Clinical Trials Update 2013

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Clinical Trials

Update 2013

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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

[email protected]

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NET Studies (in alphabetical order)

BEZ235 (2401) 1

ST

Line

Randomized phase II study of BEZ235 or everolimus in advanced pancreatic neuroendocrine tumours

Open (recruiting) Open (in follow-up) Due to be opened

NCRI ID: NCRN379; Registration: NCT01628913

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

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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

[email protected]

Dr. Pippa Corrie, Cambridge University Hospitals NHS Foundation Trust, Cambridge

[email protected]

Prof. Nick Reed, Beatson Oncology Centre, Glasgow

[email protected]

Prof. Tim Meyer, Royal Free London NHS Foundation Trust, London

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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.

Inclusion/exclusion criteria and study schema

Inclusion criteria  Advanced well-differentiated (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.

 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

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 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

[email protected]

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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

Inclusion/exclusion criteria and study schema

 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.

 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

[email protected]

Dr Christos Toumpanakis, Royal Free London NHS Foundation Trust, London

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[email protected]

Prof. Ashley Grossman, University of Oxford

Churchill Hospital

[email protected]

Dr Aled Rees, University Hospital of Wales, Cardiff [email protected] Prof. Juan W Valle, The Christie NHS Foundation

Trust, Manchester

[email protected]

Prof Andrea Frilling, Hammersmith Hospital, London

[email protected] Dr Gaurav Kapur, Norfolk and Norwich University

Hospital NHS Foundation Trust, Norwich

[email protected] Dr Tahir Shah, University Hospital Birmingham

NHS Foundation Trust, Birmingham

[email protected] Dr John Newell-Price, Sheffield Teaching Hospital

NHS Foundation Trust, Sheffield

[email protected] Dr Alan Anthoney, Leeds Teaching Hospitals NHS

Trust, Leeds

[email protected] Dr Daniel Cuthbertson, Aintree University Hospitals

NHS Foundation Trust

[email protected] Dr Rajaventhan Srirajaskanthan, Kings College

Hospital NHS Foundation Trust, London

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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)

Inclusion/exclusion criteria and study schema

 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

Planned closure: Closed Oct-2012; on follow up

[email protected]

Prof. Nick Reed, Beatson Oncology Centre, Glasgow [email protected]

 Advanced low to intermediate grade PNET

 Progression within 12 months

 PS 0-2

 Measurable disease

 No “need” for SSA

_{60 mg Pasireotide}

LAR + 10 mg

Everolimus

10 mg Everolimus

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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

Inclusion/exclusion criteria and study schema

 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

 Patients with severe functional disease who require symptomatic treatment with somatostatin analogs can not be included in the protocol.

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 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

[email protected]

Dr Was Mansoor, The Christie NHS Foundation Trust, Manchester

[email protected]

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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

Inclusion/exclusion criteria and study schema

Randomization (1:1)

A)

177

Lu-DOTA

0

-Tyr

3

-Octreotate

plus 30 mg Octreotide LAR

B)

High dose (60 mg) Octreotide LAR

 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

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 The tumour uptake observed using OctreoScan® ≥ normal liver uptake on planar imaging

 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 closure: 3 years after last enrolled subject completed wk 76 = Nov 2015

Prof. Ashley Grossman, University of Oxford

Churchill Hospital

[email protected]

Dr Prakash Manoharan, The Christie NHS Foundation Trust, Manchester

[email protected]

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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

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.

 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.

 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

[email protected]

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Foundation Trust, London

[email protected]

Dr. Judith Cave (Southampton) Email not available

Dr. Lucy Wall (Edinburgh) [email protected] Prof Daniel Palmer (Clatterbridge, Liverpool) [email protected] Prof Andrea Frilling, Hammersmith Hospital,

London

[email protected] Dr. Jonathan Wadsley (Sheffield) [email protected] Dr. Gaurav Kapur (Norfolk & Norwich University

Hospital)

[email protected] Dr. Pankaj Punia (Queen Elizabeth Hospital,

Birmingham)

Email not available Dr. Sebastian Cummins (Royal Surrey County

Hospital, Guildford)

[email protected] Dr. Ian Chau (Royal Marsden Hospital, Sutton) Email not available

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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

Inclusion/exclusion criteria and study schema

 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

Actual accrual:UK: 20 patients (167%)

Planned closure: Closed to accrual Aug-2013; on follow up

R

2:1 Everolimus 10 mg/day + BSC n=190 Placebo + BSC n=95

Advanced low and intermediate grade (well-differentiated) non-functional NET of GI or lung origin (non-pancreatic)

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Recruitment status (global, final): COUNTRY # pts enrolled Italy 66 USA 56 Germany 23 United Kingdom 20 Canada 18 Grand Total 296

[email protected]

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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

Inclusion/exclusion criteria and study schema

 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.

 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

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Recruiting centres and contact details

Date study open: Sep-2011

Prof Martyn Caplin, Royal Free Hospital, London [email protected]

[email protected]

Dr Martin Weickert, University Hospital Coventry and Warwickshire

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VIBRANT

Phase I Trial of Vandetanib Combined With 131I-mIBG to Treat Patients With Advanced Phaeochromocytoma and Paraganglioma (VIBRaNT)

Registration: NCT01941849

Inclusion/exclusion criteria and study schema

 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

 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 131I-mIBG

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Recruiting centres and contact details

Date study open: Jan-2014

Dr Debashis Sarker, King’s College, London [email protected] Dr Christina Thirlwell, Royal Free, London [email protected]

Dr Was Mansoor, The Christie NHS Foundation Trust, Manchester