177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-risk Neuroblastoma

Study Overview
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Brief Summary
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The LuDO-N Trial is a multi-centre phase II clinical trial on 177Lu-DOTATATE treatment of recurrent or relapsed high-risk neuroblastoma in children. The LuDO-N Trial builds on the experience from the previous LuDO Trial and utilises an intensified dosing schedule to deliver 2 doses over a 2-week period, in order to achieve a maximal effect on the often rapidly progressing disease. This strategy requires a readiness for autologous stem cell transplantation in all patients, but is not anticipated to increase the risk of long-term sequelae, since the cumulative radiation dose remains unchanged. The primary aim of the study is to assess the response to 177Lu-DOTATATE treatment at 1 and 4 months after ende of treatment. Secondary aims are to assess survival and treatment-related toxicity. Additional aim are to correlate tumour dosimetry with response, correlate SSTR-2 expression with 68Ga-DOTATATE uptake and to correlate the uptake with the treatment response.

Official Title
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A Phase II Trial of 177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-risk Neuroblastoma

Conditions
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Neuroblastoma Recurrent, Neuroblastoma

Intervention / Treatment
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* Combination Product: 177Lu-DOTATATE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathology 1.1. Histologically confirmed diagnosis of neuroblastoma 1.2. Immunohistochemical staining for somatostatin receptors (SSTR) performed from primary tumor tissue when available Relapsed or primary refractory high-risk neuroblastoma: International Neuroblastoma Staging System (INSS) stage 4 disease or International Neuroblastoma Risk Group Staging System (INRGSS) stage M disease Age >18 months and < 18 years of age at the time of enrolment into this study Life expectancy of greater than 3 months Performance Status 5.1. Karnofsky > 50% (for patients > 12 years of age) 5.2. Lansky > 50% (for patients ≤ 12 years of age) Prior treatment 6.1. Two-week washout from any prior treatment 6.2. Patients must have recovery of hematological toxicity following previous therapy 6.3. Adequate recovery from major surgery prior to receiving study treatment Diagnostic imaging 7.1. Uptake in the primary tumor or metastatic tumour deposits on 68Ga-DOTATATE PET/CT at least higher than the liver uptake and performed within two months prior to registration 7.2. 123I-mIBG scintigraphy to be performed within two months prior to registration 7.3. CT or MRI of the primary tumor and bulky metastatic sites within two months prior to registration Laboratory requirements to be performed within 7 days prior to commencing trial treatment 8.1. Hematology: 8.1.1. Hemoglobin, If Hb is <120 g/L then patient will receive a blood transfusion prior to commencing trial treatment 8.1.2. Absolute neutrophil count > 1.0 x 109/L 8.1.3. Absolute Platelets > 100 x 109/L 8.2. Biochemistry: 8.2.1. Bilirubin within 1.5 x ULN 8.2.2. ALT within 2.5 x ULN 8.2.3. AST within 2.5 x ULN 8.2.4. GGT within 5 x ULN 8.2.5. ALP within 5 x ULN 8.2.6. Glomerular filtration rate >50mL/min/1.73m2 assessed by a recognised method, such as inulin, 51Cr-EDTA, 99mTc-DTPA or iohexol clearance and performed within 2 months prior to registration 8.2.7. Urinary catecholamine metabolites measured within 2 months prior to registration Peripheral blood stem cells (PBSC) 9.1. A minimum of 4 x106 CD34+ cells/kg (optimally 6 x106 CD34+ cells/kg) must be available for each study subject prior to registering Written informed consent from patient and/or parent(s) or legal guardian(s) in accordance with national regulations, prior to registration or any trial-related screening procedures Exclusion Criteria: Not fit enough to undergo proposed study treatment, as assessed by national PI, considering precautions defined in the latest version of the Lutathera SmPC Pregnant or lactating patient Concurrent treatment with any anti-tumor agents Prior treatment with other radiolabeled somatostatin analogues Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient or legal guardian before registration in the trial Hypersensitivity to any component of the investigational drug Lutathera® Treatment with long-acting somatostatin analogues within 30 days prior the administration of Lutathera®

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 177Lu-DOTATATE<br>A total of two doses of 177Lu-DOTATATE will be administered intravenously. The minimum time between treatments is 2 weeks. | Combination Product: 177Lu-DOTATATE<br>* A weight-based activity of 200 MBq kg-1 will be used for the first dose. The activity of the second dose will be calculated based on whole body activity scans as well as SPECT CT scans to determine the absorbed kidney dose. The aim is to administer 177Lu-DOTATATE corresponding to a whole-body dose of 1,2 Gy, with a cumulative whole-body dose of about 2,4 Gy over two courses, and not exceeding a cumulative renal dose of 23 Gy, in order to avoid renal toxicity.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment response assessed in accordance with the Revised International Neuroblastoma Response Criteria (INRC) - 1 months after End of Treatment | Treatment response assessed in accordance with the Revised International Neuroblastoma Response Criteria (INRC) | 1 months following end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and severity of treatment-related adverse events | Number and severity of treatment-related adverse events | Up to 5 years after end of treatment | 
| Treatment response assessed in accordance with the Revised International Neuroblastoma Response Criteria (INRC) - 4 months after End of Treatment | Treatment response assessed in accordance with the Revised International Neuroblastoma Response Criteria (INRC) | 4 months following end of treatment | 
| Progression-free survival | Time to progress or death, whichever occurs first | Time from registration to progression or death, up to 5 years following end of treatment | 
| Overall survival - up to 5 years after End of Treatment | Overall survival | Time from registration to the the date of death, up to 5 years following end of treatment |