Clinical Trials Update 2013

Clinical Trials Update 2013

Clinical Trials Update 2013 Dear NET colleagues The mission of the NET subgroup is, through collaboration, to develop and participate in practice-changing clinical studies to improve outcomes for patients with neuroendocrine tumours; linking clinical research with basic science, industry partners, and patient advocacy groups and charities. The past year has seen a change of Chair and review of the subgroup membership. In the pages that follow, you will find a summary of ongoing studies (either open to recruitment; or closed to recruitment, but still in follow-up) as well as studies in advanced stages of planning and due to open contact details of investigators are provided in order to enhance clinician and patient access. The UK is increasingly seen as an important contributor to national and international NET studies; including an enhanced profile with industry through excellent recruitment (e.g. COOPERATE-2, RADIANT-4 and BEZ235 2201 studies). Well done and thank you to all investigators. In addition, translational research in NETs is being developed alongside the clinical portfolio (TRANSNET group; Chair: Tim Meyer), with the aim of opening translational studies addressing the role of imaging, pathology and biochemistry as potential biomarkers in NETs; the first of these (CALMNET) is due to open imminently. A number of pilot studies will be funded in 2014 following a recent call for proposals for NET Patient Foundation-funded grants. The future strategy of the group is to expand the current portfolio of studies from predominantly oncology-based studies in advanced disease, to include surgical studies (including adjuvant studies), and studies from non-oncology specialties (e.g. gastroenterology, interventional radiology, endocrinology) relevant to patients with NETs; we welcome any enthusiastic investigators to propose ideas or join the group. Best wishes for your respective research activities in 2014. Prof Juan W Valle Chair NET subgroup NCRI Upper GI Clinical Studies Group Juan.valle@manchester.ac.uk

NCRI Portfolio Map: Neuroendocrine Tumours

NET Studies (in alphabetical order) BEZ235 (2401) 1 ST Line Randomized phase II study of BEZ235 or everolimus in advanced pancreatic neuroendocrine tumours NCRI ID: NCRN379; Registration: NCT01628913 Open (recruiting) Open (in follow-up) Due to be opened Inclusion/exclusion criteria and study schema Inclusion criteria Advanced (unresectable or metastatic), histologically confirmed well differentiated (low to intermediate grade) pancreatic neuroendocrine tumor (pnet) Radiological documentation of progressive disease within the last 12 months prior to randomization. Measurable disease per RECIST Version 1.0 WHO performance status 2 Exclusion criteria Previous treatment with PI3K and/or mtor pathway inhibitors Uncontrolled cardiac disease, hypertension or diabetes mellitus Gastrointestinal disease that may significantly alter the absorption of BEZ235 Immunocompromised patients (chronic treatment with systemic high dose steroids or other immunosuppressive agent) including known seropositivity for HIV Diarrhea Grade 2 Primary endpoint: PFS Secondary endpoints: safety and tolerability, RR, OS, TTF Exploratory objectives: biochemical response (changes in CgA and NSE levels) and its association with PFS, tumor tissue biomarker analysis, additional exploratory biomarkers Recruiting centres and contact details Date study open: Nov 2012 Planned accrual: Global: 140 patients; UK: 15 patients

Actual accrual: Global: 51 patients; UK: 4 patients Planned closure: Closed Oct-2012; on follow up Prof. Juan W Valle, The Christie NHS Foundation Trust, Manchester Dr. Pippa Corrie, Cambridge University Hospitals NHS Foundation Trust, Cambridge Prof. Nick Reed, Beatson Oncology Centre, Glasgow Prof. Tim Meyer, Royal Free London NHS Foundation Trust, London juan.valle@christie.nhs.uk pippa.corrie@addenbrookes.nhs.uk Nick.Reed@ggc.scot.nhs.uk t.meyer@ucl.ac.uk

BEZ235 (2201) 2 nd line A multicenter, two stage, phase II study, evaluating the efficacy of oral BEZ235 plus best supportive care (BSC) versus placebo plus BSC in the treatment of patients with advanced pancreatic neuroendocrine tumours (pnet) after failure of mtor inhibitor therapy. NCRI ID: NCRN411; Registration: NCT01658436 Open (recruiting) Open (in follow-up) Due to be opened Inclusion/exclusion criteria and study schema Inclusion criteria Advanced welldifferentiated (grade 1-2) pancreatic pnet with evidence of disease progression after previous treatment with mtor inhibitor. Measurable disease per RECIST Version 1.1 If patient is on treatment with SSA, stable dose at least 2 months prior to study start is needed. Exclusion criteria Previous treatment with any PI3K inhibitor or AKT inhibitor Discontinued prior mtor inhibitor therapy due to toxicity More than 3 prior systemic treatment regimens (including cytotoxic chemotherapy, targeted therapy, immunotherapy). Uncontrolled cardiac disease Gastrointestinal disease that may significantly alter the absorption of BEZ235 Immunocompromised patients (chronic treatment with systemic high dose steroids or other immunosuppressive agent) including known seropositivity for HIV Primary endpoint: Stage 1: Primary: PFS at 16 weeks Secondary: AEs, RR, DCR, DoR

Exploratory: correlation with biochem markers, molecular profiling, proteomic / genomic analysis Stage 2: Primary: PFS (local assessment) Secondary: AEs, RR, DCR, DoR, OS Exploratory: population PKs, correlation with biochem markers, molecular profiling, proteomic / genomic analysis Recruiting centres and contact details Date study open: Nov-2012 Planned accrual: UK: 6 patients Actual accrual: UK: 3 patients Planned closure: Stage 1 completed Sept 2013. Closed pending the interim analysis Prof. Nick Reed, Beatson Oncology Centre, Glasgow Prof. Juan W Valle, The Christie NHS Foundation Trust, Manchester Nick.Reed@ggc.scot.nhs.uk juan.valle@christie.nhs.uk

CALM-NET A Phase IV, Multicentre, Open label, Single Group Exploratory Study to Assess the Clinical Value of Enumeration of Circulating Tumour Cells (CTCs) to Predict Clinical Symptomatic Response and Progression Free Survival in Patients receiving Deep Subcutaneous Administrations of Somatuline (lanreotide) Autogel to treat the Symptoms of Functioning Midgut NeuroEndocrine Tumours (NET). EudraCT Number: 2013-002194-22 Open (recruiting) Open (in follow-up) Due to be opened Inclusion/exclusion criteria and study schema Inclusion criteria Well or moderately differentiated functioning midgut NET. The clinically appropriate treatment for the patient must primarily be monotherapy with a somatostatin analogue. Patients must have had either a positive somatostatin receptor scintigraphy result or a positive 68Gallium-DOTATATE PET imaging result. Patients must have a documented urinary or plasma 5-HIAA result within the year prior to study entry which is above the laboratory reference range. Exclusion criteria The patient has been treated with a somatostatin analogue prior to study entry, unless a washout period of at least 2 weeks for subcutaneous octreotide, or at least 6 weeks for a single dose of long acting somatostatin analogue has occurred. The patient has received interferon, chemotherapy, chemoembolisation or radionuclide therapy within 3 months prior to study entry. Primary endpoint: To assess the clinical value of enumeration of circulating tumour cells (CTCs) to predict clinical symptomatic response in patients receiving Somatuline Autogel. Secondary endpoints: Serum biomarkers and its correlation with CTC numbers. Genomic profile of CTCs and density of somatostatin receptor (SSTR) subtypes 2 and 5 on CTCs. Recruiting centres and contact details Date study open: Planned accrual: Global: 50 patients Prof. Tim Meyer, Royal Free London NHS Foundation Trust, London Dr Christos Toumpanakis, Royal Free London NHS Foundation Trust, London t.meyer@ucl.ac.uk c.toumpanakis@ucl.ac.uk

Prof. Nick Reed, Beatson Oncology Centre, Glasgow Prof. Ashley Grossman, University of Oxford Churchill Hospital Dr Aled Rees, University Hospital of Wales, Cardiff Prof. Juan W Valle, The Christie NHS Foundation Trust, Manchester Prof Andrea Frilling, Hammersmith Hospital, London Dr Gaurav Kapur, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich Dr Tahir Shah, University Hospital Birmingham NHS Foundation Trust, Birmingham Dr John Newell-Price, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield Dr Alan Anthoney, Leeds Teaching Hospitals NHS Trust, Leeds Dr Daniel Cuthbertson, Aintree University Hospitals NHS Foundation Trust Dr Rajaventhan Srirajaskanthan, Kings College Hospital NHS Foundation Trust, London Nick.Reed@ggc.scot.nhs.uk ashley.grossman@ocdem.ox.ac.uk reesda@cardiff.ac.uk juan.valle@christie.nhs.uk a.frilling@imperial.ac.uk gaurav.kapur@nnuh.nhs.uk tahir.shah@uhb.nhs.uk j.newellprice@sheffield.ac.uk alan.anthoney@leedsth.nhs.uk Daniel.Cuthbertson@liverpool.ac.uk r.srirajaskanthan@nhs.net

COOPERATE-II A randomized, open-label phase II multicenter study evaluating the efficacy of oral everolimus alone or in combination with pasireotide LAR i.m. in advanced progressive pancreatic neuroendocrine tumours (PNET) NCRI ID: NCRN239; Registration: NCT01374451 Open (recruiting) Open (in follow-up) Due to be opened Inclusion/exclusion criteria and study schema Inclusion criteria Advanced low to intermediate 10 mg Everolimus grade PNET Progression within 12 months PS 0-2 R Measurable disease No need for SSA 60 mg Pasireotide LAR + 10 mg Everolimus Exclusion criteria Patients currently requiring SSA treatment or who received prior therapy with mtor inhibitors. Patients with more than 2 prior systemic treatment regimens Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent. History or active liver disease such as cirrhosis decompensated liver disease, chronic active hepatitis or chronic persistent hepatitis. Stratification factors Prior SSA (yes/no) Elevated biomarkers (yes/no): CgA >2xULN and/or NSE >1xULN Primary endpoint: PFS Secondary endpoints: ORR, DCR, DoR; OS; Safety; PK Recruiting centres and contact details Date study open: Sep-2011 Planned accrual: Global: 150 patients; UK: 7 patients Actual accrual: Global: 160 patients; UK: 14 patients Planned closure: Closed Oct-2012; on follow up Prof. Juan W Valle, The Christie NHS Foundation Trust, Manchester Dr. Pippa Corrie, Cambridge University Hospitals NHS Foundation Trust, Cambridge Prof. Nick Reed, Beatson Oncology Centre, Glasgow juan.valle@christie.nhs.uk pippa.corrie@addenbrookes.nhs.uk Nick.Reed@ggc.scot.nhs.uk

LUNA Multicenter 3-arm trial to evaluate the efficacy and safety of Pasireotide LAR or Everolimus alone or in combination in patients with well differentiated neuroendocrine carcinoma of the lung and thymus -LUNA Trial EUDRACT number: 2011-002872-17 Open (recruiting) Open (in follow-up) Due to be opened Inclusion/exclusion criteria and study schema Inclusion criteria Histological confirmed advanced (unresectable or metastatic) well differentiated neuroendocrine carcinoma of the lung and thymus (typical and atypical) Previously treated or treatment naïve patients can be included. At least one measurable lesion of disease by RECIST 1.1 criteria with radiological disease progression within 12 months prior to randomization Adequate bone marrow, liver and renal function Exclusion criteria Patients with severe functional disease who require symptomatic treatment with somatostatin analogs can not be included in the protocol.

Prior therapy with mtor inhibitors (e.g. sirolimus, temsirolimus, everolimus). Prior therapy with radioligand therapy within 6 months prior to starting study treatment or not recovered from the side effects of such therapy. Mixed tumours are excluded. Severe comorbidity, including HIV infection or hepatitis Patients with symptomatic cholelithiasis. Stratification factors Typical carcinoid tumor (TC) vs. atypical carcinoid tumor (AC) according to WHO classification Line of treatment (1st line vs. others). Primary endpoint: Proportion of patients progression-free at 12 months according to RECIST V 1.1. Secondary endpoints: PFs, Disease control rate, Time to response, Duration of response, Time to progression, Biochemical response rate, safety and tolerability of the combination with primary lung and thymus NET patients Recruiting centres and contact details Planned accrual: Global: 108 patients Prof. Tim Meyer, Royal Free London NHS Foundation Trust, London Dr Was Mansoor, The Christie NHS Foundation Trust, Manchester Prof. Nick Reed, Beatson Oncology Centre, Glasgow t.meyer@ucl.ac.uk Was.Mansoor@christie.nhs.uk Nick.Reed@ggc.scot.nhs.uk

NETTER-1 A multi-centre, stratified, open, randomized, comparator-controlled, parallel-group phase III study comparing treatment with 177Lu-DOTA0-Tyr3-Octreotate to Octreotide LAR in patients with inoperable, progressive, somatostatin receptor positive, midgut carcinoid tumours. NCRI ID: NCRN328; Registration: REC12/NW/0251 Open (recruiting) Open (in follow-up) Due to be opened Inclusion/exclusion criteria and study schema Randomization (1:1) A) 177Lu-DOTA0-Tyr3-Octreotate plus 30 mg Octreotide LAR B) High dose (60 mg) Octreotide LAR Inclusion criteria Presence of inoperable (curative intent), histologically proven, midgut carcinoid tumour. Ki67 index 20% Patients on Octreotide LAR at a fixed dose of 20 mg or 30 mg at 3-4 weeks intervals for at least 12 weeks prior to enrolment in the study. Patients must have progressive disease based on RECIST Criteria, Version 1.1 evidenced with CT scans/mri obtained within 3 years from enrolment compared with a recent scan not older than 4 weeks from the projected randomization date, and while the patient was on a fixed dose of Sandostatin LAR. Confirmed presence of somatostatin receptors on all technically evaluable tumour lesions documented by CT/MRI scans, based on positive OctreoScan imaging within 24 weeks prior to enrolment in the study

The tumour uptake observed using OctreoScan normal liver uptake on planar imaging Exclusion criteria Inadequeate renal, liver and bone marrow function Treatment with >30 mg Octreotide LAR at 3-4 weeks intervals within 12 weeks prior to enrolment in the study. Peptide receptor radionuclide therapy (PRRT) at any time prior to enrolment in the study. Uncontrolled congestive heart failure or diabetes mellitus. Stratification factors Centre OctreoScan tumour uptake score (Grade 2, 3 and 4) Length of time on the most recent constant dose of Octreotide prior to enrolment ( 6 and >6 months) Primary endpoint: PFS = time from treatment start to documented (RECIST) progression, or death (any cause).pfs evaluated over fixed period of 76 weeks since treatment start. Secondary endpoints: TTP, ORR, OS. Recruiting centres and contact details Date study open: May 2012 Planned accrual: Global: 230 patients; UK: 35 patients Actual accrual: Global: 87 patients; UK: 13 patients Planned closure: 3 years after last enrolled subject completed wk 76 = Nov 2015 Prof. Ashley Grossman, University of Oxford Churchill Hospital Dr Prakash Manoharan, The Christie NHS Foundation Trust, Manchester Prof. Nick Reed, Beatson Oncology Centre, Glasgow Martyn Caplin, Royal Free Hospital, London ashley.grossman@ocdem.ox.ac.uk Prakash.Manoharan@christie.nhs.uk Nick.Reed@ggc.scot.nhs.uk m.caplin@medsch.ucl.ac.uk

OBLIQUE A Phase IV, Observational study to assess Quality of Life in patients with Pancreatic Neuroendocrine Tumors receiving treatment with oral 10 mg Everolimus (Afinitor ) o.d.: The OBLIQUE Study CRAD001PGB12 NCRI ID: NCRN572; Registration: Portfolio number 14710 Open (recruiting) Open (in follow-up) Due to be opened Inclusion/exclusion criteria and study schema This is a non-interventional multi-centre post-marketing study, to document changes in HrQoL, assessed on the EORTC QLQ-C30 patient reported outcomes questionnaire, in adult patients with advanced pancreatic NETs being treated orally with 10 mg everolimus (Afinitor ) o.d. in routine clinical practice. This study does not impose diagnostic or therapeutic interventions on the patients. There is also no mandatory visit schedule. Inclusion criteria Diagnosis of advanced (unresectable or metastatic) well or moderately differentiated neuroendocrine tumors of pancreatic origin with radiologically documented progressive disease Patients for whom a decision has been made to start treatment with 10 mg everolimus (Afinitor ) o.d. following review of their medical history against the known safety profile of everolimus (Afinitor ). Patients taking somatostatin analogues for symptom control should be on a stable dose for at least two months prior to enrollment. Exclusion criteria Patients that have any factor in their medical history that contradicts recommendations for prescription made in the latest version of the summary of product characteristics (SmPC) for Everolimus. Primary endpoint: HrQoL as assessed by the EORTC QLQ-C30 patient reported outcome questionnaire (Global Health Status QoL score) after 6 months of oral treatment with 10 mg everolimus o.d. Secondary endpoints: OS, PFS, biochemical tumour markers, duration of everolimus, safety and tolerability Recruiting centres and contact details Date study open: June 2013 Planned accrual: UK: 33 patients Actual accrual: UK: 2 patients Planned closure: June 2015 Prof. John Ramage, Kent and Hampshire Hospitals NET Centre Prof. Tim Meyer, Royal Free London NHS john.ramage@bnhft.nhs.uk t.meyer@ucl.ac.uk

Foundation Trust, London Prof. Juan W Valle, The Christie NHS Foundation Trust, Manchester Dr. Judith Cave (Southampton) Dr. Lucy Wall (Edinburgh) Prof Daniel Palmer (Clatterbridge, Liverpool) Prof Andrea Frilling, Hammersmith Hospital, London Dr. Jonathan Wadsley (Sheffield) Dr. Gaurav Kapur (Norfolk & Norwich University Hospital) Dr. Pankaj Punia (Queen Elizabeth Hospital, Birmingham) Dr. Sebastian Cummins (Royal Surrey County Hospital, Guildford) Dr. Ian Chau (Royal Marsden Hospital, Sutton) Dr. Karin Bradley (Bristol Royal Infirmary) juan.valle@christie.nhs.uk Email not available Lucy.Wall@nhslothian.scot.nhs.uk Daniel.Palmer@liverpool.ac.uk a.frilling@imperial.ac.uk jonathan.wadsley@sth.nhs.uk gaurav.kapur@nnuh.nhs.uk Email not available sebastian.cummins@nhs.net Email not available karin.bradley@uhbristol.nhs.uk

RADIANT-4 Phase III, randomized, double-blind study of everolimus (RAD001) plus best supportive care versus placebo plus best supportive care in the treatment of patients with advanced neuroendocrine tumour (NET) of gastrointestinal (GI) or lung origin without a history of carcinoid syndrome NCRI ID: NCRN333; Registration: NCT01524783 Inclusion/exclusion criteria and study schema Inclusion criteria Open (recruiting) Open (in follow-up) Due to be opened Advanced low and intermediate grade (welldifferentiated) nonfunctional NET of GI or lung origin (nonpancreatic) R 2:1 Everolimus 10 mg/day + BSC n=190 Placebo + BSC n=95 Exclusion criteria Patients with history of or active symptoms of carcinoid syndrome More than one prior line of chemotherapy or prior targeted therapy Gastrointestinal disease that may significantly alter the absorption of oral everolimus Liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis or known history of HIV seropositivity Chronic treatment with corticosteroids or other immunosuppressive agents Stratification factors tumour origin, WHO PS and prior SSA Primary endpoint: PFS by central radiology Cross over to open-label everolimus only after interim analysis and DMC recommendation Recruiting centres and contact details Date study open: Apr-2012 Planned accrual: Global: 280 patients; UK: 12 patients Actual accrual: UK: 20 patients (167%) Planned closure: Closed to accrual Aug-2013; on follow up

Recruitment status (global, final): COUNTRY # pts enrolled Italy 66 USA 56 Germany 23 United Kingdom 20 Canada 18 Grand Total 296 Prof. Juan W Valle, The Christie NHS Foundation Trust, Manchester Dr. Pippa Corrie, Cambridge University Hospitals NHS Foundation Trust, Cambridge Prof. Nick Reed, Beatson Oncology Centre, Glasgow Prof. Tim Meyer, Royal Free London NHS Foundation Trust, London juan.valle@christie.nhs.uk pippa.corrie@addenbrookes.nhs.uk Nick.Reed@ggc.scot.nhs.uk t.meyer@ucl.ac.uk

TELESTAR A Phase 3, Randomized, Placebo-controlled, Parallelgroup, Multicenter, Double-blind Study to Evaluate the Efficacy and Safety of Telotristat Etiprate (LX1606) in Patients with Carcinoid Syndrome Refractory to Somatostatin Analog (SSA) Therapy EudraCT Number: 2012-003460-47 Open (recruiting) Open (in follow-up) Due to be opened Inclusion/exclusion criteria and study schema Inclusion criteria Histopathologically-confirmed, advanced, well-differentiated metastatic NET Documented history of carcinoid syndrome, and currently experiencing an average of 4 bowel movements per day. Currently receiving a stable-dose SSA therapy at least 3 months prior to entering the Run-in Period or patients who cannot tolerate SSA therapy. Exclusion criteria Other causes of diarrhea apart from the carcinoid syndrome Presence of more than 12 watery bowel movements per day associated with volume contraction, dehydration, or hypotension compatible with a pancreatic cholera -type clinical syndrome, as judged by the Investigator Karnofsky Performance Status 60% Treatment with any tumor directed therapy A history of substance or alcohol abuse within 2 years prior to Screening Randomization (1:1:1) Stratification factors: Baseline urinary 5-HIAA levels. Primary endpoint: Reduction from baseline in the number of daily bowel movements averaged over the 12-week double-blind portion of the trial Secondary endpoints: other efficacy parameters, safety and quality of life

Recruiting centres and contact details Date study open: Sep-2011 Planned accrual: Global: 150 patients Prof Martyn Caplin, Royal Free Hospital, London Prof. Nick Reed, Beatson Oncology Centre, Glasgow Dr Martin Weickert, University Hospital Coventry and Warwickshire mcaplin@medsch.ucl.ac.uk Nick.Reed@ggc.scot.nhs.uk martin.weickert@uhcw.nhs.uk

VIBRANT Phase I Trial of Vandetanib Combined With 131I-mIBG to Treat Patients With Advanced Phaeochromocytoma and Paraganglioma (VIBRaNT) Registration: NCT01941849 Open (recruiting) Open (in follow-up) Due to be opened Inclusion/exclusion criteria and study schema Inclusion criteria Histopathological/cytological diagnosis of advanced phaechromocytoma or paraganglioma or R1 resection post original surgical debulking Positive 123I-mIBG diagnostic scan Stable blood pressure (<140/90mmHg), if appropriate, on anti-hypertensive therapy No previous systemic therapy for advanced or metastatic disease Measurable disease (RECIST v1.1) WHO performance status 0 or 1 Adequate bone marrow and renal function Exclusion criteria Patients undergoing current treatment with curative intent Refractory nausea and vomiting, chronic gastrointestinal disease or significant bowel resection that would preclude adequate absorption Significant cardiac comorbidity Primary endpoint: Dose limiting toxicity for the combination of Vandetanib and 131ImIBG Secondary endpoints: response rate, PFS and toxicity profile

Recruiting centres and contact details Date study open: Jan-2014 Planned accrual: Global: 18 patients Dr Debashis Sarker, King s College, London Dr Christina Thirlwell, Royal Free, London Dr Was Mansoor, The Christie NHS Foundation Trust, Manchester debashis.sarker@kcl.ac.uk christina.thirlwell@ucl.ac.uk Was.Mansoor@christie.nhs.uk