E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with proved progressive (or refractory to standard systemic therapy available in Belgium at the time of inclusion) neuroendocrine tumors, not amenable to surgical resection with curative intent. |
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E.1.1.1 | Medical condition in easily understood language |
Advanced neuroendocrine tumor patients who progresses or not responding to standard systemic therapy, and not possible surgery with curative intent. |
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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 | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10062476 |
E.1.2 | Term | Neuroendocrine tumor |
E.1.2 | System Organ Class | 100000004864 |
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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 |
For each lesion: To assess the value of the following parameters (obtained through functional and molecular imaging) for predicting the lesion-by-lesion PRRT treatment outcome: - 18FDG uptake on 18FDG PET/CT, - 68Ga-octreotate uptake on 68Ga-octreotate PET/CT, - Apparent Diffusion Coefficient on Diffusion Weighted-MRI, [for these three parameters, absolute values at baseline will be assessed] - Tumor dosimetry on post-177Lu-octreotate SPECT/CT after the first cycle. |
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E.2.2 | Secondary objectives of the trial |
Secondary objective: To generate a patient-based response model based on the previously defined parameters.
Exploratory objectives: For each lesion: to assess the value of the parameters mentioned in section 3.1 for predicting the lesion-by-lesion PRRT treatment outcome: - absolute values of the three imaging parameters and their relative changes after each cycle; - serial tumor dosimetry on post-177Lu-octreotate SPECT/CT after each cycle |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria: Patient-based 1. Age above or equal to 18 years. 2. Histology-proven advanced GEP-NETs. 3. Disease progression defined as follows (at least one of the following): - Radiological disease progression (according to RECIST 1.1) on an MRI or CT over the last 12 months Or - Disease progression on a somatostatin receptor-imaging, PET/CT or SPECT/CT over the last 12 months [apparition of new lesion(s) or increase in the transaxial plane diameter of more than 30% on the same imaging modality] Or - Both of the following criteria (a+b): a. clinical progression: - sustained (for more than 2 weeks) increase of NET-specific hormonal hypersecretion related symptom frequency by 50% or, - sustained (for more than 2 weeks) increase of severity by 1 grade (according to NCI-CTCAE version 4.03). b. biochemical progression: by increase of NET-specific tumor markers (plasma Chromogranin A, plasma NSE, urine 5-HIAA or other) in two successive measurements. 4. Disease refractory to SSA’s and/or standard systemic therapy available in Belgium at the time of inclusion criteria. 5. Long-acting SSAs should be discontinued at least 4 weeks before study treatment start date and, if needed, switched to short-acting analogues which should be stopped 48h before the treatment date. 6. Adequate renal function with GFR ≥ 50 mL/min/1.73m2 (evaluated by 51Cr-EDTA test). 7. Adequate bone marrow function with hemoglobin ≥ 9 g/dL; neutrophil ≥ 1.5·103/μL; platelet count ≥ 100·103/μL. 8. Adequate liver function with total bilirubin ≤ 2 x ULN and transaminases ≤ 5 x ULN, serum albumin > 3 g/dL with normal prothrombin time (> 70%). 9. ECOG Performance Status ≤ 1. 10. Women of childbearing potential and men with partners of childbearing potential must agree to use a highly‐effective form of contraception for the duration of study participation and up to six months after the end of the treatment. A pregnancy test (serum) must be performed within 4 weeks prior to inclusion for every female patient of childbearing potential and it must be negative. 11. Patient’s written informed consent obtained prior to any study procedure. 12. All necessary baseline procedures should be performed within 4 weeks prior to first 177Lu-octreotate injection (D0).
Inclusion Criteria: Lesion-based 13. The patient must have at least one target lesion fulfilling all of the below criteria: • On the 68Ga-octreotate PET/CT: tumor uptake higher than the physiological liver uptake (grade III or IV of the Rotterdam visual score30) in a lesion with longest transaxial plane diameter ≥ 20mm (measured on the CT, part of the PET/CT); • At least one of these lesions morphologically measurable according to RECIST 1.1 and progressive on the MRI (or CT if MRI is not applicable); • Target lesion shall not have been previously irradiated.
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E.4 | Principal exclusion criteria |
1. Resectable tumor with curative intent. 2. Any major surgery within the last 6 weeks prior to inclusion in the study 3. Radiotherapy, chemotherapy, embolization, mammalian target of rapamycin (mTOR)-inhibitors, receptor tyrosine-kinase inhibitors, interferon, or other investigational therapy within the last 12 weeks prior to inclusion in the study. 4. Diffuse bone marrow infiltration on the baseline 68Ga-octreotate PET/CT confirmed by MRI. 5. Prior external beam radiotherapy on kidneys or on more than 25% of bone marrow. 6. Patients with known uncontrolled brain metastases. 7. Patients with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the investigator’s opinion, may interfere with completion of the study. 8. Pregnant or lactating patients. 9. Women of childbearing potential and men with partners of child-bearing potential refusing an adequate contraception.
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E.5 End points |
E.5.1 | Primary end point(s) |
The time to progression (TTP) for each target lesion assessed on MRI (or on CT scan if MRI is not applicable). TTP is defined as the time between treatment initiation and objective tumor progression with censoring of patients who die as a result of any cause. Progression is defined in the Treatment Modalities paragraph. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After morphological progression of the patient (according to RECIST 1.1) |
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E.5.2 | Secondary end point(s) |
Secondary endpoints: • Best morphological response according to RECIST 1.1, • Progression Free Survival (PFS). PFS is defined as the time between treatment initiation and the first of the following events: disease progression (clinical or radiological) or death resulting from any cause. Progression is defined in the Treatment Modalities paragraph. • Biochemical response (evolution of NET-specific tumoral markers, as for inclusion).
Exploratory endpoints: The time to progression (TTP) for each target lesion assessed on MRI (or on CT scan if MRI is not applicable). Progression is defined in the Treatment Modalities paragraph. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For the secondary endpoint: After morphological progression of the patient (according to RECIST 1.1)
For the exploratory endpoints: After each cycle of treatment |
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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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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
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End of study will be declared when all the following criteria will have been met: - Two years after the date of the inclusion of the last patient - Safety reporting has been done for all patients - The trial is mature for the analysis of the endpoints as defined in the protocol, if the trial reaches its endpoints - The database has been fully cleaned and frozen for all analyses
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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 | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |