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Trial registered on ANZCTR


Registration number
ACTRN12618000335291
Ethics application status
Approved
Date submitted
23/02/2018
Date registered
6/03/2018
Date last updated
6/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Circulating Tumour DNA Analysis Informing Adjuvant Chemotherapy in Early Stage Pancreatic Cancer: A Multicentre Randomised Study (DYNAMIC- Pancreas)
Scientific title
Circulating Tumour DNA Analysis Informing Adjuvant Chemotherapy in Early Stage Pancreatic Cancer: A Multicentre Randomised Study (DYNAMIC- Pancreas)
Secondary ID [1] 294109 0
ctDNA-09
Universal Trial Number (UTN)
U1111-1209-6200
Trial acronym
DYNAMIC-Pancreas
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pancreatic Cancer 306702 0
Condition category
Condition code
Cancer 305803 305803 0 0
Pancreatic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a prospective, multi-centre, randomised study enrolling 308 patients with localised pancreatic cancer who are undergoing “curative” surgery (R0 or R1 resection) and who would routinely be offered adjuvant chemotherapy. Patients will be randomised equally (1:1) to a non-biomarker driven, standard of care (SOC) adjuvant treatment arm (Cohort A) or a circulating tumour DNA (ctDNA)-informed biomarker driven arm (cohort B), where treatment will be determined by the post-surgical ctDNA results of each subject (i.e Cohort B1– ctDNA-informed, biomarker negative; Cohort B2 – ctDNA-informed, biomarker positive).

Patients should be screened within 28 days after surgery and tumour samples made available within 3 days of consent for mutation analysis. All patients will have blood drawn during week 4 (ctDNA-1) and week 8 (ctDNA-2) post-surgery for ctDNA analysis. Where patients commence chemotherapy prior to 8 weeks the ctDNA-2 blood draw will be taken immediately before the first cycle of chemotherapy. Randomisation will occur after ctDNA-1 has been collected. Additional blood collection time-points will occur at 3 and 6 months (+/- 2 weeks) from randomisation (ctDNA-3 and ctDNA-4, respectively). If patients are found to have progressive disease prior to the completion of planned adjuvant treatment, a further blood collection (ctDNA-PD) should be performed at the time of progression and prior to commencing further systemic therapy. Formalin-fixed paraffin embedded tumour tissue samples and the study blood samples will be shipped to the Vogelstein laboratory at Johns Hopkins USA for ctDNA analysis.

For the ctDNA-informed patients (cohort B), the ctDNA-1 and ctDNA-2 results will be made available to the treating clinician within 9 and 12 weeks post-operatively, respectively.
ctDNA-3, ctDNA-4 and ctDNA-PD results will not be routinely made available to the patients or treating clinicians (results can be made available on a case by case basis at clinician and/or patient request). Adjuvant chemotherapy will commence after the ctDNA-1 result becomes available. If treatment is scheduled to commence before the ctDNA-1 result is available, patients will commence on standard of care no sooner than 6 weeks post-operatively and then switch to a strategy informed by the ctDNA result once this has become available (if the patient management needs to be changed to comply with the protocol). Patients who are “ctDNA-negative” will be managed with a de-escalated adjuvant treatment strategy if the treating clinician considers this appropriate. Patients who are “ctDNA-positive” will be managed with an escalated adjuvant treatment strategy if fit to receive more intensive therapy (see treatment regimens below). In the unlikely scenario of discordant results between ctDNA-1 and ctDNA-2, patients will be managed as “ctDNA-positive” if either ctDNA-1 or ctDNA-2 is positive (i.e. patients will be placed in Cohort B2 and managed accordingly).

Treatment regimens:

Chemotherapy dose should be calculated at actual body weight. Body surface area dosing will be managed as per institutional standard of care with regards to dose capping.

Suggested single agent gemcitabine chemotherapy regimens include 24 weeks (6 cycles) of:
1. Gemcitabine, Cycle frequency: 28 days
a. 1000 mg/m2 Intravenously Day 1, 8, 15

2. Fluorouracil (5-FU) with Leucovorin, Cycle frequency: 28 days
a. 5-FU 425mg/m2/day Intravenous bolus Day 1-5
b. Leucovorin 50mg total dose or 20mg/m2/day Intravenous bolus Day 1-5

Suggested combination chemotherapy regimens include 24 weeks of the following treatment options:
1. Gemcitabine plus Capecitabine, Cycle frequency: 28 days
a. Gemcitabine 1000 mg/m2 Intravenously Day 1, 8, 15
b. Capecitabine 830 mg/m2 Orally Twice daily, Day 1-21, 7 day rest

2. FOLFIRINOX, Cycle frequency: 14 days
a. Oxaliplatin 85mg/2 Intravenously Day 1
b. Irinotecan 180mg/m2 Intravenously Day 1
c. Leucovorin 50mg Intravenously Day 1
d. Fluorouracil 400mg/m2 Intravenously Day 1
e. Fluorouracil 2400mg/m2 Continuous Intravenous Infusion pump over 46 hours Day 1
(The use of G-CSF (granulocyte colony stimulating factor) is permitted. Its use should be in accordance with institutional guidelines)

3. Gemcitabine plus nab-paclitaxel (Abraxane), Cycle frequency: 28 days
a. Nab-paclitaxel 125mg/m2 Intravenously Day 1,8,15
b. Gemcitabine 1000mg/m2 Intravenously Day 1,8,15

Study Treatments

Cohort A – Non-biomarker driven dealer's choice SOC arm (SOC chemotherapy regimen options):
• Adjuvant combination gemcitabine plus capecitabine OR
• Adjuvant single agent gemcitabine alone OR
• Adjuvant single agent fluorouracil (5-FU)

Cohort A standard of care adjuvant therapy will be administered with the intent of completing 24 weeks of therapy.

Cohort B – Biomarker driven arm

Cohort B1 – ctDNA negative
De-escalation chemotherapy strategy:
* 12 weeks of whatever treatment would be given as dealers’s choice standard of care if the patients were in cohort A OR
* Dealer’s choice standard of care treatment as per Cohort A if the treating clinician considers that de-escalation is not appropriate

Cohort B1: De-escalated treatment with 12 weeks of dealer’s choice standard of care adjuvant therapy will be administered or 24 weeks of dealer’s choice standard of care adjuvant therapy if de-escalation is not considered appropriate.

Cohort B2 – ctDNA positive
Escalation chemotherapy strategy options:
* Either adjuvant FOLFIRINOX (fluorouracil, irinotecan and oxaliplatin) OR
* Combbination gemcitabine plus nab-paclitaxel (Abraxane) at dealer’s choice OR
• Adjuvant combination gemcitabine plus capecitabine for patients not considered fit for treatment escalation

Cohort B2: Escalated adjuvant therapy will be administered to fit, suitable patients with the intent of completing 24 weeks of therapy or patients will receive the same duration of dealer’s choice standard of care treatment. For patients receiving escalated treatment dose adjustment will be allowed as per standard of care for these agents at the treating clinician’s discretion.

It is anticipated that 308 eligible patients will be enrolled over a 54-month accrual period. Details of adjuvant chemotherapy received including, start and stop dates, dose received, dose reduction, reason for dose reduction/interruption and reason for stopping treatment will be recorded. Serious Unexpected Serious Adverse Reactions (SUSAR) for patients treated with either FOLFIRINOX or combination Gemcitabine plus nab-paclitaxel (Abraxane), and treatment-related hospitalisation for all patients will also be collected.

All patients will be followed until death or study completion. Patients will be followed up as per standard of care, every 3 months for 24 months, then 6-monthly for the next 3 years. The trial will be considered complete after the last patient enrolled has had 2 years of follow-up. It is anticipated that this study will run for approximately 6.5 years.

Interim Analysis

An interim analysis will be conducted blinded to the study arm after the first 18 months of recruitment to assess the adequacy of recruitment rate, post-operative ctDNA results turn-around time, and post-operative ctDNA positivity rate. As a result of this interim analysis, the sample size may be adjusted based upon the assumption of an absolute difference in ctDNA positivity rates of 15% between arm A and B but using the observed overall positivity rate, drop-out rate and no-KRAS rate.
Subsequent to the interim analysis and final definition of the sample size, results will be unblinded to the trial statistician and recruitment may be stopped if futility can be demonstrated. In case recruitment is stopped early, patients already enrolled will be followed-up for a period of two years and survival analyses will be carried out as planned.

Additionally, a review of the ctDNA results turn-around time will be conducted after the first 50 patients have been recruited.
Intervention code [1] 300394 0
Early detection / Screening
Intervention code [2] 300395 0
Treatment: Drugs
Comparator / control treatment
Standard of Care Arm (Cohort A)

Patients will receive clinician's choice adjuvant chemotherapy as per standard of care:
• Adjuvant combination gemcitabine plus capecitabine OR
• Adjuvant single agent gemcitabine alone OR
• Adjuvant single agent fluorouracil (5-FU)

Adjuvant therapy will be administered with the intent of completing 24 weeks of therapy.
Subjects and clinicians in Standard of Care arm will be blinded to their ctDNA results.
Control group
Active

Outcomes
Primary outcome [1] 304874 0
Proportion of patients with positive ctDNA at completion of all treatment.

For ctDNA analysis, archived patient formalin-fixed paraffin embedded tumour tissue samples collected post enrollment, will be used for mutation analysis of hotspot mutations in genes frequently altered in pancreatic cancer. The mutation identified in each patient's tumour tissue will be queried and quantified in the plasma samples (i.e. circulating tumour DNA) obtained from on study blood collections. Mutation analysis will be performed by the laboratories at Johns Hopkins USA using the Safe-SeqS assay.
Timepoint [1] 304874 0
Blood collections for plasma ctDNA analysis will occur at week 4 and week 8 (+/- 1 week) post-surgery (ctDNA-1, ctDNA-2), and at 3 and 6 months (+/- 2 weeks) post randomisation (ctDNA-3, ctDNA-4). An additional blood sample may be collected if patients are found to have documented progressive disease while undergoing adjuvant therapy (ctDNA-PD).

ctDNA positivity at the different stages detailed above will be compared with serum-CA 19-9 counterparts at the same stage.

The primary outcome timepoint is based on the proportion of patients with positive ctDNA at completion of all treatment. This analysis will be conducted when all recruited patients have completed their adjuvant therapy. Based on an estimated accrual period of approximately 54 months and a maximum adjuvant treatment time of 24 weeks, analysis of the primary timepoint would occur at approximately 60 months from the commencement of the study.
Secondary outcome [1] 343443 0
Comparison of recurrence-free (date of pancreatic resection to the time of recurrence or the censor date) and overall survival (date of pancreatic resection to the time of death from any cause or the censor date) between subjects managed by standard of care adjuvant therapy with subjects managed by ctDNA-informed adjuvant therapy.

Outcomes will be assessed by clinical review, blood tumour marker CA 19-9 testing and tumour imaging with CT scans of chest/abdomen/pelvis (as per standard of care).

Timepoint [1] 343443 0
Schedule of Assessments: patients will be followed up for recurrence and survival data collection at clinical visits every 3 months from randomisation for 24 months, then 6-monthly for the next 3 years with CA 19-9 testing and CT scans conducted as per standard of care.

Eligibility
Key inclusion criteria
1. Subjects who have undergone complete macroscopic resection for adenocarcinoma of the pancreas (R0 or R1 resection) with “curative” intent.
2. A representative tumour sample is available for molecular testing within 28 days after surgery.
3. Subjects is fit for adjuvant chemotherapy.
4. Subject has ECOG performance status 0-2.
5. Subject is to attend for administration of adjuvant therapy.
6. Subject is accessible for follow up.
7. No evidence of malignant ascites, liver metastasis, spread to other distant abdominal organs, peritoneal metastasis, spread to extra-abdominal organs - Subject to have had a CT chest/ abdomen/ pelvis scan within 12 weeks prior to randomisation.
8. Fully informed written consent given
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. History of another primary cancer within the last 3 years, with the exception of non-melanomatous skin cancer and carcinoma in situ of the cervix.
2. Patient has inadequate organ function:
a. Moderate/severe renal impairment (GFR<30 ml/min), as calculated by the Cockcroft and Gault equation
b. Absolute neutrophil count <1.0x109/L
c. Platelet count <75x109/L
d. Haemoglobin <80 g/L
e. Aspartate aminotransferase/Alanine aminotransferase >2.5 x upper limit of normal
3. Patient has a medical or psychiatric condition or occupational responsibilities that may preclude compliance with the protocol.
4. Patient has TNM stage IV disease.
5. Patient has R2 resection status.
6. Patient has clinically significant cardiovascular disease - i.e. active or <12 months since e.g. cerebrovascular accident, myocardial infarction, unstable angina, New York Heart Association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, uncontrolled hypertension.

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)
Allocation to Arm A (Standard of Care) or Arm B (ctDNA-informed) is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Subjects will be randomised using a permuted block design with random block size. The blocking factor will be the centre. Randomisation lists will be generated using a computer-based randomisation algorithm module.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2 / Phase 3
Type of endpoint(s)
Statistical methods / analysis
It is anticipated that 308 eligible patients will be enrolled over a 54-month accrual period. All patients will be followed until death or study completion. The trial will be considered complete after the last patient enrolled has had 2 years of follow-up. It is anticipated that this study will run for approximately 6.5 years.
Because there are no published data regarding ctDNA positivity rates in early stage resected pancreatic cancer patients, the sample size calculation is based on the assumption that the proportion of ctDNA positivity at the end of treatment for the SOC and ctDNA-informed arms are 35.0% and 20%, respectively. Based on these assumptions, 276 patients are required at 80% power and two-sided p<0.05. Allowing for 10% drop out rate, we aim to recruit a total on 308 patients. Since these proportions are based on estimation, we plan to re-calculate the sample size at the first interim analysis. (Source: http://www.sample-size.net/sample-size-proportions/).
The primary outcome analysis of end of treatment ctDNA positivity rate will be based on the intention-to-treat population with a supplementary analysis based on per-protocol population. The primary outcome analysis will be performed by comparing proportions using the Chi-squared statistic (or z test). This analysis will be conducted when all recruited patients have completed their adjuvant treatment.
Both recurrence-free and overall survival will be estimated by Kaplan-Meier and Cox proportional hazard models. Overall survival analysis will be carried out when all patients have a minimum of 2 years follow-up post randomisation. Survival data will also be analysed when all subjects have been followed for at least 5 years to assess long-term treatment effects.
Several exploratory outcomes analyses will be undertaken including ctDNA turn-around time, proportion of patients completing planned study treatment, health economic impact, as well as the secondary outcomes of recurrence-free survival and overall survival. Comparisons will be made (1) between treatment arms as per intention to treat, (2) between patients with and without detectable ctDNA at baseline, (3) with and without detectable ctDNA post-surgery and (4) with and without detectable ctDNA at end of therapy. Statistical tests will be performed using the logrank test.
The degree of potential bias in the per-protocol analysis will be explored by comparing ctDNA positivity rate, recurrence free survival, reasons for non-compliance, uptake of escalation and de-escalation strategies and the characteristics of patients excluded from each arm. Additional analysis adjusting for non-compliance may be conducted if differing results are observed between the intention-to-treat and per-protocol analysis.
All statistical analyses will be carried out on an intention-to-treat basis, retaining patients in their randomised treatment groups and including protocol violators and ineligible patients. A sensitivity analysis excluding any ineligible patients and patients that receive less than 12 weeks of adjuvant chemotherapy will also be conducted and reported.

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)
VIC
Recruitment hospital [1] 10093 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 10096 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [3] 10097 0
The Northern Hospital - Epping
Recruitment hospital [4] 10098 0
Western Private Hospital - Footscray
Recruitment hospital [5] 10099 0
Western Hospital - Footscray - Footscray
Recruitment hospital [6] 10101 0
Box Hill Hospital - Box Hill
Recruitment hospital [7] 10102 0
Melbourne Private Hospital - Parkville
Recruitment postcode(s) [1] 21630 0
3050 - Parkville
Recruitment postcode(s) [2] 21633 0
3000 - Melbourne
Recruitment postcode(s) [3] 21634 0
3076 - Epping
Recruitment postcode(s) [4] 21635 0
3011 - Footscray
Recruitment postcode(s) [5] 21636 0
3052 - Parkville
Recruitment postcode(s) [6] 21637 0
3128 - Box Hill

Funding & Sponsors
Funding source category [1] 298745 0
Charities/Societies/Foundations
Name [1] 298745 0
Marcus Foundation
Address [1] 298745 0
1266 W. Paces Ferry Road No. 615
Atlanta, Georgia 30327
Country [1] 298745 0
United States of America
Primary sponsor type
Other Collaborative groups
Name
Australasian Gastro-Intestinal Trials Group
Address
GI Cancer Institute @Lifehouse
Level 6, 119-143 Missenden Rd
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 297918 0
Other
Name [1] 297918 0
The Walter and Eliza Hall Institute of Medical Research
Address [1] 297918 0
1G Royal Parade
Parkville
VIC 3052
Country [1] 297918 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299684 0
Melbourne Health
Ethics committee address [1] 299684 0
Level 2
South West
300 Grattan Street
Parkville Victoria 3050
Ethics committee country [1] 299684 0
Australia
Date submitted for ethics approval [1] 299684 0
26/04/2017
Approval date [1] 299684 0
03/07/2017
Ethics approval number [1] 299684 0
HREC/17/MH/38

Summary
Brief summary
The aim of the DYNAMIC-Pancreas research project is to determine whether a genetic test called “circulating tumour DNA” is a more effective way of deciding the specific type and duration of post-surgery chemotherapy than standard of care in patients with localised pancreatic cancer.
The circulating tumour DNA blood test is based on the knowledge that pancreatic cancer cells have DNA mutations that are not present in normal cells. For some people, cancer-specific DNA can be found in their bloodstream after the surgery to remove their pancreatic cancer, which may be evidence that some of the cancer cells have escaped before the pancreatic cancer has been removed. This study is trying to see if a chemotherapy decision based on the presence (positive test) or absence (negative test) of circulating tumour DNA after surgery will be more effective at determining the type and duration of chemotherapy treatment that a patient will need after surgery.

Who is it for?
You may be eligible to join this study if you are aged 18 years or more and have undergone curative surgery for localised pancreatic cancer and have been recommended adjuvant chemotherapy.

Study details
All participants in this study will have blood drawn during week 4 and week 8 post-surgery for circulating tumour DNA analysis. They will then be randomly allocated to one of two treatment groups, where the choice of chemotherapy regimen will be made prior to randomisation: One group will receive standard of care treatment as selected by their clinician: either single agent gemcitabine, single agent fluorouracil (5-FU) or a combination of gemcitabine plus capecitabine. The other group will have their treatment selection based on their circulating tumour DNA blood test results. Patients with a positive test will be offered a stronger chemotherapy than the standard treatment. Patients with a negative test will be offered a shorter duration of the standard treatment.
Patients will undergo additional blood collections for circulating tumour DNA analysis at 3 months and 6 months after being randomised into their treatment groups, and a further blood collection if cancer recurrence or progression was found to occur during chemotherapy.
All patients will be followed up every 3 months for 2 years, then every 6 months up to year 5. Follow up includes additional blood tests and radiological assessments. It is hoped that the findings from this study will provide evidence that using circulating tumour DNA results to help make a decision regarding adjuvant chemotherapy could reduce to proportion of patients that have detectable circulating tumour DNA after completing adjuvant chemotherapy, compare to standard of care treatment. This may in turn demonstrate that management of pancreatic cancer based on circulating tumour DNA results is not inferior to standard of care in terms of recurrence-free and overall survival.
Trial website
none
Trial related presentations / publications
none
Public notes

Contacts
Principal investigator
Name 81286 0
Dr Belinda Lee
Address 81286 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville
VIC 3052
Country 81286 0
Australia
Phone 81286 0
+ 61 3 9345 2893
Fax 81286 0
+61 3 9498 2010
Email 81286 0
belinda.lee@mh.org.au
Contact person for public queries
Name 81287 0
Dr Roslynn Murphy
Address 81287 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville
VIC 3052
Country 81287 0
Australia
Phone 81287 0
+61 3 9345 2895
Fax 81287 0
+61 3 9498 2010
Email 81287 0
roslynn.murphy@mh.org.au
Contact person for scientific queries
Name 81288 0
Dr Belinda Lee
Address 81288 0
The Walter and Eliza Hall Institute of Medical Research
1G Royal Parade
Parkville
VIC 3052
Country 81288 0
Australia
Phone 81288 0
+ 61 3 9345 2893
Fax 81288 0
+61 3 9498 2010
Email 81288 0
belinda.lee@mh.org.au

No information has been provided regarding IPD availability
Summary results
No Results