PRIMUS 001: A Study Looking at Two Different Chemotherapy Regimens in Patients With Metastatic Pancreatic Cancer

Study Overview
=================
Brief Summary
-----------------
This study is comparing two combinations of chemotherapy treatments in patients with metastatic pancreatic cancer. Half the participants will receive FOLFOX-A and the other half will receive AG. Treatment will continue until progression or patient/clinican decision or intolerable toxicity.

Detailed Description
-----------------
PRIMUS 001 is a multicentre, randomised, open label, two arm, phase II interventional trial with pre-clinical and translational work including in-depth molecular profiling and biomarker discovery/development. The primary objective is to look at the efficacy of FOLFOX-A compared to AG in all comers and in a biomarker positive group using progression free survival.

Official Title
-----------------
PRIMUS 001: An Adaptive Phase II Study of FOLFOX-A (FOLFOX and Nab-paclitaxel) Versus AG (Nab-paclitaxel and Gemcitabine) in Patients With Metastatic Pancreatic Cancer, With Integrated Biomarker Evaluation

Conditions
-----------------
Neoplasms Pancreatic

Intervention / Treatment
-----------------
* Drug: FOLFOX-A
* Drug: Gemcitabe and Abraxane
* Drug: G-CSF


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient has been enrolled in the Precision-Panc Master Protocol Patient has provided signed information consent for the PRIMUS 001 study Age ≥ 16 years Histologically-confirmed pancreatic ductal adenocarcinoma and its varients Measurable metastatic disease according to RECIST V1.1 Eastern Cooperative Oncology Group (ECOG) 0-1 with life expectation of no less than 12 weeks Patients must have received no previous chemotherapy or investigational therapy for the treatment of metastatic disease. Prior treatment with a fluoropyrimidine and/or gemcitabine administered in the adjuvant setting is allowed, provided at least 6 months have elapsed since completion of the last dose and no ongoing toxicities are present Adequate liver/bone marrow function as defined by: Neutrophils (ANC) ≥ 1.5 x 109/l Platelets ≥ 100 x 109/l Haemoglobin ≥ 9.0 g/dL White Blood Cells (WBC) ≥ 3 x 109/l Total bilirubin ≤ 1.5 x institutional ULN unless bilirubin rise is due to Gilbert's syndrome Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN ( <5 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) 9. Negative serum or urine 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 10. Woman of child bearing potential, and men with female partners of child bearing potential, must agree to use adequate contraceptive measures (see s section 8.1.8.1) for the duration of the study and for up to 6 months after the completion of study treatment. 11. Compliant, and can be followed up regularly The following additional inclusion criteria is ONLY required if recommended by the independent Data Monitoring Committee after interim review of study data (sites will have been informed by the Cancer Research UK (CRUK) Clinical Trials Unit (CTU) if this is the case) 12. Patient must be biomarker positive as fed back after central Precision-Panc diagnostic testing Exclusion Criteria: Prior treatment with nab-paclitaxel or oxaliplatin Prior chemotherapy for metastatic pancreatic cancer Known hypersensitivity for any component of any study drug Active infection including Herpes Zoster and chickenpox Current neuropathy ≥ grade 2 Uncontrolled brain metastasis Uncontrolled congestive heart failure (CHF), or history of myocardial ischemia (MI), unstable angina, stroke, or transient ischemia within previous 6 months Uncontrolled serious contraindicated medical condition or illness Known or suspected dihydropyrimidine dehydrogenase (DPD) deficiency Pregnant or breastfeeding History of physical or psychiatric disorder that would prevent informed consent and compliance with protocol Administration of any investigational drug within 28 days or 5 half-lives, whichever is longer, of receiving the first dose of trial treatment Any systemic anti-cancer therapy or major surgery within 28 days of randomisation Any minor surgery or radiotherapy within 7 days of randomisation Any psychological, familial, sociological or geographical consideration potentially hampering compliance with the trial protocol and follow up schedule Any patients receiving treatment with brivudin, sorivudin and analogues History of another malignancy in the last 5 years (other than treated squamous/basal cell skin cancer, treated early-stage cervical cancer or treated/biochemically-stable organ-confined prostate cancer) Any patient with severe diarrhoea (defined as ≥grade 3 diarrhoea despite maximum supportive measures and exclusion of underlying infection)

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be randomised to each of the treatments 1:1
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 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: 350 mg flat dose, IV over 2 hours, day 1 5-FU 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 standard practice)) | Drug: FOLFOX-A<br>* Patients will recieve nab-paclitaxel, oxaliplatin, Folinic Acid and 5-FU in a 14 day cycle<br>Drug: G-CSF<br>* Patients in the FOLFOX-A arm will also receive daily G-CSF as primary prophylaxis for all cycles. This will be given as per local site policy for 14 day chemotherapy regimens<br>|
| Active Comparator: Abraxane and Gemcitabine<br>nab-paclitaxel: 125 mg/m2 IV over 30 minutes, day 1, 8, and 15 (administered first) Gemcitabine 1000 mg/m2 IV over 30 minutes on days 1, 8, and 15 (immediately following nab-paclitaxel) | Drug: Gemcitabe and Abraxane<br>* Patients will receive gemcitabine and nab-paclitaxel 3 weeks out of 4<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression free survival as measured froim the date of randomisation to progression or death (from any cause) | At time of progression (estimated to be between 5 and 7.5 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ojective Response Rate | Based on RECIST version 1.1 | Measured every 8 weeks by CT scan (most patients will received 3-4 CT scans over 24-32 weeks)) | 
| Overall Survival | Survival will be measured from the date of randomisation and include all caused of death | From date of randomisation until date of death from any cause. Most patients with metastatic pancreatic cancer will die within 6-9 months from diagnosis | 
| Safety and Tolerability of FOLFOX-A treatment | Using NCI-CTCAE version 4.03 | At every chemotherapy visit (every 2 weeks) - and at end of treatment visit (within 30 days of completing chemotherapy). Chemotherapy will continue until progression (estimated at between 5-7.5 months) | 
| Safety and Tolerability of AG treatment | Using NCI-CTCAE version 4.03 | At every chemotherapy visit (3 weeks out of every 4) - and at end of treatment visit (within 30 days of completing chemotherapy). Chemotherapy will continue until progression (estimated at between 5-7.5 months) | 
| Quality of Life (EORTC QLQ-C30) | patients will complete the EORTC QLQ-C30 questionnaire at clinic | Every 8 weeks while on treatment, at end of treatment visit, which will take place within 30 days of completing treatment, and at follow-up visits (6, 9, 12, 18, 24, 36, 48 and 60 months post randomisation). | 
| Peripheral Neuropathy | Measured by GOG-NTX4 | Every 4 weeks while on treatment, at end of treatment visit and at follow-up visits (6, 9, 12, 18, 24, 36, 48 and 60 months post randomisation). | 
| Health Economics as defined to hospital resource use i.e how many nights the patient has spent in hospital and how may times they have attended hospital since the last time they were seen | Resource use will be assessed during the course of the study | At each study visit. Patient will be followed up for up to 5 years post randomistation (6, 9, 12, 18, 24, 36, 48 and 60 months post randomisation). | 
| Biomarker Discovery and Development | This will be ongoing as part of the study. This will use trial material but will be extrinsic to the trials outcomes. The biomarker will be specificed and locked down before the first interim analysis that is biomarker dependent | Ongoing during study. Recruitment will take 46 months and patients will be followed-up for up to 5 years post randomisation | 
| Quality of Life (EORTC QLQ-PAN26) | patients will complete the EORTC QLQ-PAN26 questionnaire at clinic | Every 8 weeks while on treatment, at end of treatment visit, which will take place within 30 days of completing treatment, and at follow-up visits (6, 9, 12, 18, 24, 36, 48 and 60 months post randomisation). | 
| Quality of Life (EQ-5D-5L) | patients will complete the EQ-5D-5L questionnaire at clinic | Every 8 weeks while on treatment, at end of treatment visit, which will take place within 30 days of completing treatment, and at follow-up visits (6, 9, 12, 18, 24, 36, 48 and 60 months post randomisation). |