Capecitabine ON Temozolomide Radionuclide Therapy Octreotate Lutetium-177 NeuroEndocrine Tumours Study

Phase

Condition

Carcinoid Syndrome And Carcinoid Tumours

Digestive System Neoplasms

Abdominal Cancer

Treatment

N/A

Clinical Study ID

NCT02358356

CTC0120 / AG0114NET

Ages > 18
All Genders

Study Summary

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).

Eligibility Criteria

Inclusion

Inclusion Criteria:

Adults ≥18 years old with histologically proven, moderate to well-differentiated G1/2pancreatic 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 priorsystemic therapies;
Unresectable disease, determined by an appropriately specialized surgeon or deemed notsuitable 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 ≤ 1.5 x ULN, and Alanineaminotransferase (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 stabledose 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, timingand/or nature of required assessments;
Signed, written informed consent.

Exclusion

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 torandomisation;
Uncontrolled metastatic disease to the central nervous system. To be eligible, CNSmetastases should have been treated with surgery and/or radiotherapy and the patientshould have been receiving a stable dose of steroids for at least 2 weeks prior torandomisation, with no deterioration in neurological symptoms during this time;
Poorly controlled concurrent medical illness. E.g. unstable diabetes (Note: optimalglycaemic control should be achieved before starting trial therapy); Symptomatic NYHAclass III or IV congestive cardiac failure, myocardial infarction within 6 months ofstart of the study, serious uncontrolled cardiac arrhythmia, unstable angina, or anyother clinically significant cardiac disease;
History of other malignancies within 5 years except where treated with curative intentAND with no current evidence of disease AND considered not to be at risk of futurerecurrence Patients with a past history of adequately treated carcinoma-in-situ, basalcell carcinoma of the skin, squamous cell carcinoma of the skin, or superficialtransitional 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 participateproviding evidence of viral suppression has been documented and the patient remains onappropriate anti-viral therapy;
Impairment of gastrointestinal function or gastrointestinal disease that maysignificantly alter the absorption of capecitabine/temozolomide (e.g., ulcerativedisease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome orsubstantial small bowel resection);
Presence of any psychological, familial, sociological or geographical conditionpotentially 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 potentialmust have a negative pregnancy test done within 7 days prior to registration. Men musthave been surgically sterilised or use a (double if required) barrier method ofcontraception .

Study Design

November 01, 2015

October 31, 2021

Study Description

PROTOCOL SYNOPSIS

Background

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 (mNETs).

General aim

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 and mNETs.

Design

Two parallel non-comparative group randomised, controlled, multi-centre phase II, 2 arm open-label controlled trials with 2:1 allocation (experimental : control)

Study A: pNETs: PRRT/CAPTEM vs. CAPTEM (control)
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

Population

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).

Assessments

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 v1.1.
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.

Statistical considerations

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.

Connect with a study center

Royal North Shore Hospital
St Leonards, New South Wales 2065
Australia
Site Not Available
Royal Brisbane and Women's Hospital
Herston, Queensland 4029
Australia
Site Not Available
Peter MacCallum Cancer Centre
East Melbourne, Victoria 8006
Australia
Site Not Available
Fiona Stanley Hospital
Murdoch, Western Australia 6150
Australia
Site Not Available

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