Systemic Therapy and Chemoradiation in Advanced Localised Pancreatic Cancer - 2 (SCALOP-2)

A Multi-centre Randomised Study of Induction Chemotherapy Followed by Capecitabine (+/-Nelfinavir) With High or Standard Dose Radiotherapy for Locally Advanced Non-metastatic Pancreatic Cancer

This study will evaluate the role of increasing radiotherapy dose and addition of nelfinavir to chemoradiotherapy (CRT) in patients with inoperable pancreatic cancer that has not spread beyond the pancreas.

Currently in the United Kingdom (UK), either chemotherapy alone or chemotherapy followed by CRT can be used in the management of inoperable pancreatic cancer that has not spread. CRT consists of 25-30 radiotherapy treatments in combination with chemotherapy. Although this treatment is effective in controlling local symptoms and slowing down the pace of cancer, in most cases it is unable to shrink it enough to make it operable. Some of the reasons for this could be the lack of oxygen and lack of blood flow within the tumour making it resistant to the effects of CRT. This study will investigate whether increasing the dose of radiotherapy, or increasing the oxygen and blood supply to the tumour by giving nelfinavir, or a combination of both, can improve outcomes. We also want to know what the additional toxicities from such intensive approaches are.

All participants will initially receive 12 weeks of chemotherapy, and those with stable or responding disease will receive further study treatment. The treatment allocation to 1 of the 5 options outlined below will be done at random by computer and neither the doctor nor the patient can choose the treatment option. The process of randomisation ensures that all treatment arms are equally balanced in terms of patient and tumour characteristics, and to reduce the possibility of bias.

The study will consist of 2 stages. In the 1st stage we aim to find the right dose of nelfinavir to combine with CRT, and this will require around 27 participants of whom up to 18 will receive nelfinavir together with CRT. In the 2nd stage, we want to find out the benefits of this approach over and above standard treatments and therefore we will recruit the order of 262 participants and allocate 170 to 1 of the 5 following treatment arms:

Arm A: Nelfinavir together with CRT Arm B: CRT (without nelfinavir) Arm C: Nelfinavir together with CRT (but using a higher than conventional dose of radiotherapy) Arm D: CRT without nelfinavir (but using a higher than conventional dose of radiotherapy) Arm E: Chemotherapy alone (without radiotherapy) Participants who are ineligible or refuse randomisation will be treated as per local standard but will remain in the study for follow up at 26, 39 and 52 weeks. Their data will contribute to an Overall Survival (OS) analysis.

Study Overview

• Status: Unknown
• Conditions: Pancreatic Neoplasms (Locally Advanced Non-metastatic)
• Intervention / Treatment: Drug: nab-paclitaxel; Radiation: 50.4Gy in 28#; Drug: Nelfinavir; Drug: Capecitabine; Drug: Gemcitabine; Radiation: 60Gy in 30#

• Study Type: Interventional
• Enrollment (Anticipated): 289
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Rachel Shaw; Phone Number: 01865 617078; Email: octo-scalop-2@oncology.ox.ac.uk

Study Locations

• United Kingdom
  • Bristol, United Kingdom, BS2 8ED
    • Recruiting
    • Bristol Haematoloy and Oncology Centre
    • Principal Investigator: Dr Stephen Falk
  • Cambridge, United Kingdom, CB2 0QQ
    • Recruiting
    • Addenbrookes Hospital
    • Principal Investigator: Dr Thankamma Ajithkumar
  • Cardiff, United Kingdom, CF14 2TL
    • Recruiting
    • Velindre Cancer Centre
    • Principal Investigator: Dr Seema Arif, Dr
  • Cottingham, United Kingdom, HU16 5JQ
    • Recruiting
    • Castle Hill Hospital
    • Principal Investigator: Dr Rajarshi Roy
  • Coventry, United Kingdom, CV2 2DX
    • Recruiting
    • University Hospital
    • Principal Investigator: Dr Martin Scott-Brown
  • Guildford, United Kingdom, GU2 7XX
    • Recruiting
    • Royal Surrey County Hospital
    • Principal Investigator: Dr Sebastian Cummins
  • Leeds, United Kingdom
    • Recruiting
    • St James' Hospital
    • Principal Investigator: Dr Ganesh Radhakrishna
  • London, United Kingdom, NW1 2BU
    • Not yet recruiting
    • University College London Hospital
    • Principal Investigator: Dr John Bridgewater
  • London, United Kingdom, NW3 2PF
    • Recruiting
    • Royal Free Hospital
    • Principal Investigator: Dr Roopinder Gillmore
  • London, United Kingdom, W12 0HS
    • Not yet recruiting
    • Hammersmith Hospital
    • Principal Investigator: Dr Harpreet Wasan
  • Oxfordshire
    • Headington, Oxfordshire, United Kingdom, OX3 7LE
      • Recruiting
      • Oxford University Hospitals, Churchill Cancer Centre
      • Principal Investigator: Dr Somnath Mukherjee

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. 1. Aged 18 years or over
2. Histologically or cytologically proven carcinoma of the pancreas

3. Locally advanced, non-metastatic inoperable disease as per NCCN criteria (APPENDIX 2). The following types of interventions are allowed:

   1. Palliative bypass procedure
   2. Common bile duct stenting
4. Primary pancreatic lesion 6 cm or less in diameter (taken from scan results)
5. WHO PS 0-1 (APPENDIX 1)
6. Adequate haematological function: neutrophils ≥1.5 x 109/L, platelets ≥100 x 109/L and haemoglobin ≥100g/L

7. Adequate liver function tests:

   1. Serum bilirubin ≤1.5 x ULN. In participants who have had a recent biliary drain and whose bilirubin is improving, a value of ≤3 x ULN is acceptable, however treatment should not start unless Bilirubin is ≤1.5 x ULN.
   2. AST and/or ALT ≤ 3 x ULN.
8. Adequate renal function (GFR ≥ 50ml/min (Cockcroft & Gault - APPENDIX 3))
9. Written informed consent obtained
10. Women of child-bearing potential must have negative serum or urine pregnancy test within 14 days prior to registration, must agree to use a highly effective contraception method during GEMABX treatment and for 30 days after last administration of GEMABX and to use an acceptable contraception method during chemoradiotherapy and for 6 months after completion of all treatment.
11. Male patients must be surgically sterile or must agree to use a condom during GEMABX treatment and for 90 days after last administration of GEMABX, and to use a condom during chemoradiotherapy and for three months after completion of chemoradiotherapy.

Exclusion criteria:

1. Primary resectable cancer of the pancreas.
2. Distant metastases
3. Pregnant or breast-feeding patients.
4. Any evidence of severe uncontrolled systemic diseases including uncontrolled coronary artery disease, myocardial infarction or stroke within the last 6 months, any major systemic or psychiatric co-morbidities or any other considerations that the PI judges might impact on patient safety or protocol compliance and achievement of the study aims.

5. Previous malignancies in the preceding 3 years except for:

   1. In situ cancer of the uterine cervix
   2. Adequately treated basal cell skin carcinoma
   3. Adequately treated early stage non-pancreatic malignancy in complete remission for at least 3 years
6. Renal abnormalities including adult polycystic kidney disease or hydronephrosis or ipsilateral single kidney (i.e. functioning right kidney for head tumours; left kidney for tail tumours) that may preclude upper abdominal radiotherapy without damaging functional kidneys.
7. Previous RT to upper abdomen
8. Recurrent cancer following definitive pancreatic surgery
9. Lymphoma or neuroendocrine tumours of the pancreas
10. Known haemophilia A and B, chronic hepatitis type B or C.
11. Other experimental treatment 6 weeks or less prior to registration into this study (including chemothera¬py and immunotherapy).
12. Known hypersensitivity to any of the IMPs or any of their excipients.
13. Known dihydropyrimidine dehydrogenase (DPD) deficiency
14. Known galactose intolerance, Lapp-lactose deficiency or glucose-galactose malabsorption
15. History of severe unexpected reaction to fluoropyrimidine therapies

16. If the following concomitant medications cannot be discontinued temporarily during the CRT phase then the patients cannot enter the trial:

    1. Sorivudine and analogues e.g. brivudine
    2. Methotrexate.
    3. Allopurinol and dipyridamole
17. Known HIV positive disease (but routine screening for HIV is not required)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; 12 weeks (3 cycles) of induction Gemcitabine and Nab-paclitaxel (GEMABX) chemotherapy then 1 cycle of GEMABX* whilst radiotherapy (RT) planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 50.4 Grays (Gy) in 28# *1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.	Drug: nab-paclitaxel; Abraxane is a proprietary solvent-free, protein-stabilized formulation of paclitaxel comprised of paclitaxel and human albumin in a noncrystalline amorphous state; Other Names: Abraxane; Radiation: 50.4Gy in 28#; Drug: Nelfinavir; VIRACEPT® (nelfinavir mesylate) is an inhibitor of the human immunodeficiency virus (HIV) protease.; Other Names: Viracept; Drug: Capecitabine; Given in combination with gemcitabine, known as GemCap.; Drug: Gemcitabine; Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas. It is administered as an infusion; Other Names: GEMZAR
Experimental: Arm B; 12 weeks (3 cycles) of induction GEMABX chemotherapy then 1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + 50.4Gy in 28# *1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.	Drug: nab-paclitaxel; Abraxane is a proprietary solvent-free, protein-stabilized formulation of paclitaxel comprised of paclitaxel and human albumin in a noncrystalline amorphous state; Other Names: Abraxane; Radiation: 50.4Gy in 28#; Drug: Capecitabine; Given in combination with gemcitabine, known as GemCap.; Drug: Gemcitabine; Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas. It is administered as an infusion; Other Names: GEMZAR
Experimental: Arm C; 12 weeks (3 cycles) of induction GEMABX chemotherapy then 1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + Nelfinavir** + 60Gy in 30# *1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15	Drug: nab-paclitaxel; Abraxane is a proprietary solvent-free, protein-stabilized formulation of paclitaxel comprised of paclitaxel and human albumin in a noncrystalline amorphous state; Other Names: Abraxane; Drug: Nelfinavir; VIRACEPT® (nelfinavir mesylate) is an inhibitor of the human immunodeficiency virus (HIV) protease.; Other Names: Viracept; Drug: Gemcitabine; Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas. It is administered as an infusion; Other Names: GEMZAR; Radiation: 60Gy in 30#
Experimental: Arm D; 12 weeks (3 cycles) of induction GEMABX chemotherapy then 1 cycle of GEMABX* whilst RT planned then capecitabine (830mg/m2 oral bd) + 60Gy in 30# *1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.	Drug: nab-paclitaxel; Abraxane is a proprietary solvent-free, protein-stabilized formulation of paclitaxel comprised of paclitaxel and human albumin in a noncrystalline amorphous state; Other Names: Abraxane; Drug: Gemcitabine; Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas. It is administered as an infusion; Other Names: GEMZAR; Radiation: 60Gy in 30#
Experimental: Arm E; 6 cycles of GEMABX* *1 cycle GEMABX = 28 day cycle of intravenous Abraxane 125mg/m2 followed by gemcitabine 1000mg/m2 on day 1, 8 and 15.	Drug: nab-paclitaxel; Abraxane is a proprietary solvent-free, protein-stabilized formulation of paclitaxel comprised of paclitaxel and human albumin in a noncrystalline amorphous state; Other Names: Abraxane; Drug: Gemcitabine; Gemcitabine is indicated for treatment of patients with locally advanced or metastatic adenocarcinoma of the pancreas. It is administered as an infusion; Other Names: GEMZAR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression free survival	12 months
Overall survival	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity	Common Toxicity Criteria for Adverse Effects (CTCAE) v 4.02	12 months
Quality of life	European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires (QLQ) - C30 and PAN26 for pancreatic cancer.	12 months

Collaborators and Investigators

• Sponsor: University of Oxford
• Collaborators: Cancer Research UK; Celgene
• Investigators: Principal Investigator: Somnath Mukherjee, MD, FRCP, FRCR, somnath.mukherjee@oncology.ox.ac.uk

Publications and helpful links

General Publications

• Strauss VY, Shaw R, Virdee PS, Hurt CN, Ward E, Tranter B, Patel N, Bridgewater J, Parsons P, Radhakrishna G, O'Neill E, Sebag-Montefiore D, Hawkins M, Corrie PG, Maughan T, Mukherjee S. Study protocol: a multi-centre randomised study of induction chemotherapy followed by capecitabine +/- nelfinavir with high- or standard-dose radiotherapy for locally advanced pancreatic cancer (SCALOP-2). BMC Cancer. 2019 Feb 4;19(1):121. doi: 10.1186/s12885-019-5307-z.

Study record dates

Study Major Dates

• Study Start: March 1, 2016
• Primary Completion (Anticipated): August 1, 2020
• Study Completion (Anticipated): August 1, 2020

Study Registration Dates

• First Submitted: December 23, 2013
• First Submitted That Met QC Criteria: December 30, 2013
• First Posted (Estimate): December 31, 2013

Study Record Updates

• Last Update Posted (Actual): October 16, 2018
• Last Update Submitted That Met QC Criteria: October 15, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: capecitabine; radiotherapy; gemcitabine; chemoradiotherapy; abraxane; nelfinavir
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protease Inhibitors; Antineoplastic Agents, Phytogenic; HIV Protease Inhibitors; Viral Protease Inhibitors; Gemcitabine; Paclitaxel; Capecitabine; Nelfinavir
• Other Study ID Numbers: OCTO_063