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Trial registered on ANZCTR


Registration number
ACTRN12611000207910
Ethics application status
Approved
Date submitted
22/02/2011
Date registered
22/02/2011
Date last updated
22/02/2011
Type of registration
Prospectively registered

Titles & IDs
Public title
NETTLE Study
NeuroEndocrine Tumour Therapy with Lutetium-177 octreotate and Everolimus

Neuroendocrine tumour therapy for the treatment of advanced gastroenteropancreatic neuroendocrine tumours (GEP-NETs): the NETTLE Study
Scientific title
NETTLE Study: NeuroEndocrine Tumour Therapy with Lutetium-177 octreotate and Everolimus. A Phase I/II study of Everolimus in combination with Lutetium-177 octreotate for the treatment of advanced gastroenteropancreatic neuroendocrine tumours (GEP-NETs)
Secondary ID [1] 259657 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
NETTLE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
neuroendocrine tumour 261221 0
Condition category
Condition code
Cancer 259369 259369 0 0
Neuroendocrine tumour (NET)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Phase I/II study of Everolimus in combination with Lutetium-177 octreotate radiopeptide therapy for the treatment of advanced gastroenteropancreatic neuroendocrine tumours (GEP NETs).

Lutetium-177 octreotate administered by intravenous infusion of 8 GBq for 4 cycles at intervals of 8 weeks in conjunction with amino acid solution (Synthamin Baxter Australia) as an outpatient. Everolimus (Afintor Novartis Australia) to be adminstered orally in escalating dose 5 mg for 3 patients, 7.5 mg for 3 patients and 10 mg in all subsequent patients (given manageable toxicity) each day for 6 months commencing in the week prior to start of Lutetium-177 octreotate radiopeptide therapy.
Intervention code [1] 258083 0
Treatment: Drugs
Comparator / control treatment
Historical controls of comparable phase I/II study of Lutetium-177 octreotate radiopeptide therapy combined with capecitabine +/- temozolomide chemotherapy of advanced gastroenteropancreatic neuroendocrine tumours. Previously registered ACTRN12610000440022.
Control group
Historical

Outcomes
Primary outcome [1] 262182 0
Progression-free survival measurement of target lesions on computer tomography, usings standard Response Evaluation in Solid Tumours (RECIST) criteria version 1.1 2009
Timepoint [1] 262182 0
Objective response rate evaluation at 1 year from commencement of treatment
Primary outcome [2] 262183 0
Overal survival as determined by direct individual patient folllow-up by the Investigators
Timepoint [2] 262183 0
Actuarial survival 1,2,3 years from commencement of treatment
Secondary outcome [1] 273278 0
Toxicity is assesed according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3 (CTCAE)
Timepoint [1] 273278 0
3 year from commencement of treatment. Myelotoxicity fortnightly for 8 months. Nephrotoxicity 6 monthly for 3 years

Eligibility
Key inclusion criteria
1 Presence of advanced, unresectable GEP-NET, which have progressed on standard therapy, or those with uncontrolled symptoms, or massive disease requiring urgent treatment. Tumour has been biopsy - proven and avid on 68Ga-octreotate PET CT or on tracer 177Lu-octreotate or 111In-octreotide gamma scanning
2 Age > 18 years
3 WHO performance status < 2
4 Neutrophils >1.5 x 109/L, platelets > 100 x 109/L, Hb > 90 g/L
5 Bilirubin < 1.5 x ULN, ALT/AST < 2.5 x ULN ( < 5 x ULN in patients with liver metastases)
6 Fasting serum cholesterol < 7.75 mmol/L AND triglycerides < 2.5 x ULN
7 INR < 1.5 (Anticoagulation is allowed if target INR < 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for > 2 weeks at time of enrolment
8 Serum creatinine < 1.5 x ULN
9 Signed informed consent
10 Accessible for follow-up
Minimum age
18 Years
Maximum age
90 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1 Patients who have received anti-cancer therapies within 4 weeks of start of study drug
(including chemotherapy, radiation, antibody based therapy, etc)
2 Patients who had major surgery or significant traumatic injury within 4 weeks of start of study drug, or may require major surgery during the course of the study
3 Prior treatment with an investigational drug within preceding 4 weeks
4 Patients receiving chronic systemic corticosteroids or another immunosuppressive agent.
Topical or inhaled corticosteroids allowed.
5 Patients should not receive immunization with attenuated live vaccines within 1 week of study entry or during study period and should not be in close contact with people who have received attenuated live vaccines. Live vaccines include intranasal influenza, MMR, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.
6 Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases.
7 Other malignancies within the past 3 years except for neuroendocrine tumour or adequately treated cancer of the cervix or basal/squamous cell carcinomata of the skin.
8 Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation such as: NYHA Class 111 or IV, unstable angina, symptomatic congestive cardiac failure, myocardial infarction within 6 months of start of study, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease.
9 Severely impaired lung function defined by spirometry and DLCO that is 50% of normal predicted value and/or O2 sat that is < 88% at rest on room air
10 Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN
11 Active liver infections or disease such as cirrhosis, or severe hepatic impairment (Child-Pugh class C)
12 HBV, HCV or HIV positive
13 Impairment of gastrointestinal function or GI disease that may significantly alter the absorption of everolimus (e.g ulcerative disease, uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome or substantial small bowel resection)
14 Patients with an active bleeding diathesis
15 Female patients who are pregnant/breastfeeding
16 Adults of reproductive potential and their partners who are not using effective birth control methods.
Adequate contraception must be used throughout the trial and for 8 weeks after the last dose of study drug, by both sexes.
17 Women of childbearing potential must have negative urine/serum pregnancy test within 7 days prior to administration of everolimus)
18 Patients who received prior treatment with an mTOR inhibitor (e.g sirolimus, temsirolimus,everolimus)
19 Patients with a know hypersensitivity to everolimus or other rapamycins (e.g sirolimus, temsirolimus) or to its excipients
20 History of non- compliance to medical regimens
21 Patients unwilling, or unable to comply with the protocol
22 Previous radiopeptide therapy within the last 6 months.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Oncologist referrral given fulfilment of entry criteria.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
N/A non-randomised study
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment postcode(s) [1] 3628 0
6000-6999

Funding & Sponsors
Funding source category [1] 258542 0
Hospital
Name [1] 258542 0
Fremantle Hospital & Health Service
Address [1] 258542 0
Alma Street, Fremantle WA 6160
Country [1] 258542 0
Australia
Primary sponsor type
Hospital
Name
Fremantle Hospital
Address
Alma Street, Fremantle WA 6160
Country
Australia
Secondary sponsor category [1] 257678 0
None
Name [1] 257678 0
Address [1] 257678 0
Country [1] 257678 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 260513 0
Human Research Ethics Committee South Metropolitan Area Health Service
Ethics committee address [1] 260513 0
Fremantle Hospital, Alma Street, Fremantle WA 6160
Ethics committee country [1] 260513 0
Australia
Date submitted for ethics approval [1] 260513 0
22/06/2010
Approval date [1] 260513 0
03/08/2010
Ethics approval number [1] 260513 0
1/10/0243

Summary
Brief summary
No effective standard treatment of advanced progressive neuroendocrine tumours (NETs) exists, but over the past decade at Fremantle Hospital, we have developed new radiopeptide therapies with encouraging results using Lutetium-177 octreotate. Recently, we have combined this radioisotope with radiosensitizing chemotherapy to achieve stabilization of disease in over 90% of patients and tumour shrinkage in over half the NETs. We now seek to combine Lutetium-177 octreotate with a new targeted agent, Everolimus which has proven, although minor suppressive effect on NET progression. We propose to combine a standard activity of 177Lu-octreotate with escalating doses of Everolimus to define the maximum safe dose achievable. We will then design a study to define the efficacy of this novel radiopeptide Everolimus combination in NET patients with progressive disease.
Trial website
N/A
Trial related presentations / publications
Claringbold PG, Brayshaw PA, Price RA, Turner JH. Phase II study of radiopeptide Lutetium-177 octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours. Eur J Nucl Med Mol Imaging (2011) 38:302-311
Public notes

Contacts
Principal investigator
Name 32251 0
Address 32251 0
Country 32251 0
Phone 32251 0
Fax 32251 0
Email 32251 0
Contact person for public queries
Name 15498 0
Jenny Lavin
Address 15498 0
Department of Nuclear Medicine, Fremantle Hospital, Alma Street, Fremantle WA 6160
Country 15498 0
Australia
Phone 15498 0
61 8 9431 2888
Fax 15498 0
61 8 9431 2889
Email 15498 0
Jenny.Lavin@health.wa.gov.au
Contact person for scientific queries
Name 6426 0
Professor J. Harvey Turner
Address 6426 0
Department of Nuclear Medicine, Fremantle Hospital, Alma Street, Fremantle WA 6160
Country 6426 0
Australia
Phone 6426 0
61 8 9431 2888
Fax 6426 0
61 8 9431 2889
Email 6426 0
Harvey.Turner@health.wa.gov.au

No information has been provided regarding IPD availability
Summary results
No Results