Neoplasms

All Conditions

Rare Diseases

Neuroendocrine Tumors

Sarcoma, Ewing

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Pancreatic Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Capecitabine

Temozolomide

Antimetabolites

Antineoplastic Agents, Alkylating

Alkylating Agents

7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV) on day 1 every 8 weeks for 4 cycles.

Oral capecitabine 750mg/m2 b.i.d. days 1-14 and temozolomide 75mg/m2 b.i.d. days 10-14 every 28 day cycle, up to 8 cycles.

7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV) on day 10 every 8 weeks for 4 cycles, with concurrent oral capecitabine 750mg/m2 b.i.d. days 1-14 and temozolomide 75mg/m2 b.i.d. days 10-14 up to 4 cycles.

7.8GBq 177Lu Octreotate (Lutate) given intravenously (IV)

octreotate

Nick Pavlakis, Associate Professor

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).

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)

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

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.

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

To correlate circulating \& tissue biomarkers with clinical study endpoints (relating to survival, response and safety), including but not limited to CgA, Ki-67 \& tumour MGMT expression.

Explore correlation between other measures of response relevant to this disease, eg 68Ga-DOTATATE, SUVmax tumour uptake, and other measures of response of a biochemical measure, eg. tumour markers, chromogranin A, and patient reported outcomes QOL undertaken in order to identify how progressive symptoms or biochemical response relates to conventional measures of response using structural and/or functional imaging. A formal statistical analysis plan will be formulated prior to final data analysis.

To determine the rate of progression free survival (PFS) at 12 months in pNETs (Group A), and at 24 months in mNETs (Group B). (PFS defined from time of randomisation to disease progression as defined by RECIST criteria version 1.1).

To determine objective tumour response rate (OTRR) (partial or complete response (PR/CR)).

To determine overall survival (OS) (death from any cause).

To determine safety (rates of adverse events).

To determine Quality of Life (QoL) (QoL scores from EORTC QLQ C30 and QLQ-GINET21 questionnaires)

To determine resource utilization (costs associated with treatment regimen, MBS and PBS data, and health utilities scores from EQ-5D-5L).

To evaluate the proportion of patients who have experienced a clinical benefit of the regimen(s). (Clinical Benefit is defined as the proportion of patients who experience complete or partial response (using RECIST v1.1) or stable disease at 12 months or 24 months as appropriate).

Spots Global Cancer Trial Database for intermediate grade