| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Symptoms of Neuro Endocrine tumours |
|
| E.1.1.1 | Medical condition in easily understood language |
| Neuroendocrine tumours come from the neuroendocrine system which makes hormones that regulate the workings of organs in the body.The tumours produce symptoms including diarrhoea and flushing (redness) |
|
| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10062476 |
| E.1.2 | Term | Neuroendocrine tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The principal objective in the study is to assess whether counting the number of circulating tumour cells (CTCs) in the bloodstream of patients with functioning neuroendocrine tumours (NETs) (tumours which release hormones) in the midgut region is an effective tool to predict how the symptoms patients suffer from will respond when they are taking Somatuline Autogel. This process will be of considerable benefit to patients if it is shown to be effective as it will, in effect, be a ‘liquid biopsy’ procedure which is minimally invasive and relatively quick. It will help to optimise treatment decisions for patients in the future.
The primary exploratory objective is to see whether counting the number of circulating tumour cells (CTCs)in the bloodstream of patients with funtioning neuroendocrine tumours (NETs)in the midgut region is able to predict how long these patients will survive before their disease progresses. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the effect of Somatuline Autogel on the symptoms of diarrhoea (frequent loose stools) and flushing (redness) in patients with a functioning NETs (neuroendocrine tumours which produce hormones). This will be done by using the IVRS automated call system to record and evaluate these symptoms.
To assess the effect of Somatuline Autogel treatment on the patients’ quality of life. This will be done using the EORTC QLQ-NET21 and the EORTC-QLQ-C30 questionnaires which patients will be asked to complete at enrollment, and at weeks 13, 25 and 53.
Assessment of progression free survival at one year. Patients will have a CT or MRI scan at screening, week 25 and 53 and the difference seen in the patients tumours from screening to the end of the study will be assessed using the RECIST criteria (Response Evaluation Criteria In Solid Tumors). RECIST is a set of published rules that define when cancer patients improve ("respond"), stay the same (are "stable") or worsen ("progression") d |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients MUST satisfy all of the following entry criteria before they will be allowed to participate in the study:
• Provision of written informed consent prior to any study related procedures. In this study consent may be provided by the legal guardian or carer. See section 5.2
• Patients (either sex) must be 18 years or older.
• Patients must have a documented diagnosis of a functioning midgut NET.
• In order to avoid patients with rapidly progressing tumours, only patients with well or moderately differentiated tumours and with a Ki67 proliferation index of <20% will be recruited.
• The clinically appropriate treatment for the patient must primarily be monotherapy with a somatostatin analogue.
• Patients must have had either a positive somatostatin receptor scintigraphy result or a positive 68 Gallium-DOTATATE PET imaging result.
• Patients must have a documented urinary or plasma 5-HIAA result within the year prior to study entry which is above the laboratory reference range.
|
|
| E.4 | Principal exclusion criteria |
If any of the following apply, the patient MUST not enter/continue in the study:
• If the patient is at risk of pregnancy or is breast feeding, unless treatment with Somatuline Autogel is clearly needed (as determined by the clinician).
• The patient is, in the opinion of the investigator, unable to comply fully with the protocol and the study instructions, or present any concomitant condition which could compromise the objectives of the study and/or preclude the protocol-defined procedures (e.g. severe medical conditions, brain metastases, psychiatric disorders, active or uncontrolled infection, known pituitary disease).
• The patient has been treated with any other unlicensed drug within the last 30 days before study entry or will require a concurrent treatment with any other experimental drugs or treatments.
• The patient has been treated with a somatostatin analogue prior to study entry, unless a washout period of at least 2 weeks for subcutaneous octreotide, or at least 6 weeks for a single dose of long acting somatostatin analogue has occurred.
• The patient requires medical treatment for the symptoms of the NET other than primarily monotherapy with a somatostatin analogue.
• The patient has received interferon, chemotherapy, chemoembolisation or radionuclide therapy within 3 months prior to study entry.
• The patient has a history of hypersensitivity to drugs with a similar chemical structure.
• Females of childbearing potential must provide a negative pregnancy test at the start of the study and must be using oral, double barrier or injectable contraception. Non childbearing potential is defined as being post-menopause for at least 1 year, surgical sterilisation or hysterectomy at least three months before the start of the study.
• The patient has abnormal baseline findings, any other medical condition(s) or laboratory findings that, in the opinion of the Investigator, might jeopardise the subject’s safety or decrease the chance of obtaining satisfactory data needed to achieve the objective(s) of the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measure is an assessment of the clinical value of enumeration of circulating tumour cells (CTCs) (counting the number of CTCs in the blood) to predict clinical symptomatic response in patients receiving Somatuline Autogel. Thus the endpoint is assessed using two efficacy variables; CTCs which will be enumerated (counted) at baseline and weeks 1, 5, 17, 25 and 53 and clinical symptomatic response. Clinical symptomatic response will be based on 24 hour symptom frequency (for diarrhoea and flushing) and severity (flushing only) which will be measured on a daily basis for the 7 days preceding the first study treatment, for the first 16 weeks of the study and on days 11 to 17 of each subsequent injection interval for the remainder of the study duration. After the final study drug injection at week 49, patients will provide 24 hour symptom frequency and severity on a daily basis on days 11 to 28.
The relationship between CTC presence at baseline and clinical symptomatic response will be assessed using logistic regression. The odds ratio for the effect of CTC presence on response will be estimated from this model and the associated 95% confidence interval calculated.
The relationship between CTC presence and clinical symptomatic response will also be assessed adjusted for the presence of other potentially influential patient characteristics (such as disease status (stage and grading of NET) and previous treatment) using multiple logistic regression. The potentially influential characteristics will be selected initially on the basis of simple logistic regressions. Those characteristics with a Wald test p<0.2 will be retained for inclusion in a multiple logistic regression model that will also include CTC presence. Using an appropriate stepwise procedure, a final multiple logistic regression model will be derived that includes CTC presence along with any still influential characteristics. From the final model the odds ratio for the effect of CTC presence on response, adjusted for any will be estimated and the associated 95% confidence interval calculated.
The relationship between the absolute value of CTCs and clinical symptomatic response and the use of different CTC cut-off values other than 0 for predicting clinical response will also be investigated using logistic regression if there is a sufficient range of CTC values observed in the study.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| CTC will be monitored throughout the study at different timepoints (baseline and weeks 1, 5, 17, 25 and 53). At each time point a comparison will be made to symptoms, CT/MRI scans and QoL questionnaires. |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints And Evaluations:
To assess the effect of Somatuline Autogel on the symptoms of diarrhoea and flushing in patients with a functioning NET.
To assess the effect of Somatuline Autogel treatment on quality of life via the EORTC QLQ-NET21 and the EORTC-QLQ-C30. The questionnaires will be conducted at enrolment, and at weeks 13, 25 and 53.
Assessment of progression free survival at one year. Patients will undergo a CT or MRI scan at screening, week 25 and 53 within the local investigator site. Progression will be assessed using the RECIST criteria.
Exploratory Secondary Efficacy Endpoints and Evaluations:
To assess the effect of Somatuline Autogel on plasma chromogranin A, urinary and plasma 5-hydroxyindoleacetic acid (5-HIAA) and neurokinin A, and whether these biomarkers correlate with CTC numbers.
To assess whether urinary 5-HIAA and plasma 5-HIAA levels are correlated.
To investigate the genomic profile of CTCs at week 1 and at the time of any observed progression (RECIST evaluation at 25 and 53 weeks). To investigate the genomic profile of liver metastases at the time of any observed progression (RECIST evaluation at 25 and 53 weeks) in appropriate patients.
To evaluate the presence and density of somatostatin receptor (SSTR) subtypes 2 and 5 on CTCs at weeks 1, 5, 25 and 53 of the study.
To compare the SSTR2 and SSTR5 density on CTCs with patients’ clinical symptomatic response and progression free survival during Somatuline Autogel treatment.
To compare the density of SSTR2 and SSTR5 on CTCs with that on primary tumour and liver metastasis in the patients where the primary tumour or liver metastasis samples are available.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
