177Lutetium-DOTATATE in Children with Primary Refractory or Relapsed High-risk Neuroblastoma (LuDO-N)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Neuroblastoma; Neuroblastoma Recurrent
• Intervention / Treatment: Combination product: 177Lu-DOTATATE

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jakob Stenman, MD PhD; Phone Number: 46 (0)51770000; Email: jakob.stenman@sll.se
• Study Contact Backup: Name: Kleopatra Georgantzi, MD; Phone Number: 46 (0)51770000; Email: kleopatra.georgantzi@sll.se

Study Locations

• Denmark
  • Copenhagen, Denmark, DK-2100
    • Recruiting
    • Rigshospitalet
    • Contact: Jesper S Brok, MD PhD; Email: jesper.sune.brok@regionh.dk
    • Contact: Jesper S Brok, MD PhD
• Lithuania
  • Vilnius, Lithuania, LT-08406
    • Recruiting
    • Vilnius University Hospital
    • Contact: Jelena Rascon, MD PhD; Email: jelena.rascon@gmail.com
    • Contact: Jelena Rascon, MD PhD
• Netherlands
  • Utrecht, Netherlands, NL-3584
    • Recruiting
    • Princess Máxima Center for Pediatric Oncology
    • Contact: Max M van Noesel, MD PhD; Email: M.M.vanNoesel@prinsesmaximacentrum.nl
    • Contact: Max M van Noesel, MD PhD
• Norway
  • Oslo, Norway, NO-0372
    • Recruiting
    • Oslo University Hospital, Rikshospitalet
    • Contact: Kirsten Brunsvig Jarvis, MD; Email: kirjar@ous-hf.no
    • Contact: Heidi Knüdsen, MD
• Sweden
  • Stockholm, Sweden, SE-171 76
    • Recruiting
    • Karolinska University Hospital
    • Contact: Kleopatra Georgantzi, MD; Email: kleopatra.georgantzi@sll.se
    • Contact: Jakob Stenman, MD PhD; Email: jakob.stenman@sll.se
    • Contact: Kleopatra Georgantzi, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 18 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Pathology 1.1. Histologically confirmed diagnosis of neuroblastoma 1.2. Immunohistochemical staining for somatostatin receptors (SSTR) performed from primary tumor tissue when available
2. Relapsed or primary refractory high-risk neuroblastoma: INSS stage 4 disease or INRGSS stage M disease
3. Age >18 months at the time of enrolment into this study
4. Life expectancy of greater than 3 months
5. Performance Status 5.1. Karnofsky > 50% (for patients > 12 years of age) 5.2. Lansky > 50% (for patients ≤ 12 years of age)
6. 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
7. 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
8. 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 > 50 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
9. Peripheral blood stem cells (PBSC) 9.1. A minimum of 2 x106 CD34+ cells/kg (optimally 6 x106 CD34+ cells/kg) must be available for each study subject prior to registration
10. 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:

1. Not fit enough to undergo proposed study treatment, as assessed by national PI, considering precautions defined in the latest version of the 177Lutetium-DOTATATE SmPC.
2. Pregnant or lactating patient
3. Concurrent treatment with any anti-tumor agents
4. Prior treatment with other radiolabeled somatostatin analogues
5. Hypersensitivity to any component of the investigational drug 177Lutetium-DOTATATE
6. Treatment with long-acting somatostatin analogues within 30 days, or with short-acting somatostatin analogues within 24 hours prior the administration of 177Lutetium-DOTATATE

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 177Lu-DOTATATE; A total of two doses of 177Lu-DOTATATE will be administered intravenously. The minimum time between treatments is 2 weeks.

Combination product: 177Lu-DOTATATE; 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumour dosimetry: absorbed dose per administration of 177Lu-DOTATATE	Measured by SPECT/CT	At every administered dose of 177Lu-DOTATATE throughout the trial treatment phase (5 years)
Correlation of expression of Somatostatin Receptor-2 (SSTR-2) to uptake on 68Ga-DOTATOC PET/CT	SSTR-2 expression in the histology samples from primary surgery measured by immunohistochemistry.	Throughout the trial treatment phase (5 years)
Uptake on 68Ga-DOTATOC PET/CT	Measured by SUVmax (maximum standardized uptake value)	At end of treatment, and 1 and 4 months after end of treatment.

Collaborators and Investigators

• Sponsor: Jakob Stenman
• Collaborators: Novartis; Advanced Accelerator Applications
• Investigators: Study Chair: Jakob Stenman, MD PhD, Karolinska University Hospital

Publications and helpful links

General Publications

• Sundquist F, Georgantzi K, Jarvis KB, Brok J, Koskenvuo M, Rascon J, van Noesel M, Gryback P, Nilsson J, Braat A, Sundin M, Wessman S, Herold N, Hjorth L, Kogner P, Granberg D, Gaze M, Stenman J. A Phase II Trial of a Personalized, Dose-Intense Administration Schedule of 177Lutetium-DOTATATE in Children With Primary Refractory or Relapsed High-Risk Neuroblastoma-LuDO-N. Front Pediatr. 2022 Mar 10;10:836230. doi: 10.3389/fped.2022.836230. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): May 19, 2021
• Primary Completion (Estimated): May 20, 2026
• Study Completion (Estimated): May 20, 2031

Study Registration Dates

• First Submitted: May 21, 2021
• First Submitted That Met QC Criteria: May 25, 2021
• First Posted (Actual): May 27, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 7, 2025
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Neuroblastoma; Molecular Mechanisms of Pharmacological Action; Radiopharmaceuticals; Lutetium Lu 177 dotatate
• Other Study ID Numbers: LuDO-N

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No