Two parallel phase II randomized open label trials of Lutetium-177 Octreotate
(177Lu-Octreotate) peptide receptor radionuclide therapy (PRRT) and capecitabine
(CAP)/temozolomide (TEM) chemotherapy (chemo): (i) versus CAPTEM alone in the treatment of
low to intermediate grade pancreatic neuroendocrine tumours (pNETs); (ii) versus PRRT alone
in the treatment of low to intermediate grade mid gut neuroendocrine tumours (mNETs).
Neuroendocrine tumours (NETs) are a heterogeneous group of malignancies that can arise at any
site in the gastrointestinal tract, that are known by their ability to over express
somatostatin receptors. Originally called carcinoid tumours, these tumours are rising in
incidence. In patients with incurable disease, several systemic options have demonstrated
activity but few have been compared in prospective, randomised controlled trials (RCTs).
177Lu-Octreotate peptide receptor radionuclide therapy (PRRT) and CAPTEM have shown promising
activity in initial single arm trials. Prospective RCTs are needed to build on these early
trials to determine the optimal role of these therapies in clinical practice.
CONTROL NETs is a parallel group phase II randomised open label trial of Lutetium-177
Octreotate (177Lu-Octreotate (Lutate)) peptide receptor radionuclide therapy (PRRT) and
capecitabine (CAP)/temozolomide (TEM) chemotherapy (chemotherapy): (i) versus CAPTEM alone in
the treatment of low to intermediate grade pancreatic neuroendocrine tumours (pNETs); (ii)
versus PRRT alone in the treatment of low to intermediate grade midgut neuroendocrine tumours
i) To determine the relative activity of CAPTEM/PRRT in biopsy-proven, low to intermediate
grade, unresectable, metastatic 68Ga-octreotate PET-avid NETs in the following parallel phase
II studies: Group A: pNETs and Group B: mNETs.
ii) To inform future comparative phase III RCTs to determine the optimal therapies in pNETs
Two parallel non-comparative group randomised, controlled, multi-centre phase II, 2 arm
open-label controlled trials with 2:1 allocation (experimental : control)
1. Study A: pNETs: PRRT/CAPTEM vs. CAPTEM (control)
2. Study B: mNETs: PRRT/CAPTEM vs. PRRT (control)
Randomisation will be performed using the method of minimisation.
Patients will be stratified by:
- Previous systemic therapy regimens (0,1 v 2)
- WHO tumour grade: Low Grade - G1 (Ki67<3% (mitotic count <2)) vs. Intermediate Grade -
G2 (Ki67 3-20% (mitotic count 2-20))
- visceral only vs. visceral with bone metastases
- Treating institution
The target population for this study is consenting adult patients with advanced, unresectable
low or intermediate grade (Ki-67<20%) midgut neuroendocrine tumours (mNETs) or pancreatic
neuroendocrine tumours (pNETs ), who have received ≤ 2 prior systemic therapies for advanced
unresectable disease (including long acting somatostatin analogues).
- Patients will be assessed at each treatment cycle for toxicity
- CT including a 3 phase contrast CT of the liver will be undertaken at baseline, then
every 2 months (pNET) or every 4 months (pNET) until radiologic progression by RECIST
- 68Ga-DOTATATE PET CT Scan will be undertaken at baseline, then every 4 months until
radiologic progression by RECIST v1.1.
- 18F-FDG PET Scan may be performed at the discretion of treating clinician at baseline,
then every 2 months until radiologic progression by RECIST v1.1) for G2 NETS.
- 24-h whole-body planar gamma imaging will be undertaken on the day after administration
of PRRT (every 2 months).
- Serum biomarkers will be undertaken every 4 months until disease progression.
- Quality of life assessments will be undertaken at every 2 months until disease
progression using QLC C30 and QLQ-GINET21.
- Health utilities will be evaluated with EQ-5D-5L every 2 months until completion of
study follow up.
Both studies are based on a Simon's two-stage design and are randomised using a 2:1
randomisation (Experimental: Control). A mix of approximately 30% G1 patients and 70% G2
patients is expected.
Study A, pNETs (n=90) will have 80% power with 95% confidence interval to exclude a 12 months
PFS of 60% in favour of a more interesting rate of 77% in the experimental arm.
For Study B, mNETs (n=75), the PFS at 24 months in the control arm is expected to be 52%.
Thus study B will have 80% power with 95% confidence interval to demonstrate a PFS rate at 24
months of 70% in experimental arm, a result that would warrant further investigation.
A total sample size of 165 patients for the two studies will be accrued over 2 years.
Patients will be followed up for a minimum of 2 years.
- Adults ≥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 ≤ 2 prior
- 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
- Adequate liver function (serum total bilirubin ≤ 1.5 x ULN, and Alanine
aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP) ≤
2.5 x ULN (≤ 5 x ULN for patients with liver metastases)). INR ≤ 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.
- 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
- 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