Prospectively Defining Metastatic Pancreatic Ductal Adenocarcinoma Subtypes by Comprehensive Genomic Analysis (PanGen)

• ClinicalTrials.gov Identifier: NCT02869802
• Recruitment Status: Recruiting
• First Posted: August 17, 2016
• Last Update Posted: July 19, 2021
• Sponsor: British Columbia Cancer Agency
• Collaborators: Terry Fox Research Institute; BC Cancer Foundation; Pancreas Centre BC
• Information provided by (Responsible Party): British Columbia Cancer Agency

Study Description

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.

Condition or disease	Intervention/treatment
Cancer; Pancreatic Cancer	Procedure: Tumour Biopsy; Other: Serial Collection of Plasma and Serum Samples

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.

Study Design

• Study Type: Observational
• Estimated Enrollment: 190 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Prospectively Defining Metastatic Pancreatic Ductal Adenocarcinoma Subtypes by Comprehensive Genomic Analysis
• Actual Study Start Date: October 6, 2016
• Estimated Primary Completion Date: September 2023
• Estimated Study Completion Date: September 2023

Groups and Cohorts

Group/Cohort	Intervention/treatment
Biopsy Cohort; Participants will undergo a tumour biopsy at baseline and an optional tumour biopsy at disease progression. Participants will undergo serial collection of plasma and serum samples.	Procedure: Tumour Biopsy; If there is the presence of a tumour lesion amenable to core needle biopsy as judged by a staff interventional radiologist, a minimum of 3 tumour cores will be obtained under CT or US guidance.; Other: Serial Collection of Plasma and Serum Samples; Participants will undergo serial collection of plasma and serum samples at baseline and every 4 weeks until end of study.
Archival Cohort; Genomic analyses will be performed on participants' archival tumour samples. Participants will undergo serial collection of plasma and serum samples.	Other: Serial Collection of Plasma and Serum Samples; Participants will undergo serial collection of plasma and serum samples at baseline and every 4 weeks until end of study.

Outcome Measures

Primary Outcome Measures :

1. Number of days between biopsy and return of comprehensive genomic results. [ Time Frame: An average of 8 weeks ]
   The primary endpoint is the assessment of the feasibility of returning comprehensive genomic results within a clinically meaningful timeframe. Specifically the primary endpoint is return of genomic data by 8 weeks from the time of biopsy. This endpoint will be met if the analysis data is available within 8 weeks for 80% of the first 50 patients whose tumours are successfully sequenced.

Secondary Outcome Measures :

1. Response Rate [ Time Frame: Up to an average of 1 year ]
   Response rate defined as the percentage of patients with complete (CR) or partial response (PR) per RECIST 1.1
2. Disease Control Rate [ Time Frame: Up to an average of 1 year ]
   Disease control rate defined as the percentage of patients who experience CR, PR, or stable disease by RECIST 1.1
3. Duration of Response [ Time Frame: Up to an average of 1 year ]
   Duration of response defined as the interval between the first date of CR or PR and the earliest date of disease progression or death due to any cause
4. Progression-Free Survival [ Time Frame: Up to an average of 1 year ]
   Progression-free survival (PFS) defined as the interval between the date of registration and the earliest date of disease progression or death due to any cause
5. Overall Survival [ Time Frame: Up to an average of 1 year ]
   Overall survival (OS) defined as the interval between the date of registration and the date of death.

Other Outcome Measures:

1. Engraftment rate of patient-derived xenografts [ Time Frame: 5 years ]
2. Success rate of establishing patient-derived organoids [ Time Frame: 5 years ]
3. DNA damage repair pathways [ Time Frame: 5 years ]
   Percentage of patients with somatic or germline alterations in DNA damage repair pathways
4. Hypermutated phenotype [ Time Frame: 5 years ]
   Percentage of patients with a hypermutated phenotype
5. Mismatch repair deficiency [ Time Frame: 5 years ]
   Percentage of patients with mismatch repair deficiency
6. Neo-antigen load [ Time Frame: 5 years ]
   Percentage of patients with a high tumour neo-antigen load
7. Targetable mutations [ Time Frame: 5 years ]
   Percentage of patients with rare but targetable mutations

Biospecimen Retention:   Samples With DNA

Fresh tumour tissue biopsy samples Archival tumour tissue samples Whole blood samples Plasma samples Serum samples Urine samples (at BC Cancer only)

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Probability Sample

Study Population

Patients with metastatic PDAC undergoing first-line systemic therapy with either FOLFIRINOX or GP-based regimens.

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

Contacts and Locations

Contacts

Contact: Daniel J Renouf, MD; 6048776000 ext 2445; drenouf@bccancer.bc.ca

Locations

Canada, Alberta

Tom Baker Cancer Centre; Recruiting

Calgary, Alberta, Canada, T2N 4N2

Contact: Patricia Tang, MD 403-521-3723 Patricia.Tang@albertahealthservices.ca

Cross Cancer Institute; Withdrawn

Edmonton, Alberta, Canada, T6G 1Z2

Canada, British Columbia

BC Cancer - Vancouver; Recruiting

Vancouver, British Columbia, Canada, V5Z 4E6

Contact: Daniel J Renouf, MD 6048776000 ext 2445 drenouf@bccancer.bc.ca

Sub-Investigator: Howard Lim, MD

Sub-Investigator: Janine M Davies, MD

Sub-Investigator: Sharlene Gill, MD

Canada, Ontario

The Ottawa Hospital; Recruiting

Ottawa, Ontario, Canada, K1H 8L6

Contact: Rachel Goodwin, MD 613-737-7700 rgoodwin@toh.on.ca

Sponsors and Collaborators

British Columbia Cancer Agency

Terry Fox Research Institute

BC Cancer Foundation

Pancreas Centre BC

Investigators

• Principal Investigator: Daniel J Renouf, MD; BC Cancer

More Information

Additional Information:

Integrated Addendum to International Council for Harmonization (ICH) E6(R1): Guideline for Good Clinical Practice ICH E6(R2) 

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Karasinska JM, Topham JT, Kalloger SE, Jang GH, Denroche RE, Culibrk L, Williamson LM, Wong HL, Lee MKC, O'Kane GM, Moore RA, Mungall AJ, Moore MJ, Warren C, Metcalfe A, Notta F, Knox JJ, Gallinger S, Laskin J, Marra MA, Jones SJM, Renouf DJ, Schaeffer DF. Altered Gene Expression along the Glycolysis-Cholesterol Synthesis Axis Is Associated with Outcome in Pancreatic Cancer. Clin Cancer Res. 2020 Jan 1;26(1):135-146. doi: 10.1158/1078-0432.CCR-19-1543. Epub 2019 Sep 3.

• Responsible Party: British Columbia Cancer Agency
• ClinicalTrials.gov Identifier: NCT02869802
• Other Study ID Numbers: H20-02375; H16-00291 ( Other Identifier: University of British Columbia )
• First Posted: August 17, 2016
• Last Update Posted: July 19, 2021
• Last Verified: July 2021

Keywords provided by British Columbia Cancer Agency:

Cancer; Pancreatic Cancer; Advanced Pancreatic Ductal Adenocarcinoma; PDAC; Genomic Analysis; Molecular subtyping

Additional relevant MeSH terms:

Adenocarcinoma; Pancreatic Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases