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Trial registered on ANZCTR


Registration number
ACTRN12617001268336p
Ethics application status
Submitted, not yet approved
Date submitted
24/08/2017
Date registered
1/09/2017
Date last updated
7/08/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Direct Isolation Chemotherapy for Liver Metastases
Scientific title
Phase Ib/II Study of Intra-Arterial Liver Isolation Chemotherapy in Patients with Hepatic Metastases from Colorectal Cancer
Secondary ID [1] 292673 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Liver Cancer 304420 0
Condition category
Condition code
Cancer 303749 303749 0 0
Liver
Cancer 303750 303750 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 303751 303751 0 0
Bowel - Anal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Description of Intervention/Exposure

The treatment proposed in this clinical investigation plan is to repeatedly administer intra-arterial chemotherapy to hepatic metastases from colorectal cancer when the blood flow to and from the liver has been isolated via balloon catheters. The objective of this study is to evaluate the tumour response, progression-free survival, morbidity and mortality of repeated and isolated intra-arterial hepatic infusion of oxaliplatin compared with the gold standard 5-FU/leucovorin/oxaliplatin (FOLFOX) treatment.

The treatment proposed in this study is based on the hypothesis that direct arterial infusion of chemotherapy to metastatic tumours of the liver whilst the blood flow to the organ is isolated could potentially yield benefits that cannot be achieved with existing treatment regimens.

There are three treatment stages; implantation of a vascular access device (known as the AVAS), intra-arterial chemotherapy infusions, and explantation of the AVAS.

Implantation: the participant is admitted to hospital and the AVAS is surgically implanted under general anaesthetic. The AVAS is an implantable large bore cannula with one end that can be anastomosed directly onto a peripheral vessel and the opposite end exiting the patient’s skin. The device can be opened to access the patient’s vasculature when required and closed when the device is not in use. In accordance with the manufacturer’s Instructions-For-Use (IFU), the AVAS will be implanted in the axillary artery (i.e. the upper pectoral area) or in the common femoral artery (upper thigh) by a trained vascular surgeon. The implantation procedure takes around 2 hours. After implantation, the participant is monitored overnight.

Intra-arterial chemotherapy infusions: the participant is admitted to the angiography suite and under general anaesthetic or conscious sedation, intra-arterial hepatic isolation chemotherapy infusion is administered by an interventional radiologist. The first infusion can be administered 2 days after device implantation and infusions are spread out over an 8-week period at a maximum such that the patient receives 5 to 7 infusions in total, has at least 2 full calendar days between each infusion, and there are no more than 2 infusions over any 7 consecutive days. Each infusion can take between 2-3 hours during the first few infusions but should only take 1-2 hours for the remaining infusions as the radiologist becomes familiarised with the patient’s vascular anatomy. During the Phase Ib stage, the starting dose of the oxaliplatin infused will be 50mg/m^2 and this dose will be escalated by 5mg with each patient until an optimal dose is established. The optimal dose will be used for all patients enrolled during the Phase II stage.

Explantation: the final infusion session is followed by the device explantation immediately, or at a later time depending on the availability of operating rooms and the condition of the participant. The surgical removal of the device takes approximately 1-2 hours, the participant is monitored overnight and discharged the next day.

In addition, capecitabine will be administered orally as per standard care (1000 mg/m^2 twice daily in 2 week cycles) throughout the study treatment period (from enrolment to 4-5 weeks after the AVAS explantation) as a form of systemic disease management. The oncologist may modify the capecitabine dose/frequency based on the patient’s response to the medication.
Intervention code [1] 298908 0
Treatment: Drugs
Intervention code [2] 298909 0
Treatment: Devices
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 303119 0
Response rate of tumours in liver as assessed via CT scans (RECIST criteria)
Timepoint [1] 303119 0
4-5 weeks after explantation of the AVAS
Secondary outcome [1] 337925 0
Two-year survival assessed via follow-up visits.
Timepoint [1] 337925 0
Quarterly for the first year and six-monthly for the second year after AVAS explantation,
Secondary outcome [2] 338264 0
Overall progression free survival assessed via routine CT scans (RECIST criteria).
Timepoint [2] 338264 0
As per standard of care schedule (typically quarterly scans) for 2 years after AVAS explantation.
Secondary outcome [3] 338265 0
Liver progression-free-survival assessed via routine CT scans (RECIST criteria).
Timepoint [3] 338265 0
As per standard of care schedule (typically quarterly scans) for 2 years after AVAS explantation.
Secondary outcome [4] 338266 0
Systemic side effects to chemotherapy assessed by collection of adverse events using Common Terminology Criteria for Adverse Events 4.03.
Timepoint [4] 338266 0
From enrolment until primary outcome is assessed (4-5 weeks after explanation of the AVAS).
Secondary outcome [5] 338267 0
Organ isolation capability as determined by pressure readings on catheters during infusions procedures.
Timepoint [5] 338267 0
At the completion of each infusion procedure.
Secondary outcome [6] 338268 0
Rate of conversion to resection assessed via follow-up visits.
Timepoint [6] 338268 0
Quarterly for the first year and six-monthly for the second year after AVAS explantation.
Secondary outcome [7] 338420 0
Quality of life assessed via a combined questionnaire (EORTC QLQ-C30 and QLQ-LMC21).
Timepoint [7] 338420 0
Prior enrolment, after 2 infusions, and 4-5 weeks after AVAS explantation.

Eligibility
Key inclusion criteria
1. Patients with hepatic metastases from histologically proven adenocarcinoma of the colon/rectum
2. Patients with limited extrahepatic metastases in the lung or lymph nodes (fewer than 5 nodules less than or equal to 1 cm diameter or a single nodule less than or equal to 1.7cm diameter in the lung, and lymph node involvement in a single anatomical area less than 2 cm diameter)
3. Patients in whom CT at screening has confirmed non-progressive disease, as per RECIST v1.1, after the first 6 cycles of FOLFOX ± bevacizumab
4. Patients who have had no more than 7 cycles of FOLFOX ± bevacizumab or other chemotherapy
5. Patients with Genotype: RAS mutant
6. Estimated time between last monoclonal antibody treatment and anticipated date of first infusion will be at least 6 weeks
7. Patients must be fit for repeated general anaesthesia
8. Patients with World Health Organization performance status < 3
9. Patients with haemoglobin greater than or equal to 100 g/L, ANC greater than or equal to 1.5×10^9/L, platelet count greater than or equal to 100×10^9/L
10. Patients with adequate renal function (serum creatinine less than 1.5 × Upper Limit of Normal)
11. Patients with adequate liver function (bilirubin 1.0 - 2.0 × Upper Limit of Normal, AST less than 5 × Upper Limit of Normal)
12. Patients with normal coagulation (INR less than 1.5)
13. Patient over 18 years of age
14. Patients who are able to understand the risks and benefits of the study and give written informed consent to participate
15. Patients who are available for follow-up at the study sites for the length of the study
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. CT-angiogram confirms unsuitable vascular anatomy
2. All lesions in the liver are not measurable (RECIST v1.1) in the CT scan prior to FOLFOX commencement
3. All lesions in the liver are not measurable (RECIST v1.1) in the CT scan between the 6th and 7th FOLFOX cycles
4. Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or main portal venous thrombosis
5. Allergies to contrast agents
6. Previous hypersensitivity or laryngo-pharyngeal dysaesthesia associated with oxaliplatin
7. Previous allergies associated with 5-FU or oxaliplatin
8. Grade 2 or higher peripheral neuropathy
9. Significant co-morbidities (i.e. life expectancy less than or equal to 3 months)
10. Pregnant or breastfeeding women, or women of child bearing potential and who are not on a reliable form of birth control
11. Patients who are enrolled or intend to participate in another clinical trial (of an investigational drug or device, new indication for an approved drug or device, or requirement of additional testing beyond standard clinical practice) during this clinical study
12. Patients with medical conditions that preclude the testing required by the protocol, or limit study participation

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)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The study is a PhaseIb/II study.

The Phase Ib study is a dose escalation study to establish a safe and recommended dose that will be used in the Phase II stage of the study. This stage is comprised of an accelerated stage and a confirmation stage. During the accelerated stage, patients will be treated one-by-one and the dose escalated after each patient until dose limiting symptoms are observed. From here the confirmation stage is initiated and patients can be treated with the same dose in groups of 3 until the dose limit is confirmed. The last dose used prior to the observed dose limit will be the dose used for the Phase II stage of the study. The number of patients required for the Phase Ib stage of the study cannot be reliably estimated.

The Phase II study will assess the study treatment against historical information of comparable populations to provide binary endpoints (H0: non-clinically significant improvement in response rate; H1: clinically significant improvement in response rate). Based on the known response rate of approximately 50% (P0 = 0.50) for comparable patient cohorts, it was decided that the study treatment needed to yield a response rate of at least 70% (P1 = 0.70) with a statistical power of 80% and a significance level of 0.05 to be considered as a “clinically significant” improved response rate. The null hypothesis must be rejected for the study treatment to be considered successful.

Sample Size & Stage Design - For ethical and safety reasons, the Phase II study will be split into two stages. Stage 1 will be completed once the primary endpoint (tumour response 4-5 weeks post-explantation) for the first 23 patients (not including those in the Phase Ib component) have been assessed. A minimum of 13 patients must respond to the treatment for the study to continue. If the number of responsive patients at the end of Stage 1 is less than 13, patient enrolment will be ceased, the study shall be terminated, and the null hypothesis cannot be rejected. Stage 2 is complete once the primary endpoint for a total of 37 patients (not including those in the Phase Ib component) has been assessed. A minimum of 24 patients must respond for the null hypothesis to be rejected.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 8814 0
Macquarie University Hospital - Macquarie Park
Recruitment postcode(s) [1] 16938 0
2109 - Macquarie Park

Funding & Sponsors
Funding source category [1] 297313 0
Government body
Name [1] 297313 0
NSW Health Medical Device Fund
Address [1] 297313 0
Office for Health and Medical Research
73 Miller Street
North Sydney
NSW 2060
Country [1] 297313 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
AllVascular Pty Ltd
Address
Suite 13
130-134 Pacific Highway
St Leonards
NSW 2065
Country
Australia
Secondary sponsor category [1] 296283 0
None
Name [1] 296283 0
Address [1] 296283 0
Country [1] 296283 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 298418 0
Macquarie University Human Research Ethics Committee (Medical Sciences)
Ethics committee address [1] 298418 0
Research Office
Research Hub, Building C5C East
Macquarie University
NSW 2109
Ethics committee country [1] 298418 0
Australia
Date submitted for ethics approval [1] 298418 0
09/08/2017
Approval date [1] 298418 0
Ethics approval number [1] 298418 0

Summary
Brief summary
The aim of this study is to assess the efficacy of delivering chemotherapy treatment through the arteries directly to the liver, bypassing the main blood supply throughout the body.

Who is it for?
You may be eligible for this study if you are aged over 18 years, have hepatic metastases from histologically proven adenocarcinoma of the colon/rectum, and have had some systemic chemotherapy.

Study details
Once enrolled, patients will have baseline scans and will have the AVAS device implanted. The patient will be admitted to hospital up to twice a week to be treated with the liver directed therapy until they have received 5-7 treatments of oxaliplatin, after which the device will be explanted. Oxaliplatin is approved in Australia as chemotherapy treatment for liver metastases from colorectal cancer (via IV infusion), but has not previously been approved when delivered to through the arteries to the liver using the AVAS study device. All patients will also receive Capecitabine from enrolment to 4-5 weeks after the AVAS explantation as a form of systemic disease management. The patient’s tumour will be scanned 4-5 weeks after explant of the device, and the patient will be followed up for two years.

The treatment proposed in this study is based on the hypothesis that direct arterial infusion of chemotherapy to metastatic tumours of the liver whilst the blood flow to the organ is isolated could potentially yield benefits that cannot be achieved with existing treatment regimens.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77022 0
Dr Pirooz Poursoltan
Address 77022 0
Macquarie University Clinic
Suite 302, Level 3
2 Technology Place
Macquarie University
NSW 2109
Country 77022 0
Australia
Phone 77022 0
+61 2 9887 8899
Fax 77022 0
+61 2 9887 8800
Email 77022 0
ccc@muh.org.au
Contact person for public queries
Name 77023 0
Mr Hung Tran
Address 77023 0
Faculty of Medicine and Health Sciences
Department of Clinical Medicine
Suite 407, Level 4, Building F10A - Clinic Building,
2 Technology Place
Macquarie University
NSW 2109
Country 77023 0
Australia
Phone 77023 0
+61 2 9812 3604
Fax 77023 0
+61 2 9812 3533
Email 77023 0
hung.tran@mq.edu.au
Contact person for scientific queries
Name 77024 0
A/Prof Nick Pavlakis
Address 77024 0
Northern Cancer Institute
38 Pacific Hwy
St Leonards
NSW 2065
Country 77024 0
Australia
Phone 77024 0
+61 2 8037 4100
Fax 77024 0
+61 2 8037 4111
Email 77024 0
nick.pavlakis@sydney.edu.au

No data has been provided for results reporting
Summary results
Not applicable