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

This is a prospective, multi-centre, randomised study enrolling 438 patients with localised pancreatic cancer who are undergoing either neoadjuvant (peri-operative) therapy followed by “curative” surgery (R0 or R1 resection) (n=350) or immediate “curative” surgery who would routinely be offered adjuvant chemotherapy (n=88). Patients who have received radiotherapy prior to surgery will be eligible for the study. This study will randomise patients who have received neoadjuvant chemotherapy 1:1 into either a non-biomarker-driven, standard of care adjuvant treatment arm (Cohort A) or a ctDNA-informed biomarker-driven adjuvant treatment arm (Cohort B). The adjuvant chemotherapy treatment of Cohort B participants will be guided by the post-operative ctDNA result of individual participants. Randomisation will occur after the post-operative week 4-6 blood collection and receipt of sufficient tumour tissue for ctDNA analysis. Patients who did not receive neoadjuvant chemotherapy and instead underwent immediate “curative” surgery will be enrolled into a separate non-randomised biomarker-driven adjuvant treatment group (Cohort C), where the adjuvant chemotherapy treatment will be guided by the post-operative ctDNA results of individual participants. Patients should be screened and consented within 6 weeks after surgery, and tumour samples made available within 5 working days of consent and within 7 weeks post-surgery for mutation analysis. All participants will have the first blood specimen for ctDNA analysis collected 4-6 weeks post-surgery (ctDNA-1A). Clinicians are to nominate their standard of care adjuvant chemotherapy regimen at the time of enrolment and (if applicable) prior to randomisation. Adjuvant chemotherapy must be scheduled to start within 12 weeks of surgery. Participants and clinicians in Cohort A will be blinded to their ctDNA-1A results and participants will receive adjuvant chemotherapy as per standard of care. Clinicians may commence chemotherapy treatment of participants in Cohort A with a standard of care regimen no sooner than 6 weeks post-operatively. For ctDNA-informed participants (Cohorts B and C), the ctDNA-1A results will be made available to the treating clinician approximately 4-5 weeks after receipt of sufficient tumour tissue for mutation analysis. Adjuvant chemotherapy will commence after the ctDNA-1A result becomes available and will be switched or "escalated”, or “de-escalated” according to the participants’ ctDNA-1A result. If the treating clinician wishes to commence chemotherapy before the ctDNA-1A result is available, patients may commence on standard of care chemotherapy no sooner than 6 weeks post-operatively (the exact timing will depend on the number of weeks post-surgery the patient was consented and the adjuvant chemotherapy regimen), 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” or “switched” adjuvant treatment strategy if fit to receive more intensive therapy (see treatment regimens below). The total number of additional study blood collections scheduled for ctDNA analysis will depend on the duration of adjuvant chemotherapy: All participants will have ctDNA-1B bloods collected immediately prior to the commencement of adjuvant chemotherapy and once chemotherapy is completed (ctDNA-3). Participants receiving 5-6 months of adjuvant chemotherapy will have a ctDNA blood collection scheduled approximately mid-chemotherapy (ctDNA-2A). Patients receiving 3-4 months of adjuvant chemotherapy will not be required to provide a mid-chemotherapy ctDNA blood sample. If a participant is found to have progressive disease prior to the completion of planned adjuvant treatment, a final blood collection (ctDNA-2B) should be performed at the time of disease progression and prior to commencing any further systemic therapy (in these participants, the end-of-treatment ctDNA-3 collection will no longer be required). Results for ctDNA-1B, -2A, -2B and -3 blood collections will not be routinely made available to the patients or treating clinicians (results may be made available on a case-by-case basis at clinician and/or patient request). 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. 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. Dosage modifications and reductions to adjuvant chemotherapy in line with standard clinical care are acceptable at the clinicians’ discretion. 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. Modified FOLFIRINOX, Cycle frequency: 14 days a. Oxaliplatin 85mg/2 Intravenously Day 1 b. Irinotecan 150mg/m2 Intravenously Day 1 c. Leucovorin 50mg Intravenously Day 1 d. 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 – Neoadjuvant, non-biomarker driven dealer's choice standard of care adjuvant chemotherapy arm. All participants randomised to Cohort A must have received neoadjuvant (peri-operative) chemotherapy prior to surgery. Standard of care chemotherapy should be administered with the intent of completing a total of 6 months of peri-operative chemotherapy with modified FOLFIRINOX as the recommended treatment. Cohort B – Neoadjuvant biomarker-driven arm. All participants randomised to Cohort B must have received neoadjuvant (peri-operative) chemotherapy prior to surgery. Adjuvant chemotherapy will be offered according to the ctDNA result. ctDNA negative participants may have their chemotherapy “de-escalated” and receive a SHORTER duration (recommended 3 months) of adjuvant modified FOLFIRINOX. The duration of the adjuvant treatment may be reduced at the clinician’s discretion if a longer course of neoadjuvant chemotherapy was administered. The recommendation is for a total of 6 months of peri-operative chemotherapy with at least 2 months in the post-operative setting. ctDNA positive participants may have their chemotherapy “switched” and receive a recommended 4-6 months of adjuvant gemcitabine doublet therapy (clinicians choice of nab-paclitaxel [Abraxane] or capecitabine). The duration of treatment will be at the clinician’s discretion; the length of the pre-operative treatment may be a factor in determining the duration of adjuvant chemotherapy. Cohort C - Immediate resection, biomarker-driven arm. Clinicians must indicate the intended standard of care adjuvant treatment (either modified FOLFIRINOX or gemcitabine-based doublet therapy, e.g. gemcitabine plus capecitabine) at the time of patient enrolment. ctDNA negative participants may have their chemotherapy “de-escalated” to receive a SHORTER duration (recommended 3-4 months) of whatever was the clinician’s choice standard of care adjuvant therapy. ctDNA positive participants may have their chemotherapy “escalated” to receive a LONGER duration (recommended 6 months) of whatever was the clinician’s choice of standard of care adjuvant therapy was (modified FOLFIRINOX or gemcitabine plus capecitabine). ctDNA positive participants, for whom the adjuvant therapy intent was gemcitabine doublet, also have the option of having their treatment “switched” to receive up to 6 months of adjuvant gemcitabine plus nab-paclitaxel (Abraxane) therapy at the clinician's discretion. It is anticipated that 438 eligible patients will be enrolled over a 54-month accrual period. Details of adjuvant chemotherapy administered including start and stop dates, dose received, dose reduction, reason for dose reduction/interruption and reason for stopping treatment will be recorded. Serious Unexpected Serious Adverse Reactions (SUSAR) for patients treated with either modified FOLFIRINOX or combination Gemcitabine plus Abraxane, and treatment-related hospitalisation for all patients will also be collected. All patients will be followed until death or study completion. Patients will be followed up as per standard of care, every 3 months for 24 months, then 6-monthly for the next 3 years. The trial will be considered complete after the last patient enrolled has had 2 years of follow-up. It is anticipated that this study will run for approximately 6.5 years. Interim Analysis: A review of the ctDNA results turn-around time will be conducted after the first 50 participants have been recruited. The study will be routinely monitored by the AGITG’s Independent Data Safety and Monitoring Committee (IDSMC) although no formal interim analyses are yet planned.