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Trial registered on ANZCTR


Registration number
ACTRN12615000909527
Ethics application status
Approved
Date submitted
24/06/2015
Date registered
1/09/2015
Date last updated
9/03/2022
Date data sharing statement initially provided
14/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A parallel group randomised, controlled, multi-centre phase II open label trial with two cohorts testing the combination of capecitabine and temozolomide (CAPTEM) and peptide receptor radionuclide therapy (PRRT) for the treatment of advanced pancreatic or midgut neuroendocrine tumours that are not suitable for surgery.
Scientific title
A parallel group randomised, controlled, multi-centre phase II open label trial to evaluate progression free survival in Cohort A: Pancreatic NETs - peptide receptor radionuclide therapy (PRRT)/capecitabine + temozolomide (CAPTEM) vs. CAPTEM (control) and Cohort B: Midgut NETs - PRRT/CAPTEM vs. PRRT (control).
Secondary ID [1] 286958 0
NCT02358356
Secondary ID [2] 286959 0
AG0114NET
Universal Trial Number (UTN)
U1111-1171-4163
Trial acronym
CONTROLNETS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pancreatic Neuroendocrine tumours 295416 0
Midgut Neuroendocrine tumours 295489 0
Condition category
Condition code
Cancer 295669 295669 0 0
Neuroendocrine tumour (NET)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cohort A:
CAPTEM alone: Oral capecitabine 750mg/m2 twice a day, days 1-14 and oral temozolomide 75mg/m2 twice a day, days 10-14, then repeated with capecitabine on days 29-42 and temozolomide on days 38-42 within a 56 day (8w) cycle.

Cohort B:
PRRT alone: 7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV) on day 1 every 8 weeks for 4 cycles (56 day cycle).

Cohort A and B:
PRRT/CAPTEM: 7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV) on day 10 every 8 weeks for 4 cycles, with concurrent oral capecitabine 750mg/m2twice a day, days 1-14 and temozolomide 75mg/m2 twice a day, days 10-14 every 56 day cycle, up to 4 cycles.
Intervention code [1] 292163 0
Treatment: Drugs
Comparator / control treatment
The active control arm for Cohort A is the CAPTEM alone arm. For Cohort B, the PRRT alone arm is the active control arm.
Control group
Active

Outcomes
Primary outcome [1] 295374 0
To determine the rate of progression free survival (PFS) at 12 months in pNETs, and at 24 months in mNETs.
Timepoint [1] 295374 0
Progression free survival (PFS) will be measured from date of patient randomisation to the date of first evidence of disease progression, the occurrence of new disease or death from any cause. In patients who received treatment on study without a progression date or death, the PFS will be censored on the date of last clinical assessment, tumour assessment or enrolment, whichever is the later event.
Secondary outcome [1] 315455 0
Object tumour response rate (OTRR) will be defined as the number of patients with documented partial or complete response (PR or CR) divided by the number of patients evaluable for response as defined as per the RECIST version 1.1 criteria.
Timepoint [1] 315455 0
Objective tumour response rate (OTRR) will be assessed retrospectively at 12 months in pNETS, and 24 months in mNETS participants. In order to be considered evaluable, participants must have received at least one cycle of therapy and had their disease re-evaluated afterwards.
Secondary outcome [2] 315456 0
Clinical benefit rate (CBR) will be defined as the number of patients with documented partial or complete response or stable disease (PR or CR or SD) divided by the number of patients evaluable for response as defined by the RECIST version 1.1 criteria.
Timepoint [2] 315456 0
Clinical benefit rate (CBR) will be assessed retrospectively at 12 months in pNETS, and 24 months in mNETS participants. In order to be considered evaluable, participants must have received at least one cycle of therapy and had their disease re-evaluated afterwards.
Secondary outcome [3] 315457 0
To determine in each treatment group overall survival (OS).
Timepoint [3] 315457 0
Overall survival (OS) is defined as the interval from the date of registration to date of death from any cause, or the date of last known follow-up alive.
Secondary outcome [4] 315458 0
To determine in each treatment group safety (rates of adverse events). The NCI Common Terminology Criteria for Adverse Events version 4 (NCI CTCAE v4.03) will be used to classify and grade the intensity of adverse events after each treatment cycle. Acute adverse events are those occurring within 30 days after completion of CAPTEM or 90 days after completion of PRRT or PRRT/CAPTEM treatment, classified and graded according to the NCI CTCAE v4.03
Timepoint [4] 315458 0
Adverse events will be assessed at D1 & D29 of each cycle (all treatment arms), at end of treatment (30 days after final CAPTEM/PRRT+ 90 days after final PRRT), and then 2-monthly during follow-up to 12 months (pNETS), and 24 months (mNETS).
Secondary outcome [5] 315459 0
To determine in each treatment group Quality of Life (QoL). Questionnaires for Quality of Life (HR-QOL) assessment are EORTC QLQ C30, QLQ-GINET21 and EQ-5D-5L.
Timepoint [5] 315459 0
QoL will be assessed prior to D1 of each cycle every 8 weeks until disease progression.
Secondary outcome [6] 315460 0
To determine in each treatment group resource utilisation and cost effectiveness. The EQ-5D-5L questionnaire will be used, and Medicare (MBS) and PBS data will be obtained.
Timepoint [6] 315460 0
EQ-5D-5L will be assessed prior to D1 of each cycle until the end of the follow-up period (ie: 12 months pNETS, 24 months mNETS).

Eligibility
Key inclusion criteria
*Adults greater than or equal to 18 years old with histologically proven, moderate to well-differentiated G1/2 pancreatic or midgut NETs with Ki-67 < 20%;
*The presence of somatostatin receptor avidity suitable for PRRT demonstrated on 68Ga-octreotate PET scan;
*Progressive advanced/metastatic disease that has progressed during or after less than or equal to 2 prior systemic therapies;
*Unresectable disease, determined by an appropriately specialized surgeon or deemed not suitable for liver directed therapies where liver is the only site of disease;
*ECOG performance status 0-2;
*Ability to swallow oral medication;
*Adequate renal function (measured creatinine clearance > 50 ml/min by DTPA or 51CR-EDTA), bone marrow function (Hb > 9 g/d/L, ANC > 1.5 x109L, and platelets > 100 x 10/L);
*Adequate liver function (serum total bilirubin less than or equal to 1.5 x ULN, and Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP) less than or equal to 2.5 x ULN (less than or equal to 5 x ULN for patients with liver metastases)). INR less than or equal to 1.5 (or on a stable dose of LMW heparin for >2 weeks at time of enrolment .);
*Life expectancy of at least 9 months;
*Study treatment both planned and able to start within 28 days of randomisation; )
*Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments;
*Signed, written informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
*Primary NETs other than small bowel (midgut) or pancreatic NETs;
*Cytotoxic chemotherapy, targeted therapy, or biotherapy within the last four weeks;
*Prior intrahepatic 90Y microspheres, such as SIR-Spheres in the past six months;
*Prior Peptide Receptor Radionuclide Therapy;
*Major surgery/surgical therapy for any cause within one month;
*Surgical therapy of loco-regional metastases within the last three months prior to randomisation;
*Uncontrolled metastatic disease to the central nervous system. To be eligible, CNS metastases should have been treated with surgery and/or radiotherapy and the patient should have been receiving a stable dose of steroids for at least 2 weeks prior to randomisation, with no deterioration in neurological symptoms during this time;
*Poorly controlled concurrent medical illness. E.g. unstable diabetes (Note: optimal glycaemic control should be achieved before starting trial therapy); Symptomatic NYHA class III or IV congestive cardiac failure, myocardial infarction within 6 months of start of the study, serious uncontrolled cardiac arrhythmia, unstable angina, or any other clinically significant cardiac disease;
*History of other malignancies within 5 years except where treated with curative intent AND with no current evidence of disease AND considered not to be at risk of future recurrence Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible;
*Any uncontrolled known active infection, including chronic active hepatitis B, hepatitis C, or HIV. Testing for these is not mandatory unless clinically indicated. Participants with known Hepatitis B/C infection will be allowed to participate providing evidence of viral suppression has been documented and the patient remains on appropriate anti-viral therapy;
*Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of capecitabine/temozolomide (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or substantial small bowel resection);
*Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, including alcohol dependence or drug abuse;
*Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Upon confirmation of eligibility, patients will be centrally randomised by computer. Site coordinators will enter in eligibility information into the electronic case report form (eCRF) and the randomisation will occur via the NHMRC Clinical Trial Centre's IVRS "Flexetrials" system. Treatment allocation will be displayed in the eCRF once the randomisation is complete.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomised using a minimization method, stratified by tumour grade (G1 vs G2), prior systemic therapy (<1 vs. 2 regimens), visceral only vs. visceral with bone metastases, and treating site.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
21/09/2015
Actual
1/12/2015
Date of last participant enrolment
Anticipated
30/03/2018
Actual
9/11/2018
Date of last data collection
Anticipated
30/01/2021
Actual
31/10/2021
Sample size
Target
72
Accrual to date
Final
75
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 3955 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [2] 3956 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [3] 3957 0
Peter MacCallum Cancer Institute - East Melbourne
Recruitment hospital [4] 3959 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 3960 0
St George Hospital - Kogarah
Recruitment postcode(s) [1] 9863 0
2065 - Royal North Shore Hospital
Recruitment postcode(s) [2] 9864 0
6150 - Murdoch
Recruitment postcode(s) [3] 9865 0
3002 - East Melbourne
Recruitment postcode(s) [4] 9867 0
4029 - Royal Brisbane Hospital
Recruitment postcode(s) [5] 9868 0
2217 - Kogarah

Funding & Sponsors
Funding source category [1] 291515 0
Charities/Societies/Foundations
Name [1] 291515 0
Unicorn Foundation
Country [1] 291515 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Gastro-Intestinal Trials Group
Address
GI Cancer Institute
@ Lifehouse, Level 6
119-143 Missenden Road
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 290196 0
None
Name [1] 290196 0
Address [1] 290196 0
Country [1] 290196 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293058 0
Northern Sydney Local Health District HREC
Ethics committee address [1] 293058 0
Ethics committee country [1] 293058 0
Australia
Date submitted for ethics approval [1] 293058 0
18/11/2014
Approval date [1] 293058 0
25/02/2015
Ethics approval number [1] 293058 0
HREC/14/HAWKE/422

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

Contacts
Principal investigator
Name 58282 0
A/Prof Nick Pavlakis
Address 58282 0
NHMRC CTC
Locked Bag 77 Camperdown,
NSW, 1450
Country 58282 0
Australia
Phone 58282 0
+61 2 9562 5000
Fax 58282 0
+61 2 9562 5094
Email 58282 0
controlnets@ctc.usyd.edu.au
Contact person for public queries
Name 58283 0
CONTROL NETs Trial Coordinator
Address 58283 0
NHMRC CTC
Locked Bag 77 Camperdown,
NSW, 1450
Country 58283 0
Australia
Phone 58283 0
+61 2 9562 5000
Fax 58283 0
+61 2 9562 5094
Email 58283 0
controlnets@ctc.usyd.edu.au
Contact person for scientific queries
Name 58284 0
CONTROL NETs Trial Coordinator
Address 58284 0
NHMRC CTC
Locked Bag 77 Camperdown,
NSW, 1450
Country 58284 0
Australia
Phone 58284 0
+61 2 9562 5000
Fax 58284 0
+61 2 9562 5094
Email 58284 0
controlnets@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Please contact NHMRC CTC for data sharing policy.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseMyelotoxicity of Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors: A Decade of Experience.2016https://dx.doi.org/10.1089/cbr.2016.2035
EmbasePharmacotherapeutic Management of Well-Differentiated Neuroendocrine Tumors in Older Patients: Current Status and Potential Therapies.2022https://dx.doi.org/10.1007/s40266-022-00934-1
N.B. These documents automatically identified may not have been verified by the study sponsor.