SBRT

SPARC: A Phase I trial of pre-operative, margin intensive, stereotactic body radiation therapy (SBRT) for previously untreated borderline resectable pancreatic cancer (BRPC). ,1,5

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Maria A. Hawkins* , Elizabeth Ward , Daniel Holyoake , Claire Hamill , Lang’o Odondi , Victoria Strauss , Maxwell Robinson , 2 2 3,4 4 1,5 Derek Grose , David McIntosh , David Sebag-Montefiore , Ganesh Radhakrishna , Somnath Mukherjee *Chief Investigator; 1 CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK; 2 The Beatson West of Scotland Cancer Centre, Glasgow, UK; 3 The University of Leeds, Cancer Research UK Leeds Centre, St James’s University Hospital, Leeds, UK; 4 The St James’s Institute of Oncology, St James’s University Hospital, Leeds, UK; 5 The Churchill Hospital, Oxford, UK; 6 Oncology Clinical Trials Office (OCTO), part of Oxford Clinical Trials and Research Unit (OCTRU), University of Oxford, UK; 7 Centre for Statistics in Medicine (CSM), part of Oxford Clinical Trials and Research Unit (OCTRU), University of Oxford, UK.

1. Background Standard therapy for BRPC in the UK is surgery with adjuvant chemotherapy, but rates of resection with clear margins (R0) are unsatisfactory and overall survival remains poor. Meta-analysis of single-arm studies shows the potential of neo-adjuvant chemoradiotherapy [1] but the relative radio-resistance of pancreatic cancer means the efficacy of conventional dose schedules is limited. SBRT achieves sufficient accuracy and precision to enable pre-operative margin-intensive dose escalation with the goal of increasing rates of R0 resection and local disease control. The concept of margin-intensive therapy is novel, and aims to deliver a higher radiation dose to the at risk surgical margin, which is usually around the main vessels in the retroperitoneum, while limiting toxicity to organs at risk. The use of a simultaneously integrated boost will facilitate sparing of the normal tissues as only the high risk region will be targeted.

2. Aim and Design Aim: to establish the maximum tolerated dose (MTD) for margin-intensive SBRT before resection of BRPC. SPARC will also examine clinical outcomes, late SBRT toxicities, efficacy and safety of SBRT delivered pre-operatively in the management of pancreatic cancer. Intervention: 5-fraction stereotactic body radiation therapy Main Inclusion Criteria: Eligible patients will be fit and suitable for surgical resection, and have histologically or cytologically proven previously untreated pancreatic cancer defined as borderline-resectable as per NCCN criteria [2] defined by CT +/-MRI +/- PET within 28 (+/-7) days prior to trial entry. Design: “rolling-six” single-arm study. To determine the MTD, it is anticipated that up to 24 patients will be required. Radiotherapy will be delivered in 5 daily fractions and surgery will take place 5-6 weeks after radiotherapy. MTD: The highest dose at which no more than 1 of 6 patients or 0 of 3 patients experience a Dose Limiting Toxicity (DLT). Figure 1: Study Schema

4. Study Status Target recruitment: maximum of 24 evaluable patients over a 24 month period Current Recruitment: 0 patients (as of 23 Sep 2015) Sites open to recruitment:  The Churchill Hospital, Oxford University Hospitals NHS Trust (PI Prof. Maria A. Hawkins); open 17Apr2015  The Beatson West of Scotland Cancer Centre, NHS Greater Glasgow & Clyde (PI Dr Derek Grose); open 21Aug2015 Sites in set-up:  Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust (PI Dr Ganesh Radhakrishna); target opening date 06Nov2015

5. Dose Limiting Toxicities (DLTs) DLTs are defined as the following list of SBRT treatment related adverse events (AEs) (defined according to CTCAEv4.03) seen in the period from starting SBRT treatment to the visit one month post-surgery. 1. ≥ grade 3 upper gastro-intestinal bleeding. 2. ≥ grade 4 uncontrolled nausea/vomiting after 48 hours of standard treatment 3. ≥ grade 4 pancreatitis not stent related. 4. Interruption of SBRT for > 1 week due to SBRT related AEs. 5. Grade 4 vascular events: SMV thrombosis, bowel ischemia due to SMA arteritis/ stenosis, friable vessels. 6. Other AEs that the Trial Management Group (TMG) agrees to be dose limiting and possibly related to SBRT such as ≥ grade 3 gastrointestinal fistula ≥ 30 days after surgery.

6. Statistical Considerations Evaluable Patient: a patient who has received at least 1 fraction of SBRT and experiences a DLT; a patient who has received at least 4 fractions of SBRT and is assessed at one month post-surgery or a similar time (one month after evaluation in week 3 post-SBRT), if no surgery. All evaluable patients will be included in the safety analysis. Patient Replacement: patients who are not evaluable for the primary endpoint will be replaced.

A maximum of 4 SBRT dose levels will be investigated to determine the MTD Table 1: Radiotherapy dose escalation levels

Patient numbers are based on the primary endpoint of establishing MTD. Last Patient Last Visit will be 6 months post-surgery end of study visit. This will be followed by a noninterventional phase of follow-up, which will continue for a minimum of 2 years after D1 SBRT for the last patient, or until all participants have died, whichever comes first.

7. Samples and Radiotherapy Quality Assurance (RTQA) Research blood samples: Pre-SBRT, day 3 and day 5 SBRT and 1 month post-SBRT. Quantitative RTPCR performed at the CRUK/MRC Oxford Institute for Radiation Oncology will analyse the mRNA levels of Interferon-Stimulated genes. A panel of immunological tests performed at The University of Leeds will be used to examine innate and adaptive immune responses following SBRT.

*BED 10 biological equivalent dose for acute reacting tissues (α/β=10) EQD2 = dose in 2 Gy fractions biologically equivalent to dose D given in fractions of size d, in units of Gray

Translational work will involve exploratory analyses of the cytological and humoral immunological responses to SBRT in pancreatic cancer. A potential relationship between imaging and pathology will be investigated. Radiotherapy Quality Assurance of target definition and radiotherapy planning is enforced with pre-trial test cases and on-trial review.

3. Endpoints Primary Endpoint 

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Maximum tolerated dose (MTD) Secondary Endpoints Definitive resection rate R0/R1/R2 resection margin rates Rate of pathological complete response Any late GI AE/other AE > grade 2 CTCAE v4.03 Overall survival and progression free survival at 12 and 24 months post D1 SBRT Tertiary/Exploratory Endpoints Imaging analysis before and during radiotherapy & relationship to pathology findings

Pre-trial RTQA : centre questionnaire/process document; test case for delineation and test planning case with contours provided. On-trial RTQA: rapid review of contours and plans for first 3 patients at each centre.

8. References 1. Gillen, S., et al., Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med, 2010. 7(4): p. e1000267. 2. National Comprehensive Cancer Network. Pancreatic adenocarcinoma. (Version 2.2015). http:// www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf Accessed 14th July 2015

7. Acknowledgements Funder: This work is supported by CRUK [grant number C43735/A18787] Prof Maria A. Hawkins is supported by MRC [grant number MC_PC_12001/2] Trial Management: Oncology Clinical Trials Office (OCTO) and Statistical Input: Centre for Statistics in Medicine (CSM); both part of Oxford Clinical Trials Research Unit (OCTRU), a UKCRC and NCRI registered Clinical Trials Unit Radiotherapy Quality Assurance: Mr Maxwell Robinson, Prof. Maria A. Hawkins, Dr. Daniel Holyoake, Dr. Lisa Durrant, Dr. Somnath Mukherjee Translational Work: Prof Alan Melcher, The University of Leeds; Dr. Emmanouil Fokas, CRUK/MRC Oxford Institute for Radiation Oncology