| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with inoperable, progressive, OctreoScan® positive, well-differentiated neuroendocrine tumours of the small bowel (midgut carcinoid tumours), who are treated with 20 mg or 30 mg Octreotide LAR at a fixed dose for at least 12 weeks prior to enrolment in the study. |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with tumours arisen from the small bowel and which cannot be removed completely by surgery. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052399 |
| E.1.2 | Term | Neuroendocrine tumour |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 | 10062392 |
| E.1.2 | Term | Carcinoid tumor of the small bowel |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare Progression Free Survival (PFS) after treatment with 177Lu-DOTA0-Tyr3-Octreotate plus best supportive care (30 mg Octreotide LAR) to treatment with high dose (60 mg) Octreotide LAR in patients with inoperable, progressive (as determined by RECIST Criteria), somatostatin receptor positive, well-differentiated neuroendocrine tumours of the small bowel (midgut carcinoid tumours). |
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| E.2.2 | Secondary objectives of the trial |
1.To compare the Overall Response Rate (ORR) between the two study arms;
2.To compare the Overall Survival (OS) between the two study arms;
3.To compare the Time to Tumour Progression (TTP) between the two study arms;
4.To evaluate the safety and tolerability of 177Lu-DOTA0-Tyr3-Octreotate;
5.To evaluate the health related quality of life (QoL) as measured by the EORTC QLQ-G.I.NET21 questionnaire;
6.To explore the correlation of toxicity outcomes and administered radioactivity corrected for body weight and body surface area;
7.To explore the correlation of clinical efficacy outcomes with the levels of the biomarkers Chromogranin-A (CgA) in the serum and 5-Hydroxyindoleacetic acid (5-HIAA) in the urine;
8. To evaluate dosimetry, pharmacokinetics (PK) and ECG in a subset of 20
patients;
9.To explore the correlation of clinical efficacy outcomes with OctreoScan® tumour uptake score;
10.To explore the correlation of clinical outcomes with serum levels of Alkaline Phosphatase (AP).
|
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
This study is the first controlled comparative study with a radiolabelled versus non-radioactive somatostatin analogue. In this study safety and efficacy of treatment with 177Lu-DOTA0-Tyr3-Octreotate versus Octreotide LAR will be investigated in patients with inoperable, progressive, somatostatin receptor positive midgut carcinoid tumours.
Primary Objective:
Calculate whole body and organ radiation dosimetry of 177Lu-DOTA0-Tyr3-Octreotate to determine the dose to critical organs (e.g., kidney and bone marrow) and correlate with findings of the Erasmus MC Phase I/II Clinical study.
Secondary Objectives:
- Define the pharmacokinetic profile (ADME) of 177Lu-DOTA0-
Tyr3-Octreotate;
- Correlate safety, dosimetry, and pharmacokinetic data obtain in
this study with the Erasmus MC phase I/II Clinical study to
confirm previous findings;
- Evaluate cardiac safety: determine the acute
electrophysiological changes during treatment with 177Lu-
DOTA0-Tyr3-Octreotate (through 24-hour continuous ECG
recording via 12-lead Holter machine). |
|
| E.3 | Principal inclusion criteria |
1. Presence of inoperable (curative intent) at enrolment time, histologically proven, midgut carcinoid tumour (to be centrally confirmed).
2. Ki67 index ≤ 20% (to be centrally confirmed).
3. Patients on Octreotide LAR at a fixed dose of 20 mg or 30 mg at 3-4 weeks intervals for at least 12 weeks prior to enrolment in the study.
4. Patients ≥18 years of age.
5. Patients must have progressive disease based on RECIST Criteria, Version 1.1 (Appendix 2) evidenced with CT scans/MRI within 3 years from enrolment (to be centrally confirmed); previous images must be centrally evaluated to confirm the disease progression under previous therapy: for the purpose of determining disease status the oldest CT/MRI scan must not be older than 3 years and the
most recent scan must not be older than 4 weeks from the projected randomization date. The
CT scan/MRI scan should be one that was performed while the patient was on a fixed dose of Sandostatin LAR.
6. Confirmed presence of somatostatin receptors on all technically evaluable tumour lesions documented by CT/MRI scans, based on positive OctreoScan® imaging within 24 weeks prior to enrolment in the study (to be centrally confirmed).
7. The tumour uptake observed using OctreoScan® should be ≥ normal liver uptake observed on planar imaging (to be centrally confirmed) (Appendices 5 and 6).
8. Karnofsky Performance Score (KPS) ≥60
9. Presence of at least 1 measurable site of disease.
10. [Applicable only for France] All patients included in the trial must be affiliated with a social security regime or be a beneficiary of the same in order to be included in the study.
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|
| E.4 | Principal exclusion criteria |
1. Serum creatinine >150 µmol/L or 1.7 mg/dL, or a measured creatinine clearance (or measured glomerular filtration rate (GFR) using plasma clearance methods, not gamma camera-based) of <50 mL/min.
2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x10^9/L (2000/mm3); platelets <75x10^9/L (75x10^3/mm3).
3. Total bilirubin >3 x ULN.
4. Serum albumin <3.0 g/dL unless prothrombin time is within the normal range.
5. Pregnancy (see protocol Appendix 7) or lactation.
6. For female patients of childbearing potential (defined as < 2 years after last menstruation and not surgically sterile) and male patients, who are not surgically sterile or with female partners of childbearing potential: absence of effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal gel) as defined in Appendix 7.
7. Treatment with >30 mg Octreotide LAR at 3-4 weeks intervals within 12 weeks prior to enrolment in the study.
8. Peptide receptor radionuclide therapy (PRRT) at any time prior to enrolment in the study.
9. Targeted surgery, radiotherapy (external beam), chemotherapy, embolization, interferons, mTOR-inhibitors or other investigational therapy within 12 weeks prior to enrolment in the study.
10. Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrolment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to enrolment in the study.
11. Uncontrolled congestive heart failure (NYHA II, III, IV).
12. Uncontrolled diabetes mellitus as defined by a fasting blood glucose >2 ULN.
13. Any patient who has both OctreoScan® positive and negative tumours.
14. Any patient receiving treatment with short-acting Octreotide, which cannot be interrupted for 24 h before and 24 h after the administration of 177Lu-DOTA0-Tyr3-Octreotate, or any patient receiving treatment with Octreotide LAR, which cannot be interrupted for at least 6 weeks before the administration of 177Lu-DOTA0-Tyr3-Octreotate, unless the tumour uptake observed by OctreoScan® imaging during continued Octreotide treatment is at least as high as normal liver uptake observed by planar imaging (Appendices 5 and 6).
15. Patients with any other significant medical, psychiatric, or surgical condition, currently uncontrolled by treatment, which may interfere with completion of the study.
16. Prior external beam radiation therapy to more than 25% of the bone marrow.
17. Urinary incontinence.
18. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years.
19. Patients who have not provided a signed an informed consent form to participate in the study, obtained prior to the start of any protocol related activities.
20. Patient with known incompatibility to CT Scans with I.V. contrast due to allergic reaction or renal insufficiency.
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
progression free survival (PFS).
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS is defined as the time from randomization to documented progression according to RECIST Criteria or death due to any cause, as evaluated by the Independent Review Committee, within 76 weeks of randomization. |
|
| E.5.2 | Secondary end point(s) |
The secondary efficacy variables are: Objective Response Rate (ORR), Time to Tumour Progression (TTP) and Overall Survival (OS).
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
ORR will be calculated as the proportion of patients with tumour size reduction of a predefined amount (the sum of partial responses (PR) plus complete responses (CR)) and for a minimum time period. Response duration will be calculated from the time of initial response until documented tumour progression.
TTP is defined as the number of days from randomiation to objective tumour progression.
OS will be calculated from the randomization date until the day of death due to any cause.
Survival data will be collected at the End of Study and up to 3 years after the End of Study.
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| France |
| Germany |
| Italy |
| Portugal |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The End of Study is defined as the moment that the last enrolled patient has completed 72 weeks of assessments (unless early termination) after the patient’s first treatment in either arm of the study. |
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| 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 | 8 |
| 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 | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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