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Trial registered on ANZCTR


Registration number
ACTRN12610001047088
Ethics application status
Approved
Date submitted
23/11/2010
Date registered
30/11/2010
Date last updated
30/01/2019
Date data sharing statement initially provided
30/01/2019
Date results information initially provided
30/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomised phase II study evaluating potential predictive biomarkers in the treatment of locally advanced and metastatic pancreatic cancer
Scientific title
A randomised phase II study evaluating potential predictive biomarkers and examining the efficacy and safety of oxaliplatin, 5-fluorouracil and leucovorin (as mFOLFOX6) compared to gemcitabine in the treatment of metastatic pancreatic cancer.
Secondary ID [1] 253047 0
Nil
Universal Trial Number (UTN)
Trial acronym
PAN1
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Locally advanced and metastatic pancreatic cancer 258463 0
Condition category
Condition code
Cancer 258625 258625 0 0
Pancreatic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients randomised to the intervention arm will receive modified FOLFOX6 chemotherapy (mFOLFOX6). Each cycle of mFOLFOX6 will consist of:

- Oxaliplatin 85mg/m2 given as an intravenous (IV) infusion on day 1 of a 2 week cycle.
- 5-Flurouracil 400mg/m2 given as an IV infusion on day 1 of a 2 week cycle.
- Leucovorin 400mg/m2 given as an IV infusion on day 1 of a 2 week cycle.
- 5-Flurouracil 2400mg/m2 given as an IV continuous infusion over 46 hours, commencing on day 1 of a 2 week cycle.

The cycle will be repeated every 2 weeks.

Patients will continue their assigned treatment until progression, unacceptable toxicity or any of the reasons listed in protocol section 4.4.
Intervention code [1] 257452 0
Treatment: Drugs
Comparator / control treatment
Patients randomised to the control arm will receive gemcitabine chemotherapy. Each cycle of gemcitabine will consist of:


- Gemcitabine 1000mg/m2 given as an IV infusion on days 1, 8, 15 of a 4 week cycle.

The cycle will be repeated every 4 weeks.

Patients will continue their assigned treatment until progression, unacceptable toxicity or any of the reasons listed in protocol section 4.4.
Control group
Active

Outcomes
Primary outcome [1] 259614 0
Progression free survival at 4 months
Timepoint [1] 259614 0
Progression free survival is measured as the interval between randomisation and documented evidence of disease progression, the occurrence of new disease or death from any cause. Disease progression will be defined by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 criteria and assessed every 8 weeks until progression.
Secondary outcome [1] 266414 0
Efficacy/activity of gemcitabine and FOLFOX as assessed by:
- Overall survival
- Time to progression
- Response rate according to RECIST v1.1
- CA19.9 response
Timepoint [1] 266414 0
- Overall survival time is measured as the time from the date of randomisation to the date of death due to any cause. Overall survival time will be censored at the date of the last follow-up visit for patients who are still alive.

- Time to documented disease progression is defined as the time from randomisation to the first date of documented disease progression or the occurrence of new disease. Disease progression will be defined by RECIST v1.1 criteria and assessed every 8 weeks until disease progression.

- Response rate according to RECIST v1.1. A tumour responder is defined as any patient exhibiting a best study response of complete response or partial response (based on computed tomography scan (CT scan)). Response will be assessed every 8 weeks until disease progression.

- CA19.9 will be assessed at baseline and 4 weekly from the start of treatment. CA19.9 response will be analysed as an exploratory endpoint using the following definition:
1. To be evaluable for response by CA19.9 requires 1 pre-treatment sample > twice the upper limit of normal in the absence of biliary obstruction, and at least 1 further sample after the start of treatment.
2. A response to CA19.9 has occurred if there is at least a 20% reduction in levels following the start of chemotherapy.
3. The date of response by CA19.9 is the date of the first sample with a 20% fall.
4. Documentation of any proven or suspected interval biliary sepsis or stenting is required for correlation.
Secondary outcome [2] 266415 0
Proportion of patients for whom a hENT1 result is obtained within a clinically useful timeframe.
Timepoint [2] 266415 0
Tissue samples for hENT1 testing will be collected prior to randomisation.
Secondary outcome [3] 266416 0
Progression free survival in each biomarker cohort.
Timepoint [3] 266416 0
Progression free survival is measured as the interval between randomisation and documented evidence of disease progression, the occurrence of new disease or death from any cause. Disease progression will be defined by RECIST v1.1 criteria and assessed every 8 weeks until progression.
Secondary outcome [4] 266417 0
To collect and analyse data from patient biospecimens
Timepoint [4] 266417 0
Tissue samples will be collected at baseline
Secondary outcome [5] 266418 0
Treatment related toxicity in each chemotherapy group
Timepoint [5] 266418 0
Toxicity will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) criteria v4.0 at baseline, prior to starting each chemotherapy cycle, at end of treatment and 30 days after the last study drug administration.
Secondary outcome [6] 266419 0
Ascertain if there is a relationship between biomarker status and treatment related toxicity
Timepoint [6] 266419 0
Toxicity will be assessed according to Common Terminology Criteria for Adverse Events (CTCAE) criteria v4.0 at baseline, prior to starting each chemotherapy cycle, at end of treatment and 30 days after the last study drug administration.
Secondary outcome [7] 266420 0
Establish a tissue bank from patients treated with and without gemcitabine to support further biomarker studies
Timepoint [7] 266420 0
Tissue samples will be collected at baseline

Eligibility
Key inclusion criteria
1. Males or females with radiologically and histologically confirmed metastatic pancreatic adenocarcinoma. Eligibility of patients with suspected disease must be confirmed by core biopsy prior to randomisation.
2. Adult patients; 18 years or over.
3. No previous treatment, except:
a. If adjuvant systemic therapy was received following resection, study entry is permissible if disease recurrence has occurred at least 6 months after completion of chemotherapy.
b. Previous radiotherapy is permissible if disease progression has occurred outside the radiotherapy field and disease recurrence has occurred at least 6 months after completion of radiotherapy.
c. Previous chemoradiotherapy is permissible if only radiosensitiser dose chemotherapy was used and disease progression has occurred outside of the radiotherapy field at least 6 months after completion of treatment.
4. Informed consent for all trial procedures, including:
a. Consent to undergo core biopsy to obtain tissue for biomarker analysis unless suitable archived paraffin embedded tissue (e.g. surgical specimen) is already available for human equilibrative nucleoside transporter 1 (hENT1) testing and other planned translational studies.
b. Consent for collection of peripheral blood for pharmacogenomic/pharmacogenetic analysis.
5. World Health Organisation (WHO) performance status 0-2.
6. Adequate renal, hepatic and haematological function, defined as;
a. Creatinine clearance (Cockcroft-Gault formula) >60mL/min
b. Bilirubin <1.5 x Upper Limit of Normal (ULN), aspartate aminotransferase (AST) + alanine aminotransferase (ALT) <3.0 x ULN (or <5.0 x ULN with documented liver metastases)
c. Haemoglobin >100 g/L, Platelets >150 x109/L and Neutrophils >1.5x 109/L
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous systemic treatment for metastatic pancreatic cancer.
2. Pregnant or lactating females or female patients of childbearing potential who have not been surgically sterilized or are without adequate contraceptive measures.
3. Other active malignancy or primary malignancy diagnosed within the previous 5 years, except for treated squamous or basal cell carcinoma of skin or cervical carcinoma.
4. Previous reactions to or suspected hypersensitivity to any of the investigational agents.
5. Peripheral neuropathy of any cause, of grade 2 or worse by CTCAE v4.0 criteria.
6. Seropositive for (Human Immunodeficiency Virus) HIV or Hepatitis C.
7. Active Hepatitis B not suppressed with antiviral treatment.
8. Symptomatic coronary or cardiac insufficiency.
9. History of thromboembolism, myocardial infarction or cardiovascular accident within preceding 3 months. Patients who have experienced deep venous thrombosis or pulmonary embolism within previous 6 months must be maintained on therapeutic levels of anticoagulation.
10. Diarrhoea >grade 2 and/or uncontrolled diarrhoea.

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)
Central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patients will be randomised to one of the two treatment arms in a 1:1 ratio using the minimisation method and stratified according to Locally advanced vs metastatic disease; Previous adjuvant chemotherapy (yes vs no); WHO performance status (0, 1 vs 2); and Institution.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
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,VIC,ACT,QLD,SA,WA,TAS
Recruitment outside Australia
Country [1] 2985 0
New Zealand
State/province [1] 2985 0

Funding & Sponsors
Funding source category [1] 257906 0
Other Collaborative groups
Name [1] 257906 0
Australasian Gastrointestinal Trials Group (AGITG)
Address [1] 257906 0
AGITG Coordinating Centre
Locked Bag 77
Camperdown
NSW 1450
Country [1] 257906 0
Australia
Funding source category [2] 284711 0
Charities/Societies/Foundations
Name [2] 284711 0
Avner Nahmani Pancreatic Cancer Research Fund
Address [2] 284711 0
Sydney
Country [2] 284711 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Gastrointestinal Trials Group (AGITG)
Address
AGITG Coordinating Centre
Locked Bag 77
Camperdown
NSW 1450
Country
Australia
Secondary sponsor category [1] 257102 0
None
Name [1] 257102 0
Address [1] 257102 0
Country [1] 257102 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 260102 0
Cancer Institute NSW Clinical Research Ethics Committee
Ethics committee address [1] 260102 0
PO Box 41
Alexandria NSW 1435
Ethics committee country [1] 260102 0
Australia
Date submitted for ethics approval [1] 260102 0
08/11/2010
Approval date [1] 260102 0
24/01/2011
Ethics approval number [1] 260102 0
2010C/11/145
Ethics committee name [2] 298469 0
SLHD Ethics Review Committee (RPAH Zone)
Ethics committee address [2] 298469 0
Research Development Office
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [2] 298469 0
Australia
Date submitted for ethics approval [2] 298469 0
22/10/2013
Approval date [2] 298469 0
14/11/2013
Ethics approval number [2] 298469 0
X13-0182 and HREC/13/RPAH/420

Summary
Brief summary
This study looks at whether testing for 'biomarkers' may be used to select the best treatment for patients with metastatic pancreatic cancer. A biomarker is a biological characteristic that can be measured in tumour tissue or blood, which may provide information on the behaviour of cancer or help predict the likely effect of a given treatment. We know that not all cancers or patients are the same, and that some patients may respond better to certain treatments. This study will help increase our understanding of how we might be able to select treatments to suit individual patients and their cancers. By doing this we hope to obtain the best outcomes for future patients while minimising side effects from treatment.

Who is it for?

You can join this study if you have radiologically and histologically confirmed metastatic pancreatic adenocarcinoma, confirmed by biopsy.
This is a phase II multicentre, randomised, open label study to evaluate biomarker directed treatment of metastatic pancreatic cancer.

Trial Details

Participants will be in two groups. Group 1 will receive Gemcitabine, and Group 2 will receive a combination of Oxaliplatin, Leucovorin and 5-fluorouracil (mFOLFOX6). Treatment will continue as long as it seems to be helping, provided participants do not have troublesome side effects.

Through this study we hope to gain information about the following:
1) Can testing for hENT1 help us to identify patients who are more likely to benefit from initial treatment with gemcitabine chemotherapy?
2) Is it possible to do the tests in patients quickly enough to enable use in routine clinical practice?
3) How effective is FOLFOX chemotherapy as treatment for metastatic pancreatic cancer?
4) Are there any other biomarkers in cancer cells or blood that may help us determine the best drug to use against an individual cancer?

This randomised phase II exploratory study is vital in understanding the optimal design of future studies evaluating this novel approach to the management of pancreatic cancer, and may be expanded to a phase III study if this approach is validated.
Trial website
Trial related presentations / publications
Chua YJ, Karapetis CS, Gebski V, O’Connell R, Begbie S, Nott LM, Cronk MF, Underhill C, Abdi EA, Van Hagen T, Wong N, Hall M, Ferraro DA, Sjoquist KM, Santos C, Mackey JR, Goldstein D. Human equilibrative nucleoside transporter 1 (hENT1) in gemcitabine and FOLFOX (oxaliplatin, 5-fluorouracil and leucovorin) treated patients with metastatic pancreatic cancer: the randomized phase II PAN1 study. Gastrointestinal Cancers Symposium; 16–18 Jan 2014; San Francisco.

Chua Y, Karapetis C, Underhill C, Nott L, Goldstein D, Cronk M, Gebski V, Wong N, Sjoquist K, Biankin A. PAN1: a randomized phase II study evaluating potential predictive biomarkers in the treatment of metastatic pancreatic cancer. American Society of Clinical Oncology Annual Meeting; 1–5 Jun 2012; Chicago. Abstract TPS4137
Public notes

Contacts
Principal investigator
Name 31813 0
Dr Yu Jo Chua c/- PAN1 Trial Coordinator
Address 31813 0
NHMRC Clinical Trials Centre, Locked Bag 77, Camperdown NSW 1450
Country 31813 0
Australia
Phone 31813 0
+61 2 9562 5000
Fax 31813 0
Email 31813 0
pan1@ctc.usyd.edu.au
Contact person for public queries
Name 15060 0
Ms PAN1 Trial Coordinator
Address 15060 0
NHMRC Clinical Trials Centre, Locked Bag 77, Camperdown NSW 1450
Country 15060 0
Australia
Phone 15060 0
+61 2 9562 5000
Fax 15060 0
Email 15060 0
pan1@ctc.usyd.edu.au
Contact person for scientific queries
Name 5988 0
Ms PAN1 Trial Coordinator
Address 5988 0
NHMRC Clinical Trials Centre, Locked Bag 77, Camperdown NSW 1450
Country 5988 0
Australia
Phone 5988 0
+61 2 9562 5000
Fax 5988 0
Email 5988 0
pan1@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No plans have been made to share this participant data.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
Yes
Other publication details
Citation type [1] 1069 0
Conference poster
Citation/DOI/link/details [1] 1069 0
Chua YJ, Karapetis CS, Gebski V, O’Connell R, Begbie S, Nott LM, Cronk MF, Underhill C, Abdi EA, Van Hagen T, Wong N, Hall M, Ferraro DA, Sjoquist KM, Santos C, Mackey JR, Goldstein D. Human equilibrative nucleoside transporter 1 (hENT1) in gemcitabine and FOLFOX (oxaliplatin, 5-fluorouracil and leucovorin) treated patients with metastatic pancreatic cancer: the randomized phase II PAN1 study. Gastrointestinal Cancers Symposium; 16–18 Jan 2014; San Francisco.
Attachments [1] 1069 0
Citation type [2] 1070 0
Conference poster
Citation/DOI/link/details [2] 1070 0
Chua Y, Karapetis C, Underhill C, Nott L, Goldstein D, Cronk M, Gebski V, Wong N, Sjoquist K, Biankin A. PAN1: a randomized phase II study evaluating potential predictive biomarkers in the treatment of metastatic pancreatic cancer. American Society of Clinical Oncology Annual Meeting; 1–5 Jun 2012; Chicago. Abstract TPS4137
Attachments [2] 1070 0
Results – basic reporting
Results – plain English summary
The AGITG PAN1 trial was designed to prospectively evaluate human equilibrative nucleoside transporter 1 (hENT1) as a predictive biomarker in gemcitabine-treated in locally advanced and metastatic pancreatic adenocarcinoma during a window of opportunity period when gemcitabine monotherapy was still standard. Previously untreated patients with tumour tissue available for hENT1 testing by immunohistochemistry were randomised to gemcitabine or FOLFOX (oxaliplatin, 5-fluorouracil and leucovorin) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival. The study was closed due to poorer than expected accrual after enrolling 16 of the planned 80 patients. Of the 16 patients, only one had locally advanced pancreatic cancer. 7 patients received gemcitabine and 9 patients received FOLFOX. An analysis performed of the 16 patients observed a longer survival in those patients with high hENT1 treated with gemcitabine. There was no difference in survival according to hENT1 expression in patients treated with FOLFOX. Given the small sample size this may be due to chance, but supports the need for further research into the predictive value of hENT1. There were no unexpected adverse events. The challenges faced by the study highlight the difficulties conducting clinical trials in this poor prognosis patient population, including the feasibility of prospective biomarker analysis when tumour tissue availability is often limited.