Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617001268336
Ethics application status
Approved
Date submitted
24/08/2017
Date registered
1/09/2017
Date last updated
8/07/2022
Date data sharing statement initially provided
9/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Direct Isolation Chemotherapy to Supplement Systemic Intravenous Chemotherapy for those with Liver Metastases from Colorectal Cancer
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
SYS-CAPLIOX
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
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 standard systemic chemotherapy (intravenous 5-FU + leucovorin + oxaliplatin [FOLFOX] or oral capecitabine with IV oxaliplatin [XELOX]).

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 10mg/m^2 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 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 1.1 criteria).
Timepoint [2] 338264 0
8 weeks after AVAS explantation, in addition to the standard of care schedule (typically quarterly scans) for 2 years after AVAS explantation.
Secondary outcome [3] 338265 0
Update Liver progression-free-survival assessed via routine CT scans as per standard of care.
Timepoint [3] 338265 0
8 weeks after AVAS explantation, in addition to the 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 V5.0.
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. Males or females, aged 18 years or older, with hepatic metastases from histologically proven adenocarcinoma of the colon/rectum;
2. Limited extrahepatic metastases in the lung or lymph nodes;
3. Confirmed non-progressive disease in the liver, per RECIST v1.1, halfway into the first-line systemic chemotherapy regimen after a minimum of 4 cycles of FOLFOX/XELOX ± monoclonal antibodies OR liver-dominant pre-treated or refractory patients;
4. Genotype: RAS mutant for first line patients only. All genetic mutations allowable for pre-treated or refractory patients;
5. Prior treatment with monoclonal antibody treatment is 'greater than or equal to' 4 weeks before implantation;
6. Considered medically fit for repeated general anaesthesia;
7. ECOG performance status 0-1;
8. Adequate bone marrow function (within 14 days of enrolment):
• 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;
9. Adequate renal function (within 14 days of enrolment):
• Serum Creatinine less than or equal to 1.5 × Upper Limit of Normal;
10. Adequate liver function (within 14 days of enrolment):
• Bilirubin less than or equal to 2.0 × Upper Limit of Normal;
• AST less than or equal to 5 × Upper Limit of Normal;
11. Normal coagulation (within 14 days of enrolment):
• INR less than or equal to 1.5
12. Able to understand the risks and benefits of the study and provide signed, written informed consent to participate;
13. Willing and able to comply with all study requirements and assessments;
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. CT-angiogram confirms unsuitable vascular anatomy;
2. No measurable liver disease per RECIST v1.1;
3. Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or main portal venous thrombosis;
4. Allergies to contrast agents;
5. Previous hypersensitivity or laryngo-pharyngeal dysaesthesia associated with oxaliplatin;
6. Previous allergies associated with 5-FU or oxaliplatin;
7. Grade > 2 peripheral neuropathy (CTCAE 5.0)
8. Significant co-morbidities;
9. Life expectancy less than or equal to 3 months;

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 Phase Ib/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.

Hypotheses and statistical power :

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).
The design for both cohorts has a statistical power of 80% and a significance level of 0.05 to test a “clinically significant” improved response rate. The null hypothesis must be rejected for the study treatment to be considered successful.

- Phase II/Cohort 1:
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.

- Phase II/Cohort 2:
Similar to Phase II/Cohort 1, it was assumed that the Phase II/Cohort 2 component of the study will have a median overall survival of 12 months, with a liver specific response rate (RR) of at least 25% during the treatment period. This RR (=25%) is to be compared with a historical RR of =10% reported from literature, with an improvement of at least 15% in RR.

Sample Size & Stage Design:

- Phase II/Cohort 1
For ethical and safety reasons, the Phase II/Cohort 1 study will be split into two stages (Stages 1 and 2). Stage 1 will be completed once the primary endpoint (tumour response 4 weeks post-explantation) for first 23 evaluable patients (excluding all patients in the Phase Ib component not treated with the RP2D) have been assessed. A minimum of 13 patients must been deemed as responsive to continue the study and proceed to Stage 2. If the number of responsive patients at the end of Stage 1 is less than 13, patient enrolment will be ceased, the study could be terminated for futility. Stage 2 is complete once the primary endpoint for a total of 37 patients (excluding all patients in the Phase Ib/Cohort 1 component not treated with the RP2D) has been assessed. A minimum of 24 patients must be deemed as responsive for the null hypothesis to be rejected.


- Phase II/Cohort 2
The Phase II /Cohort 2 study will be split into two stages (Stages 1 and 2). Stage 1 will be completed once the primary endpoint (tumour response 4 weeks post-explantation) for first the 22 evaluable patients have been assessed. A minimum of 3 patients must been deemed as responsive to continue the study and proceed to Stage 2. If the number of responsive patients at the end of Stage 1 is less than 3, patient enrolment might be ceased for futility. Stage 2 is complete once the primary endpoint for a total of 40 patients has been assessed (excluding all patients in the Phase Ib/Cohort 2 component not treated with the RP2D). A minimum of 8 patients must be deemed as responsive for the null hypothesis to be rejected.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
10/01/2022
Actual
Date of last participant enrolment
Anticipated
1/05/2023
Actual
Date of last data collection
Anticipated
1/05/2025
Actual
Sample size
Target
95
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 21158 0
Sydney Southwest Private Hospital - Liverpool
Recruitment hospital [2] 21159 0
Sydney Adventist Hospital - Wahroonga
Recruitment hospital [3] 21971 0
Lake Macquarie Private Hospital - Gateshead
Recruitment hospital [4] 21972 0
GenesisCare – North Shore - St Leonards
Recruitment hospital [5] 21986 0
Gold Coast Private Hospital - Southport
Recruitment postcode(s) [1] 36018 0
2170 - Liverpool
Recruitment postcode(s) [2] 36019 0
2076 - Wahroonga
Recruitment postcode(s) [3] 37067 0
2290 - Gateshead
Recruitment postcode(s) [4] 37068 0
2065 - St Leonards
Recruitment postcode(s) [5] 37087 0
4215 - Southport

Funding & Sponsors
Funding source category [1] 297313 0
Government body
Name [1] 297313 0
NSW Health Medical Device Fund
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
Approved
Ethics committee name [1] 298418 0
Macquarie University Human Research Ethics Committee (Medical Sciences)
Ethics committee address [1] 298418 0
Ethics committee country [1] 298418 0
Australia
Date submitted for ethics approval [1] 298418 0
09/08/2017
Approval date [1] 298418 0
04/12/2018
Ethics approval number [1] 298418 0
Ethics committee name [2] 309890 0
Bellberry Human Research Ethics Committee
Ethics committee address [2] 309890 0
Ethics committee country [2] 309890 0
Australia
Date submitted for ethics approval [2] 309890 0
11/02/2020
Approval date [2] 309890 0
21/04/2020
Ethics approval number [2] 309890 0
2019-11-968

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77022 0
Prof Nick Pavlakis
Address 77022 0
GenesisCare, Level 1/38 Pacific Highway, St Leonards, NSW 2065
Country 77022 0
Australia
Phone 77022 0
+61 2 8037 4100
Fax 77022 0
+61 2 8037 4111
Email 77022 0
[email protected]
Contact person for public queries
Name 77023 0
Nyan Khin
Address 77023 0
AllVascular
Suite 13
130-134 Pacific Highway
St Leonards
NSW 2065
Australia
Country 77023 0
Australia
Phone 77023 0
+61 2 9438 5228
Fax 77023 0
Email 77023 0
[email protected]
Contact person for scientific queries
Name 77024 0
Nyan Khin
Address 77024 0
AllVascular
Suite 13
130-134 Pacific Highway
St Leonards
NSW 2065
Australia
Country 77024 0
Australia
Phone 77024 0
+61 2 9438 5228
Fax 77024 0
Email 77024 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The commercial sponsors do not wish for the IPD to be published publicly as the data is intended to be published in academic/research journals.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
6709Study protocolStudy protocol is intended to be published in an academic journal between 2021 - 2022 and will be upload/cited then.   
6710Ethical approval    373491-(Uploaded-25-10-2021-14-09-42)-Study-related document.pdf
6711Informed consent form    373491-(Uploaded-08-10-2021-12-35-24)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.