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Trial registered on ANZCTR


Registration number
ACTRN12615001283561
Ethics application status
Approved
Date submitted
6/11/2015
Date registered
25/11/2015
Date last updated
24/06/2022
Date data sharing statement initially provided
2/08/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Adjuvant chemotherapy with gemcitabine and cisplatin compared to standard of care after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1 trial)
Scientific title
Efficacy and safety of adjuvant chemotherapy with gemcitabine and cisplatin compared to capecitabine after curative intent resection of cholangiocarcinoma and muscle invasive gallbladder carcinoma (ACTICCA-1)
Secondary ID [1] 287736 0
ClinicalTrials.gov Identifier: NCT02170090
Secondary ID [2] 287737 0
EudraCT Nr: 2012-005078-70
Universal Trial Number (UTN)
Trial acronym
ACTICCA-1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cholangiocarcinoma 296598 0
muscle invasive gallbladder carcinoma 296599 0
Condition category
Condition code
Cancer 296842 296842 0 0
Biliary tree (gall bladder and bile duct)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All patients eligible for the treatment phase in stage 2 will be randomized to adjuvant chemotherapy with gemcitabine and cisplatin and observation or capecitabine and observation, followed by an immediate second randomization for patients meeting the specific radiotherapy sub-study selection criteria (R1 resection, no prior abdominal radiotherapy) and consenting in participation in the substudy.

Arm A: Gemcitabine/cisplatin and observation
Therapy will be administered on days 1 and 8 every 3 weeks for 24
weeks (8 cycles), with cisplatin (25 mg per square meter of body surface area) and gemcitabine (1000 mg per square meter) (Valle, Wasan et al. 2010).

Arm B: Capecitabine and observation
Therapy will be administered from day 1 to 14 every 3 weeks for 24
weeks (8 cycles), with capecitabine 2500 mg per square meter of body surface area per day (1250 mg per square meter of body-surface area, twice daily).

In addition, eligible patients with R1 resection included in sites
participating in the radiotherapy sub-study will be randomized between 24 weeks chemotherapy (gemcitabine/cisplatin or capecitabine) or 18 weeks of chemotherapy (gemcitabine/cisplatin or capecitabine) followed by chemoradiation with capecitabine.

Arm AR: Gemcitabine/cisplatin followed by chemoradiation and observation
Therapy will be administered on days 1 and 8 every 3 weeks for 18
weeks (6 cycles), with cisplatin (25 mg per square meter of body surface area) and gemcitabine (1000 mg per square meter) (Valle, Wasan et al. 2010), followed by chemoradiation with a total dose of 45Gy to elective nodal area and 55Gy to R1 delivered as a simultaneous integrated boost in 25 daily fractions over 5 weeks with concomitant capecitabine at 1330 mg per square meter of body-surface area per day (665 mg per square meter, twice daily) on radiotherapy days (5 days per week).

Arm BR: Capecitabine followed by chemoradiation and observation
Therapy will be administered from day 1 to 14 every 3 weeks for 18
weeks (6 cycles), with capecitabine 2500 mg per square meter of body surface area per day (1250 mg per square meter, twice daily) followed by chemoradiation with a total dose of 45Gy to elective nodal area and 55Gy to R1 delivered as a simultaneous integrated boost in 25 daily fractions over 5 weeks with concomitant capecitabine at 1330 mg per square meter of body-surface area per day (665 mg per square meter, twice daily) on radiotherapy days (5 days per week).
Radiotherapy
Radiotherapy should start not more than 6 weeks after day 1 of cycle 6.
A contrast enhanced liver protocol CT must be obtained for treatment planning in custom immobilisation. A linear accelerator with at least 6 MV should be used, capable of daily image guidance and IMRT delivery. Radiation therapy will be given daily, five times weekly. Online imaging prior to each fraction of radiotherapy is mandatory.
Intervention code [1] 293134 0
Treatment: Drugs
Intervention code [2] 323121 0
Treatment: Other
Comparator / control treatment
Capecitabine will be administered in tablet form from day 1 to day 14 every 3 weeks, twice daily. 1250 mg per square metre of body surface area. Until progression, intolerable toxicity, or for a maximum of 8 cycles (24 weeks).
Post-resection evaluation of tumour recurrence will be conducted following current clinical standards (CT or MRI every 3 months for two years after randomisation followed by 6-monthly abdominal ultrasound for further 3 years) until disease recurrence (radiological signs of recurrence or histological tumour detection by cytology or biopsy) in both groups.
Control group
Active

Outcomes
Primary outcome [1] 296451 0
Disease free survival by review of 3 or 6 monthly CT/MRI/US
Timepoint [1] 296451 0
Time from randomisation to date of first observed disease recurrence or death from any cause
Secondary outcome [1] 318476 0
Disease free survival by review of 3 or 6 monthly contrast enhanced CT/MRI/US. Diagnosis of recurrence could either be made by radiological imaging or by positive cytology or biopsy.
Timepoint [1] 318476 0
24 months after recruitment end
Secondary outcome [2] 318477 0
Overall survival by review of hospital records
Timepoint [2] 318477 0
time from randomisation until date of death
Secondary outcome [3] 318478 0
Safety and tolerability of adjuvant chemotherapy. Safety assessment will include physical examinations including vital signs, ECOG performance status, clinical laboratory profile, concomitant medication and adverse events graded by NCI CTCAE v4.03, including the degree of association of each with the procedure assessed and summarized.
Renal toxicity assessed by GFR
Febrile neutropenia assessed by Temperature and ANC
Neurotoxicity assessed by clinical laboratory profile
Pneumonitis assessed by clinical laboratory profile and scans
Ototoxicity assessed by clinical laboratory profile and audiometry
Timepoint [3] 318478 0
Every 3 weeks for a maximum treatment period of 24 weeks
Secondary outcome [4] 318479 0
Quality of life assessed by EORTC QLQ-c30, QLQ-BIL21, INFO25, PEF-FB-9 and PEF-FB-Doc
Timepoint [4] 318479 0
Baseline and every 12 weeks during follow up
Secondary outcome [5] 318480 0
Function of biliodigestive anastomosis assessed in terms of surgical revision, requirement for percutaneous transhepatic cholangiography (PTCD)
Timepoint [5] 318480 0
every 12-24 months during the follow up period
Secondary outcome [6] 318481 0
Composite outcome of rate and severity of biliary tract infections assessed by review of hospital records and assessment according to NCI CTCAE v4.03
Timepoint [6] 318481 0
every 3 weeks during treatment phase, then every 12-24 weeks during follow up phase
Secondary outcome [7] 318482 0
Loco-regional control will be assessed according to local recurrence or locoregional lymph node metastases and evaluated in regard of pathological stage according to TNM version 7 at resection.
Timepoint [7] 318482 0
every 12-24 weeks during the follow up phase
Secondary outcome [8] 318833 0
Pattern of disease recurrence
Timepoint [8] 318833 0
Assessed every 3 months for 2 years and every 6 months for a further 3 years after randomisation, according to distant vs. local recurrence evaluated in regard of pathological stage according to TNM version 7 at resection.
Secondary outcome [9] 341989 0
Recurrence free survival by review of 3 or 6 monthly contrast enhanced CT/MRI/US. Diagnosis of recurrence could either be made by radiological imaging or by positive cytology or biopsy.
Timepoint [9] 341989 0
Every 12-24 weeks during the follow up phase for 3 years
Secondary outcome [10] 407404 0
Local control rate at 24 months =The local control rate will be defined as absence of locoregional recurrence after 24 months counted from the day of randomization.
Pattern of recurrence will be classified according to distant vs. local recurrence. Local
control will be defined as rate of locoregional failures (local recurrence or locoregional
lymph node metastases). Both endpoints will be evaluated in regard of pathological stage
according to TNM version 7 at resection.
Timepoint [10] 407404 0
24 months from randomisation.

Eligibility
Key inclusion criteria
Eligibility criteria for treatment phase:
1. Histologically confirmed non-metastatic adenocarcinoma of biliary tract
(intrahepatic, hilar or extrahepatic cholangiocarcinoma or muscle invasive
gallbladder carcinoma) after radical surgical therapy with macroscopically
complete resection (mixed tumor entities (HCC/CCA) are excluded) (according to
appendix H)
2. Macroscopically complete resection (R0/1) within 6 (-16) weeks before scheduled
start of chemotherapy
3. ECOG 0-1
4. Age greater than or equal to 18 years
5. Adequate hematologic function: ANC larger than or equal to 1.5 x 10^9/L, platelets larger than or equal to 100 x10^9/L, hemoglobin larger than or equal to 9 g/dl or larger than or equal to 5.59 mmol/L
6. Adequate liver function as measured by serum transaminases (AST and ALT) less than or equal to 5 x ULN and bilirubin less than or equal to 3 x ULN
7. Adequate renal function, i.e. serum creatinine less than or equal to 1.5 x ULN, glomerular filtration rate greater than or equal to 50 ml/min (determination of GFR according to local institutional standards, e.g. MDRD, (Appendix E))
8. No active uncontrolled infection, except chronic viral hepatitis under antiviral therapy
9. No concurrent treatment with other experimental drugs or other anti-cancer
therapy, treatment in a clinical trial within 30 days prior to randomization
10.Negative serum pregnancy test within 7 days of starting study treatment in pre-menopausal women and women less than 1 year after the onset of menopause (Note: a negative test has to be reconfirmed by a urine test, should the 7-day window be
exceeded)

Criteria for initial study enrolment:
11.Written informed consent
12.No prior chemotherapy for biliary tract cancer
13.No previous malignancy within 3 years or concomitant malignancy, except those
with a 5 year overall survival rate of more than 90%, e.g. non-melanomatous skin
cancer or adequately treated in situ cervical cancer
14.No severe or uncontrolled cardiovascular disease (congestive heart failure NYHA
III or IV, unstable angina pectoris, history of myocardial infarction in the last 3
months, significant arrhythmia)
15.Absence of psychiatric disorder precluding understanding of information of trial
related topics and giving informed consent
16.No serious underlying medical conditions (judged by the investigator), that could
impair the ability of the patient to participate in the trial
17.Fertile women (< 1 year after last menstruation) and procreative men willing and
able to use effective means of contraception (oral contraceptives, intrauterine
contraceptive device, barrier method of contraception in conjunction with
spermicidal jelly or surgically sterile)
18.No pregnancy or lactation

Additional eligibility criteria for patients to be included in the radiotherapy substudy:
19.R1 (microscopic positive margin)
20.No previous radiotherapy to abdomen
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Prior chemotherapy for biliary tract cancer
* Previous malignancy within 3 years or concomitant malignancy, except: those with a 5 year overall survival rate of more than 90% e.g non-melanomatous skin cancer or adequately treated in-situ cervical cancer
* Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last 3 months, significant arrhythmia
* Presence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent
* Serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial
* Fertile women (less than 1 year after last menstruation) and procreative men unwilling and unable to use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile)
* Pregnancy or lactation

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/12/2015
Actual
24/01/2017
Date of last participant enrolment
Anticipated
30/09/2022
Actual
26/05/2021
Date of last data collection
Anticipated
26/05/2025
Actual
Sample size
Target
40
Accrual to date
Final
32
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA
Recruitment hospital [1] 4508 0
Bankstown-Lidcombe Hospital - Bankstown
Recruitment hospital [2] 4509 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [3] 4510 0
Flinders Medical Centre - Bedford Park
Recruitment hospital [4] 7376 0
Nepean Hospital - Kingswood
Recruitment hospital [5] 7377 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [6] 7378 0
The Townsville Hospital - Douglas
Recruitment hospital [7] 7379 0
Prince of Wales Hospital - Randwick
Recruitment hospital [8] 7380 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [9] 7381 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [10] 11996 0
St John of God Hospital, Subiaco - Subiaco
Recruitment hospital [11] 11997 0
St George Hospital - Kogarah
Recruitment hospital [12] 14403 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 15169 0
2747 - Kingswood
Recruitment postcode(s) [2] 15170 0
2298 - Waratah
Recruitment postcode(s) [3] 15171 0
4814 - Douglas
Recruitment postcode(s) [4] 15172 0
2031 - Randwick
Recruitment postcode(s) [5] 15173 0
4102 - Woolloongabba
Recruitment postcode(s) [6] 15174 0
6009 - Nedlands
Recruitment postcode(s) [7] 24152 0
6008 - Subiaco
Recruitment postcode(s) [8] 24153 0
2217 - Kogarah
Recruitment postcode(s) [9] 27412 0
6150 - Murdoch
Recruitment outside Australia
Country [1] 7275 0
Germany
State/province [1] 7275 0
Country [2] 7276 0
Netherlands
State/province [2] 7276 0
Country [3] 7277 0
United Kingdom
State/province [3] 7277 0
Country [4] 24661 0
New Zealand
State/province [4] 24661 0
Auckland

Funding & Sponsors
Funding source category [1] 292281 0
Other Collaborative groups
Name [1] 292281 0
Australasian Gastro-Intestinal Trials Group
Country [1] 292281 0
Australia
Funding source category [2] 295423 0
Government body
Name [2] 295423 0
Cancer Australia
Country [2] 295423 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Gastro-Intestinal Trials Group
Address
GI Cancer Institute
Lifehouse, Level 6
119-143 Missenden Road
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 290966 0
Hospital
Name [1] 290966 0
Universitatsklinikum Hamburg-Eppendorf
Address [1] 290966 0
Martinistrasse 52
D - 20246 Hamburg
Country [1] 290966 0
Germany
Other collaborator category [1] 278687 0
University
Name [1] 278687 0
NHMRC Clinical Trials Centre, University of Sydney
Address [1] 278687 0
Lifehouse Level 6
119-143 Missenden Road
Camperdown NSW 2050
Country [1] 278687 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293755 0
Northern Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 293755 0
Research Office
Kolling Building, Level 13
Royal North Shore Hospital
St Leonards NSW 2065
Ethics committee country [1] 293755 0
Australia
Date submitted for ethics approval [1] 293755 0
24/06/2015
Approval date [1] 293755 0
17/09/2015
Ethics approval number [1] 293755 0
HREC/15/HAWKE/230

Summary
Brief summary
The purpose of this study is to determine whether or not treating patients with cisplatin and gemcitabine chemotherapy helps reduce the risk of cancer returning.
Who is it for?
ACTICCA-1 is a clinical research study for people who have a cancer of the biliary tract (cancer of the gall bladder or bile duct, also known as cholangiocarcinoma in medical terms) which has been removed in an operation.
Study details
These drugs are being tested as they have been shown to be the most effective chemotherapy combination in more advanced cases of biliary tract cancer, where the disease is inoperable or has spread to other areas of the body.
This is an international investigator initiated study called ACTICCA-1, which is being led by the University Medical Centre Hamburg- Eppendorf in Germany and conducted in Australia by the Australasian Gastro-Intestinal Trials Group (AGITG) in collaboration with the National Health and Medical Research Centre Clinical Trials Centre (NHMRC CTC), University of Sydney.
The study involves randomly allocating participants to receive either chemotherapy with cisplatin and gemcitabine or the current standard of care (capecitabine). The drugs used in this study are approved in Australia to treat various cancers, however they do not have a specific listing by the Australian Therapeutics Goods Administration (TGA) for biliary tract cancer
It is hoped that the findings of this study will provide details on whether giving cisplatin and gemcitabine chemotherapy following surgery for cancer of the biliary tract is a safe and effective treatment to reduce the chance of disease progression and increase survival time and quality of life.

Radiotherapy Sub-Study – Second Randomisation for R1 Patients at Participating Sites

The purpose of the radiotherapy sub-study is to assess the role of adding radiation to chemotherapy in a subgroup of participants to see whether the addition of radiation can further reduce the risk of relapse.
Only participants with R1 resections (cancer cells present microscopically at the resection margin) to will be asked to join the sub-study. Participants will be assigned into groups for a second time to either continue to complete their chemotherapy course or to receive chemoradiation (radiation therapy and capecitabine) for a period of 5 weeks, after the initial 18 weeks of chemotherapy (arms AR and BR, described below). Patients are followed up for 5 years maximum from randomisation.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 61182 0
Dr Jenny Shannon
Address 61182 0
Nepean Cancer Care Centre
Cnr Great Western Highway and Somerset St
Kingswood NSW 2747
Country 61182 0
Australia
Phone 61182 0
+612 9562 5000
Fax 61182 0
Email 61182 0
[email protected]
Contact person for public queries
Name 61183 0
ACTICCA-1 Trial Coordinator
Address 61183 0
Lifehouse Level 6
119-143 Missenden Road
Camperdown NSW 2050
Country 61183 0
Australia
Phone 61183 0
+612 9562 5000
Fax 61183 0
Email 61183 0
[email protected]
Contact person for scientific queries
Name 61184 0
Acticca-1 Clinical Lead
Address 61184 0
Lifehouse Level 6
119-143 Missenden Road
Camperdown NSW 2050
Country 61184 0
Australia
Phone 61184 0
+612 9562 5000
Fax 61184 0
Email 61184 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
As per CTC SOP


What supporting documents are/will be available?

No Supporting Document Provided



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.