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Trial registered on ANZCTR


Registration number
ACTRN12624000455561
Ethics application status
Approved
Date submitted
27/03/2024
Date registered
12/04/2024
Date last updated
12/04/2024
Date data sharing statement initially provided
12/04/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Safety and efficacy of faecal transplant and chemotherapy in the management of pancreatic cancer
Scientific title
Safety and efficacy of Faecal Microbiota Transplantation co-delivered with chemotherapy in improving pain, symptom management and treatment efficacy in patients with pancreatic cancer
Secondary ID [1] 311835 0
MRFF2024316
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
non-resectable pancreatic cancer 333366 0
Condition category
Condition code
Cancer 330053 330053 0 0
Pancreatic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Faecal microbiota transplantation (FMT) as a co-treatment of chemotherapy with Folfirinox.

FMT: Administered via oral capsules in two separate treatments. FMT will comprise whole stool anaerobically prepared and lyophilised from screened donors. Lyophilised, encapsulated FMT is supplied as 25g of lyophilised donor stool per 36 capsule dose (0.69g/capsule).

FMT1: The first FMT treatment consists of a loading dose of 36 capsules taken over three days (12 capsules (0.69g/capsule)/day, total of 25g over three days). The patients will take 4 capsules with food at breakfast, lunch and dinner over the three days. This initial dose is provided before chemotherapy.

FMT2: The second FMT treatment is done in two phases:
- An initial loading phase: 36 capsules of FMT over three days (12 capsules/day). The patients will take 4 capsules with food at breakfast, lunch and dinner over the three days.
- A consolidation phase: 3 capsules/day with food for 2 weeks.
This second dose will be provided 4 weeks after chemotherapy cessation.

Chemotherapy protocol:
A script for Folfirinox will be provided with instructions on the day of FMT provision so that chemotherapy can commence two weeks after the first FMT treatment (week 0). A specific date of commencement will be marked on documentation to the patient and phone reminders will be provided by the trial team. The treating clinician will prescribe Creon (administered via oral tablets [2x25,000U] three times a day) to facilitate digestion during chemotherapy and afterwards. The participating oncologists will review the 3-month follow-up data to make a decision on the duration of chemotherapy. Depending on the patient’s response to chemotherapy (i.e., based on measurement of disease progression or regression that are part of the standard of care), Folfirinox will be prescribed for 3 or 6 months and taken every two weeks. The Folfirinox dosage will be as follow:
• Oxaliplatin 85mg/m2 by intravenal infusion over 2 hours
• Irinotecan 150mg/m2 by intravenal infusion over 90 minutes
• Calcium folinate (Leucovorin) 50mg by intravenal bolus over 1 to 2 minutes
• Fluorouracil 2,400mg/m2 delivered by intravenal infusion through a central line via pump over 46h
Intervention code [1] 328292 0
Treatment: Drugs
Comparator / control treatment
Placebo

Administered via oral capsules in two separate treatments. Placebo will be produced by the same company than FMT capsules, and capsules will look identical to preserve blinding. Placebo will contain dietary sugars and saline.

Placebo 1: The first placebo treatment consists of a loading dose of 36 capsules taken over three days (12 capsules (0.69g/capsule)/day, total of 25g over three days). The patients will take 4 capsules with food at breakfast, lunch and dinner over the three days. This initial dose is provided before chemotherapy.

Placebo 2: The second placebo treatment is done in two phases:
- An initial loading phase: 36 capsules of placebo over three days (12 capsules/day). The patients will take 4 capsules with food at breakfast, lunch and dinner over the three days.
- A consolidation phase: 3 capsules/day with food for 2 weeks.
This second dose will be provided 4 weeks after chemotherapy cessation.

Chemotherapy protocol:
A script for Folfirinox will be provided with instructions on the day of FMT provision so that chemotherapy can commence two weeks after the first FMT treatment (week 0). A specific date of commencement will be marked on documentation to the patient and phone reminders will be provided by the trial team. The treating clinician will prescribe Creon (administered via oral tablets [2x25,000U] three times a day) to facilitate digestion during chemotherapy and afterwards. The participating oncologists will review the 3-month follow-up data to make a decision on the duration of chemotherapy. Depending on the patient’s response to chemotherapy (i.e., based on measurement of disease progression or regression that are part of the standard of care), Folfirinox will be prescribed for 3 or 6 months and taken every two weeks. The Folfirinox dosage will be as follow:
• Oxaliplatin 85mg/m2 by intravenal infusion over 2 hours
• Irinotecan 150mg/m2 by intravenal infusion over 90 minutes
• Calcium folinate (Leucovorin) 50mg by intravenal bolus over 1 to 2 minutes
• Fluorouracil 2,400mg/m2 delivered by intravenal infusion through a central line via pump over 46h
Control group
Placebo

Outcomes
Primary outcome [1] 337817 0
Safety and tolerability of FMT as a co-treatment to chemotherapy with Folforinox.
Timepoint [1] 337817 0
Continuous until the end of the trial, but will be recorded for final evaluation at 3, 6, 12 months after chemotherapy initiation.
Primary outcome [2] 337818 0
Safety and tolerability of FMT as a co-treatment to chemotherapy with Folforinox.
Timepoint [2] 337818 0
Continuous until the end of the trial, but will be recorded for final evaluation at 3, 6, 12 and 18 months after chemotherapy initiation.
Secondary outcome [1] 433385 0
Changes in visceral pain and symptoms will be analysed as a composite outcome of the following: heartburn, reflux, nausea, upper abdominal pain and discomfort, stomach fullness, loss of appetite, bloating, lower abdominal pain and discomfort, chest pain and discomfort, retching, stomach enlargement, vomiting, capacity to finish a normal size meal, feeling of fullness after a meal.
Timepoint [1] 433385 0
At baseline, 3, 6, 12, and 18 months after chemotherapy initiation
Secondary outcome [2] 433386 0
Length of survival
Timepoint [2] 433386 0
Continuous until the end of the trial
Secondary outcome [3] 433387 0
Quality of life
Timepoint [3] 433387 0
At baseline, 3, 6, 12, and 18 months after therapy initiation
Secondary outcome [4] 433388 0
Changes in the number of tumours as a surrogate measure of treatment efficacy/disease progression
Timepoint [4] 433388 0
At baseline, 3, 6, 12 and 18 months after chemotherapy initiation
Secondary outcome [5] 433389 0
Treatment efficacy/disease progression
Timepoint [5] 433389 0
At baseline, 3, 6, 12, and 18 months after chemotherapy initiation
Secondary outcome [6] 433391 0
Changes in gut microbiota composition as a surrogate marker of gut flora restoration and treatment efficacy
Timepoint [6] 433391 0
At baseline, 3, 6, and 12 months after chemotherapy initiation
Secondary outcome [7] 433393 0
Changes in inferred faecal microbial enzymatic potential as a surrogate marker for microbial metabolic activity and gut function
Timepoint [7] 433393 0
At baseline, 3, 6, and 12 months after chemotherapy initiation
Secondary outcome [8] 433394 0
Rate of surgical resection after treatment completion
Timepoint [8] 433394 0
At the conclusion of study.
Secondary outcome [9] 433668 0
Changes in tumour size as a surrogate measure of treatment efficacy/disease progression
Timepoint [9] 433668 0
Baseline, 3, 6, 12 and 18 months after chemotherapy initiation

Eligibility
Key inclusion criteria
Participants who will be included are patients with a pancreatic cancer diagnosis who underwent an initial CT scan, and whose tumour is not surgically resectable at first assessment (including borderline resectable). The patients must be:

• Adults aged between 18 and 75 years of age
• Seen by a participating clinician for their first assessment between the study start date and the end of recruitment date
• Administered Folfirinox as a chemotherapy agent
• Eastern Cooperative Oncology Group Performance status (ECOG PS) of 0-1.
• Presenting an adequate bone marrow function with haemoglobin > 100 g/L, platelets > 100 X 10^9/L neutrophils > 1.5 X 10^9/L within 7 days of enrolment.
• Presenting an adequate renal function, with calculated creatinine clearance >40 mL/min (Cockcroft and Gault) within 7 days of enrolment.
• Presenting an adequate hepatic function with serum total bilirubin < 1.25 X upper limit of normal range (ULN) and alanine transaminase (ALT) or aspartate aminotransferase (AST)<2.5xULN (<5x ULN) if liver metastases present) within 7 days of enrolment
• Presenting a magnesium close to the lower limit of normal range within 7 days of enrolment.
• With a life expectancy of at least 12 weeks.
• Returning a negative pregnancy test around 72 hours before commencing study treatment (women of childbearing potential only).
• Speaking English or attending appointments accompanied with an English speaking next of kin
• Able to provide a signed informed consent
• Willing and able to comply with all study requirements, including treatment timing and nature of required assessments
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Patients:
• Aged under 18 years old or over 75 years old at first assessment
• With resectable pancreatic tumour who are predicted to receive surgery
• Already receiving chemotherapy treatment either for pancreatic cancer or another cancer
• Who have already received chemotherapy treatment for pancreatic cancer.
• With prior pelvic radiotherapy, systemic chemotherapy, immunotherapy, approved proteins/antibodies or any investigational agent within 4 weeks prior to commencing study treatment.
• Who received radiotherapy within 14 days of commencing study treatment.
• With unresolved toxicities from prior systemic therapy or radiotherapy that, in the opinion of the investigator, does not qualify the patient for study treatment.
• Wwith medical or psychiatric conditions that compromise the patient’s ability to give informed consent or to complete the protocol.
• With prior systemic therapy, including with drugs targeting EGFR such as cetuximab, panitumumab or erlotinib
• Pregnant or breastfeeding women
• Severely immunocompromised patients (neutropenic as defined by <1,500 neutrophils cells/µL; this is to optimise the safety of FMT administration)
• With diagnosed dysphagia or other disorder affecting swallowing
• Who received prebiotic or probiotic within 4 weeks of randomisation (to exclude recent manipulation of the gut microbiota)
• Who used antibiotic within 8 weeks of randomisation (to exclude recent manipulation of the gut microbiota)
• For which the pancreatic tumour(s) were identified as a secondary cancer
• With known allergy to Creon and/ or Maxolon
• With known anaphylactic food allergy
• With a history of interstitial pneumonitis, pulmonary fibrosis or evidence of interstitial pneumonitis, or pulmonary fibrosis on baseline chest CT scan.
• With a history of Gilbert syndrome.
• With known cirrhosis, chronic active hepatitis, or chronic persistent hepatitis.
• With active bleeding diathysis.
• With uncontrolled clinically significant cardiac disease, arrhythmias or angina pectoris
• With active inflammatory bowel disease or other bowel disease causing chronic diarrhoea (defined as CTC grade 2 [CTCAE version 4.3])
• Who receive chronic treatment with immunosuppressives.
• Wth a known history of HIV seropositivity.
• Who have any severe and/or uncontrolled medical conditions or infections
• Who have a history of another primary malignant disease apart from non-melanotic skin cancer or carcinoma in situ of the uterine cervix or any other cancer treated with curative intent >2 years previously without evidence of relapse.
• Presenting brain metastasis.
• Women and partners of women of childbearing potential who are not using effective contraception. Adequate contraception must be used throughout study treatment and for 6 months following the completion of all study treatment.
• With history of serious drug adverse reactions.

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)
All investigational products will be produced and stored at the production site until ready for utilisation. Once a participant has signed their consent form, they will be allocated to either placebo or FMT by the person in charge of randomisation. This person will be the only person knowing which treatment a given participant has been allocated to and will not interact with patients.

Each bottle of capsules present a batch number. This batch number will be used by the person in charge of randomisation to allocate a batch to a specific patient. The trial staff distributing the investigational product to the patient will only know which batch number to distribute to the patient and not the content of the bottle. The batch number provided to a patient will be recorded on the patient's trial records.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The trial staff in charge of randomisation, will allocate patients who provided signed informed consent to either FMT or placebo on a 1:1 ratio using block randomisation; taking the following characteristics into account the participants’ age and sex. Recruitment will continue until we have reached saturation (n=60).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Quantitative

Main study outcomes

The statistical methods will include an “intention to treat” (ITT) analysis as this is preferred to a per protocol analysis as it compares all participants in the groups to which they were originally randomly assigned (despite withdrawal, treatment failure or cross-over).

A Table 1 will be constructed with descriptive statistics of patient’s demographic and disease-related variables for both treatment and placebo groups: mean and standard deviation for normally-distributed continuous variables, median and interquartile range (IQR) for skewed continuous variables and frequency and percentage for categorical variables. Disease-related variables taken at 3, 6, 12 and 18 months after the start of chemotherapy include: FMT tolerability and acceptability, average changes in Quality of Life score from baseline, tumour placement, average changes in tumour number and size from baseline, and average change in CA-19-9 concentrations from baseline.

The outcomes: mortality at 3, 6, 12 and 18 months will be compared with treatment/placebo group in separate unadjusted binary logistic Generalized Estimating Equations (GEE) models, controlling for clustering on hospital as a random effect. The sample size of 60-70 participants with only a few deaths will not allow for multivariable models.

Length of survival will be measured in months as time from D0 to death or time from D0 to study end versus treatment/placebo group using survival analysis (Kaplan-Meier curves and Cox Proportional hazard models), controlling for clustering on hospital as a fixed effect.

The association between the outcome: Quality of life measured by the EQ-5D-5L instrument and predictor: treatment/placebo group will be assessed using an unadjusted ordinal logistic GEE model controlling for repeated measurements over time, and clustering on hospital as a fixed effect. If possible with limited sample size, adjusted regressions could then be performed, the predictor being treatment/placebo group, hospital as a fixed effect and one model for each of the potential confounders: age, gender, BMI, cancer stage, length of chemotherapy (3 or 6 months), and pain meds used.

The association between the outcomes: number of tumours, tumour size and CA-19-9 concentrations and predictor: treatment/placebo group will be assessed using unadjusted linear mixed-effects models controlling for repeated measurements over time, and clustering on hospital as a random effect. Adjusted regressions could be performed as mentioned above.


Differences in microbial composition and activity between the two arms.

Metagenomic sequences obtained from extracted stool samples and 16rDNA gene sequences obtained from collected tumour samples will be cleaned and analysed using Quantitative Insights Into Microbial Ecology version 2(QIIME2). Kraken2 will be used in conjunction with the National Centre for Bioinformatics (NCBI) database to assign sequences to the lowest common ancestor. Taxonomic profiles will be obtained using the mOTU profiler v2.571 and filtered to retain species observed at a relative abundance of 10^-5 in around 2% of samples. The alpha diversity will be calculated using the GreenGene2 database and Observed species, Chao-1 and Shannon's diversity indices, and b-diversity will be calculated with unweighted UniFrac and weighted UniFrac by using a PERMANOVA test in R. Microorganisms that have been impacted by the treatment will be identified from the analysis.
Gene functional profiles will be obtained from mappings against a global microbial gene catalogue (GMGCv1, Coelho et al72, http://gmgc.embl.de/), by summarising read counts from eggNOG v4.573 annotations to orthologous groups and KEGG modules. Features with a relative abundance of 10^-5 in around 15% of samples will be retained. Microbial diversity will be compared to other outcomes and factors using a principal component analysis (PCA) to reduce the dimension of the analysis. The main factors identified will be selected to run either multiple regression analyses or a mixed effect linear model depending on the auto-correlation of the data obtained.

To keep the blinding intact and avoid bias until the end of the trial, the diversity profiles and differences in enzymatic activity will be compared between arms and to donor profiles once the trial has ended (BiomeBank will share the donor data at the end of the trial only). In research outputs, diversity profiles, scores and the inferred microbial enzymatic activity will be presented by patient (de-identified codes, different to their unique identification number to avoid potential re-identification) and as an average diversity score or microbe abundance by treatment (i.e., FMT vs placebo).

Economic evaluation of FMT in patients with non-resectable pancreatic cancer

Taking a health system perspective, a within-trial cost-utility analysis will be conducted to evaluate both costs (including potential costs savings due to, for example, reduced use of healthcare resources) and quality of life. Using data from the trials and financial records, a range of cost items including the cost of FMT capsules, chemotherapy and hospital services (including costs of treating complications following surgery and utilisation of critical care) will be included in the analysis. After obtaining appropriate approvals to access cost data, Medicare data and data held by the state Department of Health will be used to estimate direct costs associated with the use of healthcare resources (i.e., out of hospital services, pharmaceuticals, hospital admissions and emergency department presentations) over the follow-up period (i.e., 18 months). The cost data from different sources will be matched to create an individual cost profile record. The EQ-5D-5L instrument will be used at baseline, 3, 6, 12 and 18 months to estimate utility values that inform quality-adjusted life-year (QALY) gains for each patient using the area under the health utility curve method. Generalised linear models will be fitted to compare differences in costs and QALYs between the study groups. If no dominant scenario, the incremental cost-effectiveness ratio will be estimated with respect to differences in QALYs between the study arms for each trial. A bootstrapping approach will be applied to represent the uncertainty around mean estimates. Sensitivity of the results obtained to variation in inputs into economic evaluation (e.g. cost of FMT) will be undertaken using deterministic sensitivity analysis. Analyses will be overseen by investigator Hossein Afzali.

Qualitative

Descriptive statistics will be used to analyse the results of the FMT tolerability survey. Where applicable, the same methods than for the main study outcomes will be applied.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/05/2024
Actual
Date of last participant enrolment
Anticipated
31/01/2025
Actual
Date of last data collection
Anticipated
31/07/2026
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA,VIC

Funding & Sponsors
Funding source category [1] 316180 0
Government body
Name [1] 316180 0
Department of Health and Aged Care - Medical Research Future Fund (MRFF)
Country [1] 316180 0
Australia
Primary sponsor type
Government body
Name
Central Adelaide Local Health Network (CALHN)
Address
Country
Australia
Secondary sponsor category [1] 318365 0
None
Name [1] 318365 0
Address [1] 318365 0
Country [1] 318365 0
Other collaborator category [1] 282993 0
University
Name [1] 282993 0
The University of Adelaide
Address [1] 282993 0
Country [1] 282993 0
Australia
Other collaborator category [2] 282994 0
University
Name [2] 282994 0
Flinders University
Address [2] 282994 0
Country [2] 282994 0
Australia
Other collaborator category [3] 282995 0
Commercial sector/Industry
Name [3] 282995 0
Epworth Healthcare
Address [3] 282995 0
Country [3] 282995 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315001 0
Central Adelaide Local Health Network HREC
Ethics committee address [1] 315001 0
https://www.rah.sa.gov.au/research/for-researchers/central-adelaide-local-health-network-human-research-ethics-committee
Ethics committee country [1] 315001 0
Australia
Date submitted for ethics approval [1] 315001 0
08/01/2024
Approval date [1] 315001 0
26/03/2024
Ethics approval number [1] 315001 0
2024/HRE00002

Summary
Brief summary
This study is investigating whether aiming to restore a healthy microbiota, gut barrier and digestion through faecal microbiota transplantation (FMT) alongside chemotherapy can effectively treat and relieve symptoms and pain in non-resectable pancreatic cancer.

Who is it for?
You may be eligible for this study if you are aged between 18 and 75 years of age, and have been diagnosed with non-resectable pancreatic cancer (i.e. pancreatic tumours that cannot be removed through surgery).

Study details
Participants will be randomly assigned to either receive FMT or placebo capsules in 2 separate treatment periods: one before chemotherapy and one 4 weeks after chemotherapy cessation. All participants will receive Folfirinox chemotherapy for either 3 or 6 months depending on the treating oncologist's review of their clinical response at 3 months. Safety, tolerability and efficacy data will be collected from participants over the course of their participation in this study.

This study represents a unique opportunity to provide a novel and promising intervention for the management of pancreatic cancer and its symptoms to Australian patients to improve their health outcomes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 133382 0
Prof Guy Maddern
Address 133382 0
Division of Surgery, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville SA, 5011.
Country 133382 0
Australia
Phone 133382 0
+61 8 8222 6756
Fax 133382 0
Email 133382 0
[email protected]
Contact person for public queries
Name 133383 0
Virginie Gaget
Address 133383 0
Division of Surgery, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, 5011.
Country 133383 0
Australia
Phone 133383 0
+61 8 8133 4013
Fax 133383 0
Email 133383 0
[email protected]
Contact person for scientific queries
Name 133384 0
Virginie Gaget
Address 133384 0
Division of Surgery, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville, SA, 5011.
Country 133384 0
Australia
Phone 133384 0
+61 8 8133 4013
Fax 133384 0
Email 133384 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Unidentified metagenomic data from stool samples
When will data be available (start and end dates)?
Immediately following publication, no end date
Available to whom?
anyone who wishes to access it
Available for what types of analyses?
any purpose
How or where can data be obtained?
Unrestricted access via NCBI's gdGAP platform (https://www.ncbi.nlm.nih.gov/gap/)


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
21990Study protocol    The study protocol will be published in a peer rev... [More Details]



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