incidence and grade of adverse events (AEs)
Proportions of patients who experience given grades of toxicity will be reported in as well as rates of Grade 3/4 toxicities as defined by the Common Terminology Criteria for Adverse Events (CTCAE v4.03).
Timepoint [1] 337681 0
Safety and toxicity will be continuously assessed during the study until 30 days after the last study participant has finished treatment.
Secondary outcome [2] 337682 0
Objective Response Rate (ORR). Objective response rates will be calculated as the number of patients achieving CR or PR using RECIST 1.1 as a proportion of the number of patients who are evaluable for tumour response.
Timepoint [2] 337682 0
Tumour imaging will be conducted 8 weekly until disease progression.
Secondary outcome [3] 337683 0
Overall survival (OS).
Timepoint [3] 337683 0
This will be measured from the date of enrolment to date of death from any cause. Patients remaining alive or lost to follow-up will be censored at the date of last follow-up.

Eligibility
Key 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).
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Single arm phase Ib/II dose-finding safety and tolerability study.

During the dose-finding (phase Ib) portion participants with mCRC that have received and failed one prior chemotherapy regimen will be enrolled into cohorts in order to establish the maximum tolerated dose of trifluridine/tipiracil in combination with panitumumab and irinotecan.
Once the MTD is established the dose expansion phase (Phase II) participants that have received no prior treatment for mCRC will be recruited.
It is anticipated that approximately 50 patients will be enrolled over a period of 12 months.
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
During the dose escalation phase patients will be enrolled in cohorts. Each cohort will consist of a minimum of 3 newly enrolled evaluable patients. If there are not DLTs in the first 3 patients within the cohort, we will proceed to a new cohort at the next dose level (Please refer to the Description of Interventions/exposure). 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.
Once the MTD is declared an additional 50 patients will be enrolled in the expansion phase to enable inclusion of a total of 50 measurable patients treated at the MTD.

The primary analysis will be based on the proportion of patients (calculated as the Kaplan-Meier product-limit estimate) who have not progressed by 6 months. Estimates of activity will be described together with the 95% confidence intervals. Time to progression and overall survival will be displayed using Kaplan-Meier survival curves. Analyses for treatment activity performed on all enrolled patients and, if appropriate, those who have commenced the first cycle of treatment. Exploratory analyses will be performed using univariate and multivariate regression (linear, logistic and proportional hazards) methods.

Objective response rates will be calculated as the number of patients achieving complete or partial response (CR/PR) using RECIST 1.1 as a proportion of the number of patients who are evaluable for tumour response. This rate will also be reported excluding deaths/withdrawals within one month. These rates will be summarised using percentages together with the appropriate 95% confidence intervals. Toxicity will be analysed for patients having received at least one dose of assigned therapy and according to treatment received. Proportions of patients who experience given grades of toxicity will be reported in as well as rates of Grade 3/4 toxicities.
Patients receiving ongoing therapy at a dose level lower than the MTD can dose escalate to the MTD however they will not be evaluable for the phase II component.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
31/07/2018
Actual
Date of last participant enrolment
Anticipated
1/07/2019
Actual
Date of last data collection
Anticipated
28/02/2020
Actual
Sample size
Target
60
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 8702 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [2] 8704 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [3] 8705 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 8706 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 16815 0
5011 - Woodville
Recruitment postcode(s) [2] 16817 0
5042 - Bedford Park
Recruitment postcode(s) [3] 16818 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 297203 0
Commercial sector/Industry
Name [1] 297203 0
Institute de Researches Internationales Servier (I.R.I.S.) – Servier Laboratories (Australia) Pty Ltd
Country [1] 297203 0
France
Funding source category [2] 297204 0
Commercial sector/Industry
Name [2] 297204 0
Amgen Australia Pty Ltd
Country [2] 297204 0
Australia
Primary sponsor type
Hospital
Name
Central Adelaide Local Health Network Incorporated
Address
Level 3, Margaret Graham Building
Royal Adelaide Hospital,
North Terrace, Adelaide
South Australia, 5000
Country
Australia
Secondary sponsor category [1] 296211 0
None
Name [1] 296211 0
Address [1] 296211 0
Country [1] 296211 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298360 0
Human Research Ethics Committee (TQEH/LMH/MH)
Ethics committee address [1] 298360 0
The Queen Elizabeth Hospital
Ethics: DX465101
Ground Floor, Basil Hetzel Institute
28 Woodville Road
WOODVILLE SOUTH SA 5011
Ethics committee country [1] 298360 0
Australia
Date submitted for ethics approval [1] 298360 0
15/05/2017
Approval date [1] 298360 0
11/08/2017
Ethics approval number [1] 298360 0
HREC/17/TQEH/93

Summary
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.
Trial website
Trial related presentations / publications
Public notes
HREC approved, awaiting Research Governance approval.

Contacts
Principal investigator
Name 76834 0
Prof Timothy Price
Address 76834 0
The Queen Elizabeth Hospital
Haematology and Oncology
28 Woodville Road
Woodville South
South Australia 5011
Country 76834 0
Australia
Phone 76834 0
+61 8 8222 6000
Fax 76834 0
+61 8 8222 7486
Email 76834 0
[email protected]
Contact person for public queries
Name 76835 0
Jerneen Williams
Address 76835 0
The Queen Elizabeth Hospital
Haematology and Oncology
28 Woodville Road
Woodville South
South Australia 5011
Country 76835 0
Australia
Phone 76835 0
+61 8 8222 6410
Fax 76835 0
+61 8 8222 7486
Email 76835 0
[email protected]
Contact person for scientific queries
Name 76836 0
Timothy Price
Address 76836 0
The Queen Elizabeth Hospital
Haematology and Oncology
28 Woodville Road
Woodville South
South Australia 5011
Country 76836 0
Australia
Phone 76836 0
+61 8 8222 6000
Fax 76836 0
+61 8 8222 7486
Email 76836 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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