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

Phase 2

Terminated

• Conditions: Neoplasms Pancreatic
• Interventions: Drug: AG; Drug: FOLFOX-A

• Registration Number: NCT04176952
• Lead Sponsor: Judith Dixon-Hughes

Brief Summary

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

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 Timeline

• Study Start: 2019-03-05
• Study First Submitted: 2019-10-28
• Study First Submitted QC: 2019-11-21
• Study First Posted: 2019-11-26
• Primary Completion: 2021-08-19
• Study Completion: 2021-08-19
• Status Verified: 2022-05
• Last Update Submitted: 2022-05-17
• Last Update Posted: 2022-05-24

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 31

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Abraxane and Gemcitabine	AG	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).
FOLFOX-A	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).

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
Response post neo-adjuvant chemotherapy	CT scan will be performed at baseline and then post neo-adjuvant chemotherapy (approximately 3 months later)	CT scans will be reported to RECIST 1.1 and best response will be evaluated
R0 rate post surgery	Post surgery which will be approximately 4 months post registration	R0 rate will be assessed post surgery
Safety and tolerability of study drugs: NCI CTCAE 4.03	Assessed at every clinic visit during treatment, for approximately 3 months post registration	Safety and tolerability will be assessed as per NCI CTCAE 4.03
Quality of life assessed by EORTC QLQ-PAN26	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 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)
Proving liquid biopsies can be used to define patient subgroups	From date of registration to date of surgery. On average 4 months after registration	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
College of American Pathologists tumour regression grade	Post surgery which will be approximately 4 months post registration	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
Safety and tolerability of chemoradiotherapy: 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	Safety and tolerability of chemoradiotherapy will be assessed as per NCI CTCAE 4.03
Surgical complication rate	Assessed post surgery, approximately 4 months post registration	Rate of surgical complication as assessed by NCI CTCAE 4.03
Overall survival	From date of registration until date of death assessed for up to 5 years post registration	Overall survival will be assessed in all patients
Disease free survival	from date of registration until date of disease recurrence assessed for at least 24 months post registration	Disease free survival will be assessed at every follow up visit
Neurotoxicity	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	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)
Health Economics	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	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)
Quality of life assessed by EORTC QLQ-C30	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 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

Trial Locations

Locations (3)

Western General; 🇬🇧 Edinburgh, United Kingdom

Beatson West of Scotland Cancer Centre; 🇬🇧 Glasgow, United Kingdom

Royal Free Hospital; 🇬🇧 London, United Kingdom