The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12612001252808
Ethics application status
Approved
Date submitted
21/11/2012
Date registered
27/11/2012
Date last updated
22/01/2013
Type of registration
Prospectively registered

Titles & IDs
Public title
Everolimus Treatment in patients with Pancreatic Cancer
Scientific title
A Phase II Study to evaluate progression free survival following Everolimus treatment in Patients with FDG-PET positive intermediate grade (Ki-67 3-20%) Pancreatic Neuroendocrine Tumours (PNETs)
Secondary ID [1] 281570 0
Clinical TRial Number assigned by TGA - 2012/0677
Universal Trial Number (UTN)
Nil
Trial acronym
INTERNET
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pancreatic Neuroendocrine Tumours 287854 0
Condition category
Condition code
Cancer 288212 288212 0 0
Pancreatic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Active Name - Everolimus
Trade Name - Afinitor
Patients will take 2 tablets of 5 mg (10mg) of everolimus orally, once daily for 6 months. A treatment cycle is defined as 28 days.
Intervention code [1] 286094 0
Treatment: Drugs
Comparator / control treatment
Nil
Control group
Uncontrolled

Outcomes
Primary outcome [1] 288403 0
To estimate the treatment effect of Everolimus in patients with intermediate grade FDG-avid pNET on progression free survival at 6 months from start of treatment
Timepoint [1] 288403 0
PFS at 6 months
Secondary outcome [1] 300060 0
To estimate the functional imaging response rate (based upon FDG and Ga-DOTA-octreotate PET), and structural radiological response rate and its duration
Timepoint [1] 300060 0
Composite secondary outcome:

1) Functional imaging response:
(i) FDG-PET response measured following 3 months duration of treatment,
(ii) Response according to Ga-DOTA-octreotate PET at 3 months (where applicable)
2) Structural imaging response rate:
(i)Objective Response Rate (ORR) - ORR = Sum of patients achieving best response of CR or PR as per RECIST 1.1.1
(ii) Disease Control Rate (DCR) - DCR = ORR + SD as per RECIST 1.1.1
(iii)Duration of response; From time of best structural imaging response i.e. CR/PR/SD to time of documented disease progression (patients who have died without disease will be censored)
Secondary outcome [2] 300132 0
Define the toxicity of everolimus
Timepoint [2] 300132 0
Worst grade of AEs, SAEs, changes from baseline in laboratory results (haematology, biochemistry), using (CTCAE version 4.0)

Assessed at the following timepoints:
Cycle 1 day 1 to Cycle 6 day 1, end of cycle 6 and follow up every 3 months until progression
Secondary outcome [3] 300133 0
Define Overall survival
Timepoint [3] 300133 0
Defined as the time from date of treatment start to date of death
Secondary outcome [4] 300134 0
To assess QoL
Timepoint [4] 300134 0
As per EORTC QLQ-C30 and G.I.NET21 instrument completed at screening and at regular intervals during treatment: days 1 of cycles 2, 4 , day 28 cycle 6 and then every 3 months in follow-up until progression
Secondary outcome [5] 300135 0
Assess symptomatic (based on QOL measures), biochemical and imaging (anatomical and functional) responses and toxicity among patients who proceed to Peptide Receptor Radio-Chemo therapy (PRCRT)
Timepoint [5] 300135 0
As per EORTC QLQ-C30 and G.I.NET21 instrument prior to each therapy and at 2 weeks after treatment, CTCAE version 4.0, serum tumor markers (e.g. Cg-A response), composite imaging criteria incorporating functional and anatomical imaging results: FDG and Ga-DOTA-octreotate PET response, and structural imaging response
Functiona imaging PET will be performed at baseline, end of cycle 3 and 6 and follow up every 3 months until disease progression. If the disease demonstrates somatostatin-receptor e xpression at baseline, Gal-DOTA octreotate PET will be performed at the end of cycle 3 and then every 6 months after during treatment or on follow up until progression. Structural imaging will be performed at baseline, cycle4 day 1, cycle 6 day 28 and follow up every 3 months until progression

Patients with Grade 3-4 Octreotide-avid disease concordant with FDG avid sites, may be suitable for consideration of Lutetium-177 Octreotate PRRT with and without infusional 5FU (as a radiation sensitiser) in consultation with the Nuclear Medicine Department.
Among patients who proceed to PRCRT, toxicity will be assessed as per the NCI CTCAE (version 4.0),2 based on bloods being taken for haematology and biochemistry at prior to Lutetium-177 Octreotate PRRT, weekly during the 5FU infusion (where used) and 2 and 4 weeks post therapy as well as clinical review at these time points.

Eligibility
Key inclusion criteria
1) Newly diagnosed locally advanced or metastatic histologically confirmed pancreatic NET of intermediate grade (Ki67 of 3-20%), not suitable for radical or aggressive resection or hepatic-directed approaches (including ablation, TACE or SIRT therapy)
2) Functional imaging criteria:
(i)Disease must be FDG-avid and
(ii)Disease may or may not express somatostatin-receptor (SSTR) on In-111 octreotide SPECT/CT or Ga-68 octreotate PET/CT
3)Measurable/evaluable disease per RECIST Version 1.1,1 determined by relevant imaging based on disease site (i.e. by multiphase MRI or triphasic CT scan for hepatic metastasis)
4) ECOG PS 0-2
5) Age > 18 years
6)Adequate organ function
i)Bone marrow: Platelets > 100x10^9/L, Neutrophils > 1.5x10^9/L
ii) Liver: Bilirubin less than or equal to 2.5 xUNL, INR less than or equal to 1.3, AST/ALT less than or equal to 2.5 xUNL (if no hepatic metastases) or AST/ALT less than or equal to 5.0 xUNL (if hepatic metastases).
iii) Serum lipase and amylase less than and equal to 2 x ULN
iv) Renal: Creatinine clearance (CrCl) greater than and equal to 40mL/min (assessed by modified Cockroft-Gault or nuclear renal scan)
Minimum age
19 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Poorly differentiated pancreatic NET with Ki67 > 20%
2) Well differentiated pancreatic NET with Ki67 less than and equal to 2%, unless FDG-avid (in which case confirmatory re-biopsy with estimation of Ki67 is required. If on re-biopsy the ki67 is greater than 20% the patient will be excluded)
3) Patients requiring ongoing SSA for symptomatic control or control of hormone secretory syndromes
4) Patients who have received prior therapy with mTOR inhibitors (e.g. sirolimus, temsirolimus)
5) Patients who have received any cytotoxic chemotherapy, targeted therapy, or biotherapy for pNETs
6) Patients with a known hypersensitivity to everolimus or other rapamycin analogs (sirolimus, temsirolimus) or to their excipients.
7) Prior treatment with radiolabelled SSAs within the last 12 months.
8) Patients with hepatic artery embolization, cryoablation or radiofrequency ablation of hepatic metastasis within the last 3 months prior to registration.
9) Patients who have received radiotherapy of target lesions, unless documented progression at that site.
10) Patients who have received local radiotherapy of non-target lesions for local symptom control within the last 2 weeks must have recovered from any adverse effects of radiotherapy prior to therapy.
11) Patients who have undergone major surgery/surgical therapy for any cause within 1 month.
12) Patients who have not recovered from any previous treatment for any cause and who have not reached ECOG performance status 0-2 before entering the study.
13) Patients receiving chronic treatment with corticosteroids or another immunosuppressive agent.
14) Patients who are not biochemically euthyroid. Patients with a history of hypothyroidism are eligible if they are on adequate and stable replacement thyroid hormone therapy and have been for at least 3 months.
15) Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
i) Uncontrolled diabetes as defined by HbA1c greater than and equal to 8% despite adequate therapy,
ii) Fasting serum cholesterol > 7.75 mmol/L or fasting triglycerides > 2.5 ULN despite appropriate lipid lowering medication.
iii) Severely impaired lung function defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air. DLCO should be adjusted to haemoglobin value and patient lung volumes.
iv) Patients with the presence of active or suspected acute or chronic uncontrolled infection or with a history of immunodeficiency, including a positive HIV test result (ELISA and Western blot)
v) Non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with this study treatment.
vi) Liver disease such as cirrhosis, decompensated liver disease, chronic active hepatitis or chronic persistent hepatitis, except carriers of or chronic hepatitis B and C.
16) Patients who have a history of another primary malignancy within the last 3 years, with the exception of locally excised non-melanoma skin cancer and carcinoma in situ of uterine cervix
17) Symptomatic CNS metastases requiring corticosteroid therapy.
18) Patients who have any current or prior medical condition that may interfere with the conduct of the study or the evaluation of its results in the opinion of the Investigator or the Sponsor’s Medical Monitor.
19) Patients with a history of non-compliance to medical regimens or who are considered potentially not able to complete the entire study.
20) Patients who are currently part of, or have participated in, any clinical investigation with an investigational drug within 1 month prior to dosing.
21) Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum hCG laboratory test (> 5 mIU/mL). Patients with elevated hCG at baseline that is judged to be related to the tumour are eligible if hCG levels do not show the expected doubling when repeated 5-7 days later, or pregnancy has been ruled out by vaginal ultrasound.
22) Women of child-bearing potential, unless they are using adequate birth control methods.
i) Adequate barrier methods of contraception include: diaphragm, intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent).
ii) Reliable contraception should be maintained throughout the study and for 8 weeks after discontinuation of everolimus, whatever comes last.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



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

Recruitment
Recruitment status
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)
NSW,VIC

Funding & Sponsors
Funding source category [1] 286365 0
Commercial sector/Industry
Name [1] 286365 0
Novartis Pharmaceuticals Australia Pty Ltd
Address [1] 286365 0
PO Box 101, North Ryde, NSW 1670
Country [1] 286365 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
St Andrews Place, East melbourne-3002, VIC
Postal Address: Locked Bag 1, A'Beckett St, VIC 8006
Country
Australia
Secondary sponsor category [1] 285146 0
None
Name [1] 285146 0
Address [1] 285146 0
Country [1] 285146 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288441 0
Peter MacCallum Cancer Centre Ethics Committee
Ethics committee address [1] 288441 0
Locked Bag 1, A'Beckett St, VIC - 8006
Ethics committee country [1] 288441 0
Australia
Date submitted for ethics approval [1] 288441 0
Approval date [1] 288441 0
27/09/2012
Ethics approval number [1] 288441 0
12/77

Summary
Brief summary
The aim of this study is to estimate the treatment effect of Everolimus in patients with pancreatic neuroendocrine tumours (PNET). Who is it for? You may be eligible to join this study if you are aged over 18 years and have newly diagnosed locally advanced or metastatic confirmed pancreatic neuroendocrine tumour (NET) of intermediate grade. Trial details All participants will receive treatment with Everolimus. This is a drug that can block activity of a protein called mTOR, and can slow the growth of different tumours including pancreatic NETs in the laboratory. Large studies in patients with pancreatic NET have shown that Everolimus treatment decreased the rate of tumour growth and increased patient survival. Two tablets of 5 mg Everolimus will be given daily for 6 months. Participants will be assessed regularly throughout the treatment period, and every 3 months after treatment has stopped in order to determine treatment effect. CT and PET scans will be used to measure tumour response and questionnaires will also be supplied to patients to assess symptomatic response to treatment.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 34972 0
Address 34972 0
Country 34972 0
Phone 34972 0
Fax 34972 0
Email 34972 0
Contact person for public queries
Name 18219 0
Asso Prof Michael Michael
Address 18219 0
Peter MacCallum Cancer Centre

Locked Bag 1, A'Beckett Street, VIC - 8006
Country 18219 0
Australia
Phone 18219 0
+ 61 3 9656 1111
Fax 18219 0
Email 18219 0
michael.michael@petermac.org
Contact person for scientific queries
Name 9147 0
Asso Prof Michael Michael
Address 9147 0
Peter MacCallum Cancer Centre

Locked Bag 1, A'Beckett Street, VIC - 8006
Country 9147 0
Australia
Phone 9147 0
+61 3 9656 1111
Fax 9147 0
Email 9147 0
michael.michael@petermac.org

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