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

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

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

Study Overview

• Status: Terminated
• Conditions: Neoplasms Pancreatic
• Intervention / Treatment: Drug: FOLFOX-A; Drug: AG

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom
    • Western General
  • Glasgow, United Kingdom
    • Beatson West of Scotland Cancer Centre
  • London, United Kingdom
    • Royal Free Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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)
2. Signed informed consent given for PRIMUS 002 study
3. Age ≥ 16 years
4. Resectable or borderline resectable pancreatic cancer as defined by National Comprehensive Cancer Network criteria following discussion at the Multi Disciplinary Team
5. Measurable Disease as per RECIST 1.1
6. Histological or cytologically proven pancreatic ductal adenocarcinoma (including variants)
7. Able to undergo biliary drainage using a covered or partially covered self-expanding metal stent if jaundiced
8. Eastern Cooperative Oncology Group performance status 0 and 1

9. Adequate liver/bone marrow function as defined by:

   1. Neutrophils (ANC) ≥ 1.5 x 109/l
   2. Platelets ≥ 100 x 109/l
   3. Haemoglobin ≥ 9.0g/dL
   4. White Blood Cells (WBC) ≥ 3 x 109/l
   5. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) unless bilirubin rise is due to Gilbert's syndrome
   6. Aspartate transaminase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN (or <5 x ULN in the presence of liver metastases)
   7. Estimated creatinine clearance ≥ 60 mL/min (as calculated by Cockcroft and Gault or Wright formula or measured by EDTA clearance)
10. 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
11. 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.
12. Able to comply with protocol requirements and deemed fit for surgical resection, chemotherapy and CRT

Exclusion Criteria:

1. Distant metastatic disease
2. 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
3. Prior chemotherapy or CRT for pancreatic cancer
4. Known hypersensitivity for any component of any study drug
5. Active infection including Herpes Zoster and chickenpox
6. Uncontrolled congestive heart failure (CHF), or history of myocardial ischemia (MI), unstable angina, stroke, or transient ischemia within previous 6 months.
7. Serious medical or psychological condition precluding neo-adjuvant treatment and surgical resection
8. New York Heart Association Classification Grade III or IV
9. Liver cirrhosis (except for Child-Pugh A)
10. Major surgery within 28 days prior to trial entry
11. 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
12. Any patient with severe diarrhoea (defined as ≥grade 3 diarrhoea despite maximum supportive measures and exclusion of underlying infection)
13. Patients with known malabsorption
14. Patients with known or suspected dihydropyrimidine dehydrogenase (DPD) deficiency
15. Grade ≥ 2 peripheral neuropathy
16. Administration of any investigational drug within 28 days or 5 half-lives, whichever is longer, prior to receiving the first dose of trial treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FOLFOX-A; 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; 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.)
Active Comparator: Abraxane and Gemcitabine; 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; 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).

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Judith Dixon-Hughes
• Collaborators: NHS Greater Glasgow and Clyde; University of Glasgow
• Investigators: Principal Investigator: Derek Grose, NHS Greater Glasgow and Clyde

Study record dates

Study Major Dates

• Study Start (Actual): March 5, 2019
• Primary Completion (Actual): August 19, 2021
• Study Completion (Actual): August 19, 2021

Study Registration Dates

• First Submitted: October 28, 2019
• First Submitted That Met QC Criteria: November 21, 2019
• First Posted (Actual): November 26, 2019

Study Record Updates

• Last Update Posted (Actual): May 24, 2022
• Last Update Submitted That Met QC Criteria: May 17, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: PRIMUS0022016

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Clinical data will be made available on request once clinical study report has been written and primary publication accepted by peer reviewed journal
• IPD Sharing Time Frame: Once clinical study report has been written and primary publication accepted by peer reviewed journal
• IPD Sharing Access Criteria: On request to trial management group
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No