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Trial registered on ANZCTR


Registration number
ACTRN12619000409178
Ethics application status
Approved
Date submitted
5/02/2019
Date registered
13/03/2019
Date last updated
1/08/2019
Date data sharing statement initially provided
13/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Randomised Phase II Study of MFOLFIRINOX And Stereotactic Radiotherapy (SBRT) for Pancreatic Cancer With High Risk and Locally Advanced Disease (MASTERPLAN)
Scientific title
A Randomised Phase II Study of MFOLFIRINOX And Stereotactic Radiotherapy (SBRT) for Pancreatic Cancer With High Risk and Locally Advanced Disease (MASTERPLAN)
Secondary ID [1] 297204 0
CTC 0245
Secondary ID [2] 297319 0
AG0118PS
Secondary ID [3] 298909 0
TROG 18.04
Universal Trial Number (UTN)
Trial acronym
MASTERPLAN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
PANCREATIC CANCER 311331 0
Condition category
Condition code
Cancer 309971 309971 0 0
Pancreatic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm B: Patients will commence with initial chemotherapy* for 12 weeks followed by SBRT** (intervention arm) prior to consideration of surgical resection.
Following restaging, resectable patients will proceed to surgery followed by adjuvant chemotherapy with mFOLFIRINOX as per Option 1 below or gemcitabine/capecitabine***

Those not suitable for resection due to disease being unresectable (PR, SD) or for medical reasons should continue with mFOLFIRINOX as per Option 1 below OR gemcitabine + nab-paclitaxel.

*Options for Initial Chemotherapy:
Option 1: (Preferred) mFOLFIRINOX (6 cycles)
6 x 14 day cycles of oxaliplatin (85mg/m2 IV), irinotecan (150mg/ m2), 5-fluorouracil (2400mg/m2 CIV), leucovorin (50mg IV bolus)

Option 2: Gemcitabine + nab-paclitaxel (3 cycles)
3 x 28 day cycles of gemcitabine and nab-Paclitaxel
Gemcitabine (1000mg/m2 IV) and nab-Paclitaxel (125mg/m2 IVI) day 1, day 8 and day 15 of 28 day cycle

**Arm B patients, intervention:
Radiation: Stereotactic Radiotherapy (SBRT)
40 Gray (Gy) in 5 fractions over two weeks, 8 Gy per fraction. Maximum of four treatments per week, with two consecutive days permitted but not three.

***Adjuvant Chemotherapy: 3 x cycles of 1000 mg/m2 gemcitabine administered once a week for three of every 4 weeks (one cycle) with 830 mg/m2 oral capecitabine administered for 21 days followed by 7 days rest (one cycle).
Intervention code [1] 313515 0
Treatment: Other
Comparator / control treatment
Arm A: Chemotherapy only
Patients will commence with initial chemotherapy for 12 weeks* prior to consideration of surgical resection.
Following restaging, resectable patients will proceed to surgery followed by adjuvant chemotherapy with mFOLFIRINOX as per option 1 below or gemcitabine/capecitabine**

Those not suitable for resection due to disease being unresectable (PR, SD) or for medical reasons should continue with mFOLFIRINOX as per Option 1 below OR gemcitabine + nab-paclitaxel.

*Options for Initial Chemotherapy:
Option 1: (Preferred) mFOLFIRINOX (6 cycles)
6 x 14 day cycles of oxaliplatin (85mg/m2 IV), irinotecan (150mg/ m2), 5-fluorouracil (2400mg/m2 CIV), leucovorin (50mg IV bolus)

Option 2: Gemcitabine + nab-paclitaxel (3 cycles)
3 x 28 day cycles of gemcitabine and nab-Paclitaxel
Gemcitabine (1000mg/m2 IV) and nab-Paclitaxel (125mg/m2 IVI) day 1, day 8 and day 15 of 28 day cycle

**Adjuvant Chemotherapy: 3 x cycles of 1000 mg/m2 gemcitabine administered once a week for three of every 4 weeks (one cycle) with 830 mg/m2 oral capecitabine administered for 21 days followed by 7 days rest (one cycle).
Control group
Active

Outcomes
Primary outcome [1] 318886 0
Locoregional Control
Any patient, who experiences synchronous locoregional and distant progression within 12 months of randomisation will be deemed to have a locoregional failure. Locoregional failure is defined as progressive disease using RECIST 1.1 criteria which is characterized by at least a 20% increase in the sum of diameters of the tumour and a minimum of a 5 mm increase.
Local and regional relapse will be determined based on imaging findings and/or biopsy (if performed).
Timepoint [1] 318886 0
within 12 months of randomisation
Secondary outcome [1] 366318 0
Safety
All patients will have toxicity recorded at all clinical follow up visits. The CTCAE v5.0 will be used to grade toxicity.
Timepoint [1] 366318 0
Safety Assessment before each cycle of chemotherapy, post chemotherapy treatment, following SBRT and surgery (if applicable) then at 3, 6, 9 and 12 months post-randomisation and 6 monthly during year 2, 3 and 4.
Secondary outcome [2] 366319 0
Surgical morbidity/mortality
Timepoint [2] 366319 0
Length of stay, death within 30 days, frequency and severity of adverse events at the time of discharge, at 30 and 90 days post surgery as defined by Clavien grading system.
Hospital admission during surgery will be calculated from day of surgery to date of discharge from acute care hospitalisation. The length of stay in acute hospital care will include intensive care admissions.
Secondary outcome [3] 366320 0
Radiological response rates (RECIST v1.1)
Timepoint [3] 366320 0
Radiological response rates will be measured using RECIST v1.1 at each imaging time point:
CT chest/abdomen/pelvis (CAP) and 18-FDG-PET at baseline. In SBRT arm, repeat CT CAP following initial chemotherapy (must be prior to SBRT). In both arms repeat staging will occur 4-6 weeks post completion of initial treatment (prior to confirmation of eligibility for surgery), 3 ,6, 9 and 12 months post-randomisation and 6 monthly during year 2, 3 and 4.
Secondary outcome [4] 366321 0
Progression Free Survival (PFS)
Timepoint [4] 366321 0
Disease progression or death.
PFS will be calculated from the time of randomisation to the time of first documented clinical or imaging relapse or the date of death from any cause, whichever occurs first. Disease progression is defined according to RECIST v1.1. Participants who die without a reported prior progression will be considered to have progressed on the date of their death. Participants who did not have any study tumour assessments and did not die will be censored on the date they were randomised. Participants who started any subsequent anti-cancer therapy without a prior reported progression will be
censored at the date of commencement of the subsequent anti-cancer therapy. Twelve-month PFS rate will be calculated using the proportions obtained by the method of Kaplan-Meier.
Secondary outcome [5] 366322 0
Pathological response rates
Timepoint [5] 366322 0
Tumour regression grade.
Pathological complete response (pCR) rates will be recorded as per the College of American Pathology tumour regression grade (TRG) at SBRT/surgery compared to baseline.
Secondary outcome [6] 366323 0
Surgical resection rates
Timepoint [6] 366323 0
Rates of attempted resection excluding ‘open and close’ operations.
Rates of patients undergoing/attempting surgical resection among patients receiving chemotherapy +/- SBRT. Resectability will be defined by central radiologist review utilising AGITG guidelines and definitions. Attempted resection is defined as an attempt at tumour removal (excluding ‘open and close’ operations).
Surgical resection rates will be calculated by summing the number of patients undergoing/attempting surgical resection, and dividing this by the total number of participants evaluable.
The timepoint for this outcome is: at the time of surgery, post initial treatment
Secondary outcome [7] 366324 0
R0 resection rates (>1mm)
Timepoint [7] 366324 0
Complete macroscopic resection of gross tumour with negative surgical margins.
All surgical specimens will be sent for retrospective histopathological assessment to determine the completeness of resection. This will be graded as either complete resection (R0) or incomplete resection (R1). R0 resection is defined as all margins are microscopically clear (a distance from tumour to resection margin of 1.0mm or greater will be regarded as complete resection (R0)). The distance from residual tumour to the resection margin will be measured in millimetres. R1 resection is defined as macroscopically clear resection but microscopically positive margins. The rate of R0 resections will be compared with the rate of R1 resections.
Synoptic PC histology reporting as outlined in Royal College of Pathologists of Australasia (RCPA).
The timepoint for this outcome is: at the time of surgery, post initial treatment
Secondary outcome [8] 366325 0
Quality of Life (QOL)
Timepoint [8] 366325 0
QOL will be assessed using the European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires - QLQ C-30 at the following timepoints:

Baseline, Day 1 of each cycle of initial chemotherapy, prior to SBRT, post completion of initial chemotherapy +/- SBRT, prior to surgery, day 1 of each cycle of ongoing/adjuvant chemotherapy, 30 days post end of treatment,
at months 3, 6,9 and 12 post randomisation
6 monthly in years 2, 3 and 4.
Secondary outcome [9] 366326 0
Deterioration-Free Survival (DFS)
Timepoint [9] 366326 0
Measured using EORTC QLQ-C30.
The DFS endpoint constructed as a marker of overall net clinical benefit of treatment. DFS is defined as the time until the first of the following events: a 10-point deterioration in health status from baseline, disease progression, death, or treatment discontinuation.
Secondary outcome [10] 366327 0
Overall Survival (OS)
Timepoint [10] 366327 0
Death from any cause;
OS is defined as the interval from the date of randomisation to date of death from any cause, or the date of last known alive. Participants will be censored at the date of commencement of the subsequent anti-cancer therapy. This will summarised using the method of Kaplan-Meier
The maximum timepoint is up to 6 monthly in years 2, 3 and 4.

Eligibility
Key inclusion criteria
*Adults, aged between 18-75 years, with histological confirmation of pancreatic adenocarcinoma
*Any of the following: T3 (tumour greater than 4 cm), Extrapancreatic extension, node positive (stage IIB), borderline resectable pancreatic cancer, locally advanced pancreatic cancer
*Measurable disease according to RECIST v1.1
*ECOG performance status 0-1
*Adequate renal and haematological function
*Adequate hepatic function. Defined as bilirubin less than 1.5 X ULN (Upper Limit of Normal), AST + ALT less than 3.0 X ULN. In patients who have had a recent biliary drainage and whose bilirubin is descending, a value of less than or equal to 3 X N is acceptable
*Study treatment planned to start within 14 days of registration
*Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments
*Signed, written informed consent
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
. Tumour size greater than 70mm
. Duodenal infiltration seen on endoscopy
. Prior abdominal radiotherapy
. Evidence of metastatic disease on baseline radiologic investigations
. History of another malignancy within 2 years prior to randomisation, except adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial transitional cell carcinoma of the bladder, or any Stage 1 endometrial carcinoma. Patients with a history of other malignancies are eligible if they have been continuously disease free for at least 2 years after definitive primary treatment
. Concurrent illness, including severe infection that may jeopardise the ability of the patient to undergo the procedures outlined in this protocol with reasonable safety
. Neuroendocrine pancreatic carcinoma
. Life expectancy of less than 3 months
. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to randomisation. Men must use a reliable means of contraception
. Serious medical or psychiatric conditions that might limit the ability of the patient to comply with the protocol

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 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The primary analysis will be the proportion of patients in the intervention and control groups for cohorts A and B (separately) experiencing LRR at or before 12 months estimated by the method of Kaplan-Meier. This analysis will be performed according to the intention-to-treat principle.

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,QLD,SA,VIC
Recruitment hospital [1] 13045 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 13046 0
Prince of Wales Hospital - Randwick
Recruitment hospital [3] 13047 0
Liverpool Hospital - Liverpool
Recruitment hospital [4] 13048 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [5] 13049 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [6] 14381 0
The Chris O’Brien Lifehouse - Camperdown
Recruitment hospital [7] 14382 0
St George Hospital - Kogarah
Recruitment hospital [8] 14383 0
Icon Cancer Care Southport - Southport
Recruitment postcode(s) [1] 25548 0
2065 - St Leonards
Recruitment postcode(s) [2] 25549 0
2031 - Randwick
Recruitment postcode(s) [3] 25550 0
2170 - Liverpool
Recruitment postcode(s) [4] 25551 0
3000 - Melbourne
Recruitment postcode(s) [5] 25552 0
5000 - Adelaide
Recruitment postcode(s) [6] 27386 0
2050 - Camperdown
Recruitment postcode(s) [7] 27387 0
2217 - Kogarah
Recruitment postcode(s) [8] 27388 0
4215 - Southport

Funding & Sponsors
Funding source category [1] 301752 0
Government body
Name [1] 301752 0
Australian Government Department of Health, Medical Research Future Fund (MRFF)
Address [1] 301752 0
Australian Government, Department of Health
GPO Box 9848
Canberra ACT 2601
Country [1] 301752 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Gastro-Intestinal Trials Groups (AGITG)
Address
Lifehouse, Level 6
119 - 143 Missenden Road
Camperdown NSW 2050
Australia
Country
Australia
Secondary sponsor category [1] 301614 0
University
Name [1] 301614 0
The University of Sydney
Address [1] 301614 0
NHMRC Clinical Trials Centre
92 - 94 Parramatta Road
Camperdown NSW 2050
Country [1] 301614 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302476 0
Sydney Local Health District, Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 302476 0
Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 302476 0
Australia
Date submitted for ethics approval [1] 302476 0
21/01/2019
Approval date [1] 302476 0
08/03/2019
Ethics approval number [1] 302476 0

Summary
Brief summary



Update

The aim of this study is to assess the benefit of adding high precision radiotherapy to chemotherapy and surgery for the treatment of pancreatic cancer.

Who is it for?
You may be eligible for this study if you are aged 18 to 75 years old, have pancreatic cancer and have adequate liver function. You must not have received prior treatment for your pancreatic cancer.

Study details
Participants will be randomised by chance into two groups. Both of the groups will undergo a chemotherapy regimen which includes either one of the following drug combinations; 1) mFOLFIRINOX or 2) Gemcitabine/Nab-paclitaxel. One of the groups will have additional high precision radiotherapy called stereotactic radiotherapy. After this treatment, you may go on to have surgery.. Whether or not you have surgery, the treating team will then have a discussion with participants about further treatment with chemotherapy. All participants will complete a number of questionnaires, consent to their biopsies and resected tissue being analysed in a laboratory. Participants will be followed up for up to 4 years.

This research may demonstrate that the addition of high precision radiotherapy to pancreatic cancer treatment improves patient outcomes and reduces the rates of cancer recurrence.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90350 0
Dr Andrew Oar
Address 90350 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 90350 0
Australia
Phone 90350 0
+61 2 9562 5000
Fax 90350 0
Email 90350 0
masterplan@ctc.usyd.edu.au
Contact person for public queries
Name 90351 0
Ms Christine Aiken
Address 90351 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 90351 0
Australia
Phone 90351 0
+61 2 9562 5000
Fax 90351 0
Email 90351 0
masterplan@ctc.usyd.edu.au
Contact person for scientific queries
Name 90352 0
Dr Andrew Oar
Address 90352 0
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country 90352 0
Australia
Phone 90352 0
+61 2 9562 5000
Fax 90352 0
Email 90352 0
masterplan@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
What supporting documents are/will be available?
No other documents available
Summary results
No Results