| 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. |
|
| 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. |
|
| 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 | 20.0 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| 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) |
|
| 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).
|
|
| E.2.2 | Secondary objectives of the trial |
• To compare the Objective Response Rate (ORR) between the two study arms;
• To compare the Overall Survival (OS) between the two study arms;
• To compare the Time to Tumour Progression (TTP) between the two study arms;
• To evaluate the safety and tolerability of 177Lu-DOTA0-Tyr3-Octreotate;
• To evaluate the health related quality of life (QoL) as measured by the EORTC QLQ-G.I.NET21 questionnaire; |
|
| 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.
Dosimetry, PK, ECG substudy:
A dosimetry, pharmacokinetics and ECG substudy is conducted in a
subset of 20 patients at selected sites to provide a more complete
assessment of the safety aspects of 177Lu-DOTA0-Tyr3-Octreotate.
To facilitate the patients recruitment in this substudy, a non-randomized cohort (177Lu-DOTA0-Tyr3-Octreotate only) is temporarily activated at all sites participating in the substudy in order to accelerate the collection
of the relevant information required by the Agencies. As soon as the
Study Protocol Amendment 4.1 is approved by the substudy site IRB, the randomization protocol of the study is halted at the substudy sites until a cumulative 20 patients are enrolled in the substudy and all the patients included in the substudy sites will be treated in arm A (4 infusions of 177Lu-DOTA0-Tyr3-Octreotate +30 mg Octreotide LAR). During this period, the sites not participating in the substudy continue to enroll
patients using the randomization protocol of the main study. When the target for the substudy will be reached the randomization protocol (Study Protocol 4.0) will restart again in the substudy sites.
In order to not bias the results obtained from randomized patients in the main study, the data of the patients enrolled in the substudy according to the Study Protocol version 4.1 (after the activation of the nonrandomized 177Lu-DOTA0-Tyr3-Octreotate cohort) will be analyzed descriptively only and they will not be considered in the primary and secondary analysis of the main study groups. Patients participating in the substudy will be patients who have been determined to be eligible for the main study and have signed the informed consent specific for the substudy.
Aside from the specific tests conducted in the dosimetry study, as
described in protocol Section 6.6 and the separate substudy manual, the treatment regimen and patient care management remain identical to that implemented in the main study.
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 metastasized or locally advanced, inoperable (curative
intent) at enrollment 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 randomization in the study.
4. Patients ≥18 years of age.
5. Patients must have progressive disease based on RECIST Criteria, Version 1.1 (§Appendix 2) while receiving an uninterrupted fixed dose of Octreotide LAR (20-30 mg/3-4 weeks). Disease progression must be centrally confirmed. In order to make the assessment, two CT (or MRI) scans are required. The oldest scan must not be older than 3 years from the date of randomization. The most recent scan must not be older than 4 weeks from the date of randomization. Both scans must be obtained while the patient is receiving the same fixed dose of Octreotide LAR (20-30 mg/3-4 weeks) with the following exceptions; 1) it is acceptable if the oldest scan is obtained within 12 weeks of the patient receiving a fixed dose regimen of Octreotide LAR (20-30 mg/3-4 weeks); AND 2) it is acceptable for either scan to be obtained before or during the time a patient receiving a fixed dose of Octreotide LAR has switched to an equivalent dose of short acting Octreotide for up to 6 weeks in order to obtain an OctreoScan®, provided the patient returns to the Octreotide LAR fixed dose after the OctreoScan® has been obtained.
6. Confirmed presence of somatostatin receptors on all target lesions (for target/non-target/measurable lesions definition see §Appendix 2, Section 1 and 2, RECIST Criteria, Version 1.1) documented by CT/MRI scans, based on positive OctreoScan® imaging within 24 weeks prior to randomization in the study (to be centrally confirmed). The OctreoScan® should be one that was performed while the patient was on a fixed dose of Octreotide LAR. If a patient has had an OctreoScan® performed while Octreotide LAR treatment-naïve, the patient must have a repeat OctreoScan® performed after 3 months of Octreotide LAR treatments before entering the clinical study to prove that the index lesions or new lesions still meet the criteria for inclusion. It is acceptable to have patients temporarily switched to Octreotide s.c. (up to six weeks) in order to obtain an OctreoScan®, provided they return to the same fixed dose of Octreotide LAR prior to the scan.
7. The tumour uptake observed in each target lesion (for target/nontarget/measurable lesions definition see §Appendix 2, Sections 1 and 2, RECIST Criteria, Version 1.1) using OctreoScan® must 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. |
|
| E.4 | Principal exclusion criteria |
1. Either serum creatinine >150 μmol/L (>1.7 mg/dL), or creatinine clearance <50 mL/min calculated by the Cockroft Gault method, eventually confirmed by measured creatinine clearance (or measured glomerular filtration rate (GFR) using plasma clearance methods, not gamma camera-based) <50 mL/min (the measured creatinine clearance / GFR is required only as confirmatory exam).
2. Hb concentration <5.0 mmol/L (<8.0 g/dL); WBC <2x109/L (2000/mm3); platelets <75x109/L (75x103/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 §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 randomization in the study.
8. Peptide receptor radionuclide therapy (PRRT) at any time prior to randomization in the study.
9. Any surgery, radioembolization, chemoembolization, chemotherapy and radiofrequency ablation within 12 weeks prior to randomization in the study.
10. Interferons, Everolimus (mTOR-inhibitors) or other systemic therapies within 4 weeks prior to randomization in the study.
11. Known brain metastases, unless these metastases have been treated and stabilized for at least 24 weeks, prior to enrollment in the study. Patients with a history of brain metastases must have a head CT with contrast to document stable disease prior to randomization in the study.
12. Uncontrolled congestive heart failure (NYHA II, III, IV).
13. Uncontrolled diabetes mellitus as defined by a fasting blood glucose >2 ULN.
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 on target lesions observed by OctreoScan® imaging during continued Octreotide LAR 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 the completion of the study.
16. Prior external beam radiation therapy to more than 25% of the bone marrow.
17. Current spontaneous 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 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. If such a patient can be imaged with MRI, then the patient would not be excluded.
21. Patients who have participated in any therapeutic clinical study/received any investigational agent within the last 30 days are excluded from participation in this trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable of this study is PFS measured from the randomization date. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS is defined as the time from randomization to documented centrally assessed progression according to RECIST Criteria or death due to any cause, as evaluated by the Independent Review Committee, i.e. the time from randomization until the date of last evaluable tumour assessment or date of death. |
|
| 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 |
Response rates and 95% CIs will be calculated for the ORR by treatment group. Frequencies in the two treatment groups will be compared by Fisher’s exact test.
TTP is defined as the time (number of days) from randomization to objective tumour progression centrally assessed.
OS is defined as the time from the date of randomization to the date of death due to any cause or the date of last contact (censored observation) at the date of data cut-off. |
|
| 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 | 4 |
| 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 |
| 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. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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