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Trial registered on ANZCTR


Registration number
ACTRN12615001328561
Ethics application status
Approved
Date submitted
26/11/2015
Date registered
4/12/2015
Date last updated
4/12/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Phase II study evaluating the efficacy of Pasireotide long-acting release (LAR; SOM230) dose escalation in patients with refractory non-functional gastroenteropancreatic neuroendocrine tumors (GEP NETs).
Scientific title
Phase II study evaluating the efficacy of Pasireotide LAR (SOM230) dose escalation in patients with refractory non-functional GEP NETs
Secondary ID [1] 287979 0
Novartis Protocol Number: CSOM230FAU04T
Universal Trial Number (UTN)
Trial acronym
DESNET2
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Gastro-entero-pancreatic neuroendocrine tumours 296857 0
Condition category
Condition code
Cancer 297091 297091 0 0
Neuroendocrine tumour (NET)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a multicentre (5 Australian sites), prospective, open label, single-arm phase II study. Overall 30 patients with non-functional GEP NETs with radiological disease progression during treatment with octreotide 30mg every 28 days will undergo therapy with increasing doses of pasireotide subject to imaging response.

The aim of this study is to evaluate the efficacy and safety of dose escalating pasireotide LAR in patients with non-functional well differentiated NETs who had progressed whilst on octreotide 30mg/q28d.

There will be 2 dose levels (possibly 3) evaluated, with intra-patient dose escalation:
Dose Level 1: Pasireotide LAR 40mg every 28 days
Dose Level 2: Pasireotide LAR 60mg every 28 days
Dose Level 3: Subject to MTD of dose escalation phase I trial from Novartis, possibly 80-90mg. (ClinicalTrials.gov identifier: NCT01364415).

The mode of administration of Pasireotide will be via intramuscular injection and each dose is given as a single dose every 28 days. Patients will have there dose escalated to the next dose level only if there is evidence of disease progression.

The maximum duration of treatment with Pasireotide will be two years. Patients will remain on treatment until disease progression. Patients who continue on treatment and have not progressed when the study ends, will need to complete End of STudy assessments.

All doses will be given and supervised by study/hospital staff and any deviations to the study treatments will be notified to the study team.
Intervention code [1] 293321 0
Treatment: Drugs
Comparator / control treatment
No control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 296694 0
To estimate the antiproliferative effect of dose escalated pasireotide LAR in patients who have radiologically progressed on octreotide 30mg/q28d on progression-free survival at 96 weeks from start of treatment.

This endpoint will be assessed by progression free survival at 96 weeks from time of commencement of pasireotide 40mg LAR therapy until date of radiological progression (via CT.MRI) at the maximum dose of pasireotide LAR as evaluated by RECIST 1.1 criteria.

A radiological primary endpoint is appropriate given that the study is endeavouring to evaluate the antiproliferative effects of dose escalation.
Timepoint [1] 296694 0
PFS at 96 weeks from time of commencement of pasireotide 40mg LAR therapy.
Secondary outcome [1] 319135 0
To estimate the functional imaging response rate based on Gatate avidity (Ga-DOTA-octreotate PET).
Timepoint [1] 319135 0
At Week 24 and 48 weeks of treatment compared to baseline.
Secondary outcome [2] 319136 0
To estimate the biochemical tumour marker (Chromogranin A) response of treatment using a blood serum assay.
Timepoint [2] 319136 0
At 4, 12, 24 and 48 weeks of treatment compared to baseline (in patients with baseline increase).
Secondary outcome [3] 319137 0
Estimate the Quality Of Life (QoL) impact as per the EORTC QLQ-C30 and G.I.NET21 scoring manuals,
Timepoint [3] 319137 0
At 4, 12, 24, 36 and 48 weeks of treatment.
Secondary outcome [4] 319245 0
To estimate structural radiological response (via CT.MRI scan) and its duration by RECIST 1.1.
Timepoint [4] 319245 0
From time of first structural imaging response i.e. CR/PR/SD to time of documented disease progression (patients who have died without disease will be censored).
This is a composite secondary outcome.
Secondary outcome [5] 319246 0
Change in target lesion volume via CT/MRI scan and Gatate scan..
Timepoint [5] 319246 0
At Week 12, 24, 36, 48 weeks of treatment compared to baseline.
Secondary outcome [6] 319247 0
Define toxicity (adverse events). Known adverse events include:
-Gastrointestinal effects; assessed by physical exam
-Weight loss; assessed by physical exam
-Hair loss; assessed by physical exam
-Tiredness; assessed by physical exam
-Elevated blood potassium; assessed by blood test
-Back, muscle and joint pain; assessed by physical exam
-Elevated blood liver biochemistries; assessed by blood test
-Gallstones and inflammation of the gallbladder; as assessed by ultrasound
-Pain at injection site; assessed by physical exam
-Elevated blood glucose level; as assessed by blood test.
Timepoint [6] 319247 0
Severe and non-severe AEs together with collecting clinical, biochemical parameters (including glycaemic control) and changes in vital signs at any visit. These events will be assessed every 4 weeks for the duration of treatment.

Eligibility
Key inclusion criteria
1. Male or female, over 18 years
2. Patients with an histologically documented diagnosis of non-functional WDNET, defined according to the last WHO classification criteria for NET of gastro-entero-pancreatic (WHO/ENET 2010), bronchial and thymic origin (WHO 2004)
2. Radiologic disease progression after at least 3 months of octreotide LAR 30mg/28 days
3. Measurable/evaluable disease per RECIST Version 1.1,1 (as determined by relevant imaging based on disease site (i.e. for example by multiphase MRI or triphasic CT scan for hepatic metastasis)
4. ECOG PS 0-2
5. Adequate organ function:
Bone marrow: Platelets greater than or equal to 100x10^9/L, Neutrophils greater than or equal to 1.5x10^9/L, Hb greater than or equal to 9g/L
Liver: Bilirubin less than or equal to 2.0 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 x UNL (if hepatic metastases).
Renal: Serum creatinine less than or equal to 2.0 X ULN
6. Females of childbearing potential must provide a negative pregnancy test at the start of the study. Female patients who are at risk of becoming pregnant must agree to use an effective method of contraception. Female patients must agree to use 2 medically acceptable methods of contraception, 1 being an oral contraceptive, dermal patch, or progestin (implantation or injection), and the other being a medically acceptable barrier method; alternatively, 2 medically acceptable barrier methods may be used. Medically acceptable barrier methods of contraception that may be used by the participant and/or his/her partner include: abstinence; diaphragm with spermicide; intrauterine device (IUD); condom together with foam, spermicide, or vaginal spermicidal suppository. Prohibited methods include the rhythm method, withdrawal, condoms alone, or diaphragm alone
7. Male patients must agree that, if their partner is at risk of becoming pregnant, they will use an effective method of contraception as described above.
8. Informed and written consent as per the Participant Information and Consent Form
9. Compliance with trial therapy or trial-related investigations/evaluations by the patient
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patients with intermediate (Grade 2) or high grade (grade 3) NET
2. SSA Naive patients
3. Patients that have undergone surgery related to NET within 4 weeks prior to study entry or has surgery planned during the study
4. Patients that have previously received any specific anti-tumour treatment such as chemotherapy (within the previous 4 weeks), (chemo) embolisation (within the previous 3 months), radiotherapy (within the previous 4 weeks) or interferon (within the previous 4 weeks) or PRRT within the last 6 months.
5. Patients that have had a previous cancer (except basal cell carcinoma of the skin, in situ carcinoma of the cervix/uterus, thyroid microcarcinoma, or eradicated thyroid or prostate cancers). Patients with a history of cancer that was not the above mentioned case can be included if they have been treated with curative intent and have been free from disease for more than 3 years.
6. Diabetic patients with poor glycemic control as evidenced by HbA1c >8%
7. Patients with risk factors for torsades de pointes, i.e. patients with a baseline QTcF >450 ms in males, and >460ms in females. Or patients with uncontrolled (despite supplementation) hypokalemia or hypomagnesaemia, uncontrolled hypothyroidism, family history of long QT syndrome, or concomitant medications known to prolong QT interval
8. Patients with clinically significant valvular disease
9. Patients with symptomatic cholelithiasis
10. Patients who have congestive heart failure (NYHA Class III or IV), unstable angina, sustained ventricular tachycardia, clinically significant bradycardia, advanced heart block, history of acute myocardial infarction less than one year prior to study entry or clinically significant impairment in cardiovascular function
11. Patients with liver disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis, or patients with ALT/AST > 2.5 X ULN, serum bilirubin > 2.0 X ULN, in the absence of liver metastases
12. Patients who have a history of alcohol or drug abuse in the 6 month period prior to receiving pasireotide
13. Patients who have participated in any clinical investigation with an investigational drug within 1 month prior to dosing
14. Patients with the presence of active or suspected acute or chronic uncontrolled infection
15. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will be unable to complete the entire study
16. Pregnant or lactating women
17. At the time of inclusion, on-going AE considered to be related to the treatment with SSA with a severity higher than grade 1
18. Patients on lower doses than octreotide LAR 30mg every 28 days.

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
Safety/efficacy
Statistical methods / analysis
This is an exploratory proof of concept study, thus 30 patients has been selected as a pragmatic sample size. With a sample size of 30 patients, the power to detect a difference of 11 months to 14.7 months in median survival is 36%, assuming 22 month accrual and 12 months follow up, one-sided test at significance level alpha=0.05. (It should be noted that a study with 80% power would require about 107 patients recruited in a similar time period – which is not feasible for this project). However, the study of 30 patients will have 80% power to detect a median survival of over 8.6 months – still of clinical interest.

Assessment of primary endpoint:
Using Kaplan-Meier methodology, radiological PFS at 96 weeks will be estimated from the time of commencement of pasireotide 40mg LAR therapy until date of radiological progression at the maximum dose of pasireotide LAR or death from whatever cause, among all patients who began therapy.

A close-out date will be applied. The close out date will generally be taken to be the earliest of the dates of last contact, at which the assessments relevant to the identification of the events were made, of the patients who are still alive and being followed up. Thus, with the exception of any patients who have been lost to follow-up, the status of all patients in the trial, regarding the events of interest, should be known at this date. Ninety-five percent confidence intervals for the percentage surviving at particular times, including 96 weeks, will be calculated using the logit transformation. Graphs will be prepared. A p-value will be reported to assess whether the median progression free survival is greater than 11 months.

Assessment of secondary endpoints:
Descriptive statistics, (including number, percentage, exact 95% CIs, mean, median and range) will be used to summarise patient demographics (including patient demographics, medical history, physical examination, ECOG performance status), treatment compliance/dose intensity, laboratory data, toxicity reports (AEs by worst grade reported as per NCI CTCAE version 4. SAEs, changes in lab values and vital signs meeting CTCAE version 4 definitions for AEs) and response (ORR and DCR) assessed by Ga-DOTA-octreotate PET and radiological response by the RECIST version 1.1 criteria.

Duration of response will be assessed using Kaplan-Meier methods.

Change in target lesions volume and percentage change in chromogranin A from baseline will be analysed by means of descriptive statistics and graphical methods such as Box-&-Whisker plots. If appropriate, a repeated measures analysis, using the method of residual maximum likelihood, will be used to compare the measures among patients separated into different groups.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
15/12/2015
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final

Funding & Sponsors
Funding source category [1] 292446 0
Commercial sector/Industry
Name [1] 292446 0
Novartis Pty Ltd
Country [1] 292446 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
Office of Cancer Research
Level 3
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne VIC 3002
Country
Australia
Secondary sponsor category [1] 291142 0
None
Name [1] 291142 0
Address [1] 291142 0
Country [1] 291142 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293906 0
Peter MacCallum Cancer Cente Human Research Ethics Committee
Ethics committee address [1] 293906 0
Ethics committee country [1] 293906 0
Australia
Date submitted for ethics approval [1] 293906 0
21/09/2015
Approval date [1] 293906 0
19/11/2015
Ethics approval number [1] 293906 0
HREC/15/PMCC/63

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 61778 0
A/Prof Michael Michael
Address 61778 0
Department of Haematology and Medical Oncology
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne VIC 3002
Country 61778 0
Australia
Phone 61778 0
+61 3 9656 1701
Fax 61778 0
+61 3 9656 1408
Email 61778 0
michael.michael@petermac.org
Contact person for public queries
Name 61779 0
Michael Michael
Address 61779 0
Department of Haematology and Medical Oncology
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne VIC 3002
Country 61779 0
Australia
Phone 61779 0
+61 3 9656 1701
Fax 61779 0
+61 3 9656 1408
Email 61779 0
michael.michael@petermac.org
Contact person for scientific queries
Name 61780 0
Michael Michael
Address 61780 0
Department of Haematology and Medical Oncology
Peter MacCallum Cancer Centre
St Andrews Place
East Melbourne VIC 3002
Country 61780 0
Australia
Phone 61780 0
+61 3 9656 1701
Fax 61780 0
+61 3 9656 1408
Email 61780 0
michael.michael@petermac.org

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Results publications and other study-related documents

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