Clinical trial NCT02869802: Prospectively Defining Metastatic Pancreatic Ductal Adenocarcinoma Subtypes by Comprehensive Genomic Analysis
Official title: Prospectively Defining Metastatic Pancreatic Ductal Adenocarcinoma Subtypes by Comprehensive Genomic Analysis
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Cancer
Pancreatic Cancer
Keywords: Cancer
Pancreatic Cancer
Advanced Pancreatic Ductal Adenocarcinoma
PDAC
Genomic Analysis
Molecular subtyping
Lead sponsor: British Columbia Cancer Agency
Sponsor class: OTHER
Collaborators: name: Terry Fox Research Institute
name: BC Cancer Foundation
name: Pancreas Centre BC
name: American Society of Clinical Oncology
First posted: 2016-08-17
Enrollment: 190
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients with metastatic PDAC undergoing first-line systemic therapy with either FOLFIRINOX or GP-based regimens.

Brief summary: Researchers are looking for better ways of understanding and treating pancreatic cancer. The purpose of this study is to see how useful it is to look for changes and characteristics in your genes (molecules that contain instructions for the development and functioning of the cells) and the genes within the tumour. These characteristics may be useful in choosing treatments for patients in the future. Changes (mutations) in genes have been shown to be an important characteristic in cancers. Looking at differences in genes in patients with advanced pancreatic ductal adenocarcinomas and comparing this information with response to their initial chemotherapy treatment may help to learn which treatments may be better for certain patients after initial treatment.

Detailed description: This is a prospective non-randomized study of patients with metastatic pancreatic ductal adenocarcinoma (PDAC) undergoing first-line systemic chemotherapy with either folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine and nab-paclitaxel (GP)-based regimens, where tumour samples, baseline and serial blood samples, and standardized clinical and radiological assessments will be obtained. Patients planned for treatment with an investigational agent(s) within a clinical trial using either FOLFIRINOX or GP as the chemotherapy backbone will also be eligible, as long other eligibility criteria for the study are met.

A total of 190 patients will be recruited over the study period. Patients will undergo fresh tumour biopsy at study baseline for comprehensive molecular characterization (biopsy cohort). Patients whose biopsy was unable to undergo whole genome and transcriptome sequencing (e.g. due to insufficient tumour content) but fulfill all other eligibility criteria will comprise the archival cohort, where limited genomic analyses will be performed on archival tumour samples. Patients with a radiological diagnosis of metastatic PDAC without a confirmatory histological diagnosis may be eligible; in these cases, tumour biopsy for establishing a pathological diagnosis will be given first priority. Remaining tumour samples will be used for research purposes only after the diagnosis of PDAC has been established. In the rare event (\<5%) where the histological diagnosis is other than PDAC, patients will be censored from the study and all tumour materials stored for future clinical use outside of this study.

All patients will undergo serial collection of plasma and serum samples at baseline and every 4 weeks until end of study. These will be used for exploratory biomarker analyses. Serum cancer antigen 19-9 (CA19-9), also known as carbohydrate antigen 19-9, will also be measured at baseline and every 4 weeks thereafter as part of routine standard of care until end of study. In addition, a whole blood sample will be collected at baseline to study germline DNA variants. CT chest, abdomen and pelvis will be performed at baseline and every 8 weeks, with radiological response to therapy assessed using RECIST 1.1.

Patients must have at least one tumour lesion amenable to biopsy from which a minimum of 3 tumour cores can be safely obtainable under CT or ultrasound guidance, as assessed by a staff interventional radiologist. A maximum of 5 tumour cores will be taken from each patient at baseline prior to treatment with FOLFIRINOX or GP. At the time of radiological disease progression, an optional second tumour biopsy will be collected from patients in the biopsy cohort to study changes in the molecular characteristics of tumours under the selection pressure of first-line systemic therapy. This tumour biopsy will be performed using exactly the same procedures described for the baseline biopsy. Tumour biopsies will be coordinated with the British Columbia (BC) Cancer Personalized Oncogenomics (POG) program and the data and/or samples shared between the two studies to avoid re-sampling the patient for both POG and PanGen, if the patient is participating in both studies. Molecular analyses will be performed by BC Cancer. Depending on the amount of tumour material obtained from each patient, molecular analyses will be prioritized to first establish or confirm histological diagnosis and then use for whole genome sequencing, whole transcriptome sequencing, proteomics, and patient-derived models.

The primary endpoint of PanGen is the generation of molecular and phenotypic signatures of individual tumours in a clinically relevant timeframe. The signature data will be correlated with clinical outcome. One of the key strengths of this cohort approach will be the rigorous annotation of PDAC patients' clinical features and outcomes to all treatments (first-line and other) linked to the molecular profile. The investigators have the potential to be nimble as more data is generated, more hypotheses can be explored and others fine-tuned or eliminated.

Eligibility criteria: Inclusion Criteria:

* Histological and/or radiological diagnosis of metastatic PDAC. Patients without a histological diagnosis of PDAC must undergo confirmatory tumour biopsy prior to treatment start date.
* Planned for first-line systemic therapy with FOLFIRINOX or GP, either in routine care or in combination with an investigational agent(s) within a clinical trial.
* Age ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Adequate organ function
* Life expectancy of \> 90 days as judged by the investigator
* Ability to give informed consent
* Measurable disease by RECIST 1.1
* Presence of a tumour lesion amenable to core needle biopsy as judged by a staff interventional radiologist. A minimum of 3 tumour cores must be safely obtainable under CT or US guidance.
* Fit enough to safely undergo a tumour biopsy as judged by the investigator
* Ability to lie supine for \> 60 minutes

Patients in the archival cohort must also fulfil the following criteria:

* Archival tumour sample available (either a previous tumour diagnostic biopsy or resection specimen)

Exclusion Criteria:

* Absence of distant or lymph node metastases. Patients with borderline resectable or locally advanced PDAC are not eligible.
* Received prior systemic therapy (chemotherapy or any other anti-cancer agent) in the advanced setting. Patients who received adjuvant chemotherapy after surgical resection of early stage disease are eligible.
* Currently receiving anti-cancer therapy (chemotherapy or any other anti-cancer agent)
* Not fit for combination chemotherapy as judged by the investigator
* Presence of brain metastases
* Female patients with positive pregnancy test
* Patients who are not safe to include in the study as judged by the investigator for any medical or non-medical reason
* Unable to comply with study assessments and follow-up

Primary outcomes:
measure: Number of days between biopsy and return of comprehensive genomic results.
timeFrame: An average of 8 weeks
Secondary outcomes:
measure: Response Rate
timeFrame: Up to an average of 1 year
measure: Disease Control Rate
timeFrame: Up to an average of 1 year
measure: Duration of Response
timeFrame: Up to an average of 1 year
measure: Progression-Free Survival
timeFrame: Up to an average of 1 year
measure: Overall Survival
timeFrame: Up to an average of 1 year
Other outcomes:
measure: Engraftment rate of patient-derived xenografts
timeFrame: 5 years
measure: Success rate of establishing patient-derived organoids
timeFrame: 5 years
measure: DNA damage repair pathways
timeFrame: 5 years
measure: Hypermutated phenotype
timeFrame: 5 years
measure: Mismatch repair deficiency
timeFrame: 5 years
measure: Neo-antigen load
timeFrame: 5 years
measure: Targetable mutations
timeFrame: 5 years
Locations:
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: BC Cancer - Vancouver
state: British Columbia
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
Study officials:
affiliation: BC Cancer
name: Daniel J Renouf, MD
role: PRINCIPAL_INVESTIGATOR
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