Circulating Tumour DNA Analysis Informing Adjuvant Chemotherapy in Early Stage Pancreatic Cancer: A Multicentre Randomised Study (DYNAMIC- Pancreas)

INTERVENTION: 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 CONDITION: Pancreatic Cancer PRIMARY OUTCOME: 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. SECONDARY OUTCOME: 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). ; ; 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