PRIMUS002: Looking at 2 Neo-adjuvant Treatment Regimens for Resectable and Borderline Resectable Pancreatic Cancer

Study Overview
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Brief Summary
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PRIMUS 002 is looking at 2 different chemotherapy regimens in the neo-adjuvant setting for pancreatic cancer. Each treatment will be given for 3 months prior to surgery

Detailed Description
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This is an integrated, open label, non-randomised, phase II trial of 2 neo-adjuvant regimens (FOLFOX-A and AG) assessing efficacy and toxicity with integrated translational work. The study is powered on testing a proposed DNA damage response deficient biomarker for responsiveness in patients treated with FOLFOX-A; patients being treated with AG are recruited concurrently. The study has a prospective safety assessment of neo-adjuvant chemotherapy and neo-adjuvant chemotherapy followed by chemoradiotherapy consisting of conventional radiotherapy with concomitant capecitabine. This safety assessment will include all patients (FOLFOX-A and AG)

Official Title
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PRIMUS002: An Umbrella Phase II Study Examining Two Neo-adjuvant Regimens (FOLFOX-A and AG) in Resectable and Borderline Resectable Pancreatic Ductal AdenoCarcinoma (PDAC), Focusing on Biomarker and Liquid Biopsy Development

Conditions
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Neoplasms Pancreatic

Intervention / Treatment
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* Drug: FOLFOX-A
* Drug: AG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has been enrolled in the Precision-Panc Master Protocol and their tissue has been deemed suitable for Next Generation Sequencing analysis (a Precision-Panc Master Protocol identifier will be required at the time of study enrolment) Signed informed consent given for PRIMUS 002 study Age ≥ 16 years Resectable or borderline resectable pancreatic cancer as defined by National Comprehensive Cancer Network criteria following discussion at the Multi Disciplinary Team Measurable Disease as per RECIST 1.1 Histological or cytologically proven pancreatic ductal adenocarcinoma (including variants) Able to undergo biliary drainage using a covered or partially covered self-expanding metal stent if jaundiced Eastern Cooperative Oncology Group performance status 0 and 1 Adequate liver/bone marrow function as defined by: Neutrophils (ANC) ≥ 1.5 x 109/l Platelets ≥ 100 x 109/l Haemoglobin ≥ 9.0g/dL White Blood Cells (WBC) ≥ 3 x 109/l Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless bilirubin rise is due to Gilbert's syndrome Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (or <5 x ULN in the presence of liver metastases) Estimated creatinine clearance ≥ 60 mL/min (as calculated by Cockcroft and Gault or Wright formula or measured by EDTA clearance) Negative serum Human Chorionic Gonadotropin (HCG) test for females with child bearing potential. Postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential Woman of child bearing potential, and men with female partners of child bearing potential, must agree to use adequate contraceptive measures (see section 7.1.11.1) for the duration of the study and for up to 6 months after the completion of study treatment. Able to comply with protocol requirements and deemed fit for surgical resection, chemotherapy and CRT Exclusion Criteria: Distant metastatic disease History of previous or concurrent malignancy diagnosis (except curatively treated basal cell carcinoma of skin or carcinoma in situ of cervix) in the last 3 years Prior chemotherapy or CRT for pancreatic cancer Known hypersensitivity for any component of any study drug Active infection including Herpes Zoster and chickenpox Uncontrolled congestive heart failure (CHF), or history of myocardial ischemia (MI), unstable angina, stroke, or transient ischemia within previous 6 months. Serious medical or psychological condition precluding neo-adjuvant treatment and surgical resection New York Heart Association Classification Grade III or IV Liver cirrhosis (except for Child-Pugh A) Major surgery within 28 days prior to trial entry Any patients receiving treatment with brivudin, sorivudin and analogues or patients who have not stopped these drugs at least 4 weeks prior to the start of study treatment Any patient with severe diarrhoea (defined as ≥grade 3 diarrhoea despite maximum supportive measures and exclusion of underlying infection) Patients with known malabsorption Patients with known or suspected dihydropyrimidine dehydrogenase (DPD) deficiency Grade ≥ 2 peripheral neuropathy Administration of any investigational drug within 28 days or 5 half-lives, whichever is longer, prior to receiving the first dose of trial treatment

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients are registered to receive either FOLFOX-A or AG depending on their age and performance status
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FOLFOX-A<br>FOLFOX A arm (14-day cycle) nab-paclitaxel: 150mg/m2 IV over 30 minutes, day 1 (administered first). Oxaliplatin: 85mg/m2, IV over 2 hours, day 1. Folinic acid: 350mg flat dose, IV over 2 hours, day 1. Fluorouracil infusion:1200mg/m2/day, as a continuous IV infusion over 2 days, day 1 and day 2 (for a total dose of 2400mg/m2 over 46 hours or 48 hours as per local practice.) Patients will also receive daily G-CSF as primary prophylaxis against neutropenic events for all cycles. This should be given as per local policy for chemotherapy regimens given every 14 days e.g. it may be started on day 4 for 7 days (preparation and dose should be given as per local policy). | Drug: FOLFOX-A<br>* nab-paclitaxel: 150mg/m2 IV over 30 minutes, day 1 (administered first). Oxaliplatin: 85mg/m2, IV over 2 hours, day 1. Folinic acid: 350mg flat dose, IV over 2 hours, day 1. Fluorouracil infusion:1200mg/m2/day, as a continuous IV infusion over 2 days, day 1 and day 2 (for a total dose of 2400mg/m2 over 46 hours or 48 hours as per local practice.)<br>|
| Active Comparator: Abraxane and Gemcitabine<br>Nab-Paclitaxel + Gemcitabine (AG) arm (28-day cycle) nab-paclitaxel: 125mg/m2 IV over 30 minutes on days 1, 8 and 15 (administered first). Gemcitabine 1000mg/m2 IV over 30 minutes on days 1, 8 and 15 (immediately following nab-paclitaxel). | Drug: AG<br>* nab-paclitaxel: 125mg/m2 IV over 30 minutes on days 1, 8 and 15 (administered first). Gemcitabine 1000mg/m2 IV over 30 minutes on days 1, 8 and 15 (immediately following nab-paclitaxel).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression post FOLFOX-A induction treatment | date of progression after FOLFOX-A neo-adjuvant chemotherapy as assessed by RECIST 1.1 | CT scans will take place at baseline, pre chemoradiotherapy and pre surgery, over approximately 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proving liquid biopsies can be used to define patient subgroups | a liquid biopsy will be taken and analysed using circulating tumour DNA at different timepoints to see if these can be used to define patient subgroups | From date of registration to date of surgery. On average 4 months after registration | 
| Response post neo-adjuvant chemotherapy | CT scans will be reported to RECIST 1.1 and best response will be evaluated | CT scan will be performed at baseline and then post neo-adjuvant chemotherapy (approximately 3 months later) | 
| College of American Pathologists tumour regression grade | CAP tumour regression grade (grade 0-3 with 0 being no viable residual tumour and 3 being poor to no response) will be assessed post surgery | Post surgery which will be approximately 4 months post registration | 
| R0 rate post surgery | R0 rate will be assessed post surgery | Post surgery which will be approximately 4 months post registration | 
| Overall survival | Overall survival will be assessed in all patients | From date of registration until date of death assessed for up to 5 years post registration | 
| Disease free survival | Disease free survival will be assessed at every follow up visit | from date of registration until date of disease recurrence assessed for at least 24 months post registration | 
| Safety and tolerability of study drugs: NCI CTCAE 4.03 | Safety and tolerability will be assessed as per NCI CTCAE 4.03 | Assessed at every clinic visit during treatment, for approximately 3 months post registration | 
| Safety and tolerability of chemoradiotherapy: NCI CTCAE 4.03 | Safety and tolerability of chemoradiotherapy will be assessed as per NCI CTCAE 4.03 | Assessed at every chemoradiotherapy visit and pre-surgery (once Chemoradiotherapy added). Chemoradiotherapy will take place 5 days a week for three weeks | 
| Surgical complication rate | Rate of surgical complication as assessed by NCI CTCAE 4.03 | Assessed post surgery, approximately 4 months post registration | 
| Neurotoxicity | Assessed by GOG NTX4 (4 questions graded from 0 (not at all) to 4 (very much). quality of life will be assessed using the GOG NTX4 tool at the following timepoints: Baseline, month 1, month 2, month 3, pre chemoradiotherapy, between fraction 11 and 15 of chemoradiotherapy, pre surgery, at every follow-up visit (6, 9, 12 months post registration then every 6 months) | Neurotoxicity will be assessed from registration until study is completed at various timepoints until patient death. Each patient will be followed up for at least 24 months post registration | 
| Quality of life assessed by EORTC QLQ-C30 | quality of life will be assessed using the EORTC QLQ C30 tool at the following timepoints: Baseline, month 1, month 2, month 3, pre chemoradiotherapy, between fraction 11 and 15 of chemoradiotherapy, pre surgery, at every follow-up visit (6, 9, 12 months post registration then every 6 months for a minimum of 24 months). The Quality of life tool is comprised of 28 questions that the patient answers either 1-4 (1 = not at all, 4 = Very much) and 2 questions that are on al scale of 1 - 7 where 1 = very poor and 7 = excellent | Quality of life will be assessed from registration until study is completed at various timepoints until patient death. Each patient will be followed up for at least 24 months post registration | 
| Quality of life assessed by EORTC QLQ-PAN26 | quality of life will be assessed using the EORTC QLQ-PAN26 tool at the following timepoints: Baseline, month 1, month 2, month 3, pre chemoradiotherapy, between fraction 11 and 15 of chemoradiotherapy, pre surgery, at every follow-up visit (6, 9, 12 months post registration then every 6 months for a minimum of 24 months). The Quality of life tool is comprised of 26 questions that the patient answers either 1-4 (1 = not at all, 4 = Very much) | Quality of life will be assessed from registration until study is completed at various timepoints until patient death. Each patient will be followed up for at least 24 months post registration | 
| Health Economics | Health economics defined as number of visits to hospital per patient, both as an inpatient and as an outpatient will be assessed at the following timepoints: Baseline, month 1, month 2, month 3, pre chemoradiotherapy, between fraction 11 and 15 of chemoradiotherapy, pre surgery, at every follow-up visit (6, 9, 12 months post registration then every 6 months for a minimum of 24 months) | Health economics will be assessed from registration until study is completed at various timepoints until patient death. Each patient will be followed up for at least 24 months post registration |