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
Chief Investigator: Prof Somnath Mukherjee
Sponsor: University of Oxford
ClinicalTrials.gov Number: NCT02024009
EudraCT number: 2013-004968-56
SCALOP-2 Trial Office
Stage 1: Rolling six dose finding safety run-in that will determine the Maximum Tolerated Dose (MTD) of nelfinavir in combination with capecitabine and 50.4Gy in 28 fractions of RT and to establish the dose to take forward to Stage 2.
Stage 2: Open label, randomised clinical trial with 2 x 2 factorial + observation cohort. This commenced following successful completion of Stage 1 (safety run-in). The final dose of nelfinavir used in the randomised phase was determined in the safety run‐in.
Patients with locally advanced, non-metastatic, inoperable pancreatic cancer
- Stage 1: 27 patients enrolled (16 treated with nelfinavir)
- Stage 2: 168 patients enrolled (96 randomised)
Stage 1: Completed - closed to recruitment 22Jun2017
Stage 2: Closed to recruitment 12May2020
Stage 2 sites in recruitment:
- Aberdeen Royal Infirmary
- Addenbrookes, Cambridge
- Belfast City Hospital, Northern Ireland
- Bristol Haematology and Oncology Centre
- Castle Hill Cancer Centre, Hull
- Churchill Hospital, Oxford
- City Hospital, Nottingham
- Clatterbridge Cancer Centre, Wirral
- Colchester Hospital
- Derriford Hospital, Plymouth
- Hammersmith Hospital, London
- Milton Keynes Hospital
- Norfolk and Norwich University Hospitals
- North Middlesex Hospital
- Royal Free Hospital, London
- Royal Surrey Hospital, Guilford
- St James University Hospital, Leeds
- The Christie Hospital, Manchester
- United Lincolnshire Hospitals NHS Trust
- University College London, London
- University Hospital, Coventry
- Velindre Cancer Centre, Cardiff
- Weston Park Hospital, Sheffield
“• Randomisation of new patients to arms A & C closed on 26Feb2020. Randomisation to arms B & D will continue until at least 96 patients have been randomised to arms A-D.
• Arm E closed in November 2019”
Participants meeting the following criteria may be included in the trial:
- Aged 18 years or over
- Histologically or cytologically proven carcinoma of the pancreas
- Locally advanced, non-metastatic inoperable disease as per NCCN criteria. The following types of interventions are allowed:
- Palliative bypass procedure
- Common bile duct stenting
- Primary pancreatic lesion 6 cm or less in diameter (taken from scan results)
- World Health Organisation Performance Status 0-1
- Adequate haematological function: neutrophils ≥1.5 x 109/L, platelets ≥100 x 109/L
- Adequate liver function tests:
- 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.
- AST and/or ALT ≤3 x ULN.
- Adequate renal function (GFR ≥ 40ml/min (using a validated creatinine clearance calculation (e.g. Cockcroft & -Gault , Wright formula, or as per local standard).
- Written informed consent obtained
- Women of child-bearing potential must have negative serum or urine pregnancy test within 14 days prior to registration and must agree to use an adequate contraception method (defined as barrier methods in conjunction with spermicide, approved contraceptive implants, long-term injectable contraception or intrauterine hormonal devices) during GEMABX treatment and for 6 months after the last administration of GEMABX, as well as during chemoradiotherapy and for 6 months after completion of all treatment.
- Male patients must be surgically sterile or must agree to use a condom during GEMABX treatment and for 6 months after last administration of GEMABX, and to use a condom during chemoradiotherapy and for three months after completion of chemoradiotherapy or, whichever date comes last.
If any of the following criteria apply, patients cannot be included in the trial:
- Primary resectable cancer of the pancreas.
- Distant metastases
- Pregnant or breast-feeding patients.
- 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.
- Previous malignancies in the preceding 3 years except for:
- In situ cancer of the uterine cervix
- Adequately treated basal cell skin carcinoma
- Adequately treated early stage non-pancreatic malignancy in complete remission for at least 3 years
- 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.
- Previous RT to upper abdomen
- Recurrent cancer following definitive pancreatic surgery
- Lymphoma or neuroendocrine tumours of the pancreas
- Known haemophilia A and B, chronic hepatitis type B or C.
- Other experimental treatment 6 weeks or less prior to registration into this study (including chemotherapy and immunotherapy).
- Known hypersensitivity to any of the IMPs or any of their excipients.
- Known dihydropyrimidine dehydrogenase (DPD) deficiency
- Known galactose intolerance, Lapp-lactose deficiency or glucose-galactose malabsorption
- History of severe unexpected reaction to fluoropyrimidine therapies
- If the following concomitant medications cannot be discontinued temporarily during the CRT phase then the patients cannot enter the trial, as they interact with capecitabine:
- Sorivudineand analogues e.g. brivudine
- Allopurinol and dipyridamole
- Known HIV positive disease (but routine screening for HIV is not required)
The objective of Stage 1 was to determine the Maximum Tolerated Dose (MTD) of nelfinavir to be administered alongside chemoradiotherapy.
The established MTD of nelfinavir is 1250mg (BD). This dose will be taken forward into Stage 2.
- Does increasing radiotherapy dose schedule from 50.4Gy (in 28 fractions) to 60Gy (in 30 fractions) improve overall survival (OS) in LANPC?
- Does the addition of nelfinavir to CRT improve progression free survival (PFS) in LANPC?
STAGE 2: SECONDARY OBJECTIVES:
- To evaluate safety, overall survival, resection rates and compliance with the addition of nelfinavir to CRT
- To study the effect of increasing radiotherapy dose schedule on progression free survival, 12-month overall survival rate, resection rates, and safety
- To assess the quality of life for each arm.
- To measure CA19-9 level, 1-year local control rate for each arm
- To determine disease response rate for each arm
Stage 2: Exploratory objective
To evaluate the proportion of patients receiving subsequent treatment and median time to receive subsequent systematic treatment for each arm.
First site open to recruitment: 08 March 2016
Stage 1 accrual completion: 22 June 2017
Planned Stage 2 accrual completion: 31 May 2020
Planned trial duration: 5 years
Funding and Acknowledgements:
This work is supported by CRUK [grant number C28958/A17139 Application Title: CRUK/07/040: SCALOP-2]
Celgene are providing a grant and free nab-paclitaxel to support the study.
Radiotherapy Trials Quality Assurance provided by NCRI Radiotherapy Trials Quality Assurance Team (RTTQA)
Trial Management: Oncology Clinical Trials Office & Statistical Input: Centre for Statistics in Medicine both part of Oxford Clinical Trials Research Unit (OCTRU), a UKCRC and NCRI registered Clinical Trials.
SCALOP-2 Trial Office (OCTO)
General Enquires: Tel +44 (0)1865 617078