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RecruitingLast updated: 9 April 2024

SIOPEN: This study is assessing induction and consolidation chemotherapies and radiation therapy for people with high-risk neuroblastomaHigh-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma

Clinical summary

Summary

This study includes three sequential randomisations to assess the efficacy of induction and consolidation chemotherapies and radiation therapy for people with high-risk neuroblastoma.

The first randomisation (R-I) will compare the efficacy of two induction chemotherapies (RAPID COJEC and GPOH regimens) in a phase III setting. 

The second randomisation (R-HDC) will compare the efficacy of single high-dose chemotherapy (HDC) consolidation with Bu-Mel versus tandem HDC with Thiotepa followed by Blue-Mel.

The impact of local treatment in this phase III setting will be assessed, according to the presence or not of a macroscopic residual disease after surgery and HDC.

In case of macroscopic residual disease, 21.6 Gy radiation therapy to the preoperative tumour bed will be randomised (R-RTx) versus the same treatment plus a sequential boost of additional 14.4 Gy to the residual tumour.

In the case of no macroscopic residual disease, 21.6 Gy radiation therapy will be delivered to the preoperative tumour bed.

Note: The eligibility critieria for this trial are complex and vary depending on each randomisation, please speak to your doctor about whether you might be eligible to participate. 

Conditions

This trial is treating patients with high-risk neuroblastoma

Cancer

Brain and Spinal Cancers Brain and Spinal

Age

People0 - 20

Phase

III

Trial Acronym

SIOPEN

More information

Trial Identifiers

Use the hyperlinks, where available to access additional clinical trial information.

Trial sponsor

Gustave Roussy, Cancer Campus, Grand Paris

Scientific Title

High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma

Eligibility

Inclusion

At diagnosis (or up to 21 days after one cycle of chemotherapy for patients with localized neuroblastoma with MYCN amplification).

R-I eligibility criteria:

  1. Established diagnosis of neuroblastoma according to the SIOPEN-modified International Neuroblastoma Risk Group (INRG) criteria, High-risk neuroblastoma defined as:

    • Stage M neuroblastoma above 365 days of age at diagnosis (no upper age limit) and Ms neuroblastoma 12-18 months old, any MYCN status* or
    • L2, M or Ms neuroblastoma any age with MYCN amplification or focal high level MYC or MYCL amplification * In Germany, patients aged less than 18 months with stage M and without MYCN amplification will not be enrolled in HR-NBL2 trial.
  2. No previous chemotherapy or up to 21days one cycle of chemotherapy for patients with localized neuroblastoma with MYCN amplification or patients with metastatic neuroblastoma treated in emergency
  3. Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment. Sexually active patients must agree to use acceptable and appropriate contraception while on HRNBL2 study drug and for one year after stopping the study . Acceptable contraception is defined in CTFG Guidelines "Recommendations related to contraception and pregnancy testing in clinical trials". Female patients who are lactating must agree to stop breast-feeding.
  4. Written informed consent to enter the R-I randomization from patient or parents/legal representative, patient, and age-appropriate assent.
  5. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
  6. Patients should be able and willing to comply with study visits and procedures as per protocol.

In case of parents'/patient's refusal to R-I, or organ toxicity, exclusion criteria at diagnosis, patients can still be enrolled in HR-NBL2 trial with parents'/patient's consent within 3 weeks from the beginning of chemotherapy. Patients will be treated with the standard induction regimen per country (rapid COJEC or GPOH) and will be potentially eligible for subsequent randomizations.

Randomization for HDC strategy will be performed at the end of induction after the disease evaluation and after surgery of the primary tumor for those patients who will receive surgery before HDC.

R-HDC eligibility criteria:

  1. - Stage M neuroblastoma above 365 days of age at diagnosis, any MYCN status, EXCEPT patients with stage M or Ms 12-18 months old with numerical chromosomal alterations only, and in complete metastatic response at the end of induction: in this case, patients will have surgery but will not be eligible for R-HDC and will not be able to pursue the trial.

    OR

    - L2, M or Ms neuroblastoma any age with MYCN amplification or focal high level MYC or MYCL amplification

  2. Age < 21 years
  3. Complete response (CR) or partial response (PR) at metastatic sites:

    • Bone disease: MIBG uptake (or FDG-PET uptake for MIBG-nonavid tumors) completely resolved or SIOPEN score ≤ 3 and at least 50% reduction in mIBG score (or ≤ 3 bone lesions and at least 50% reduction in number of FDG-PET-avid bone lesions for MIBG-nonavid tumors).
    • Bone marrow disease: CR and/or minimal disease (MD) according to International Neuroblastoma Response Criteria [Park JR, JCO 2017; Burchill S, Cancer 2017].
    • Other metastatic sites: complete response after induction chemotherapy +/- surgery.
  4. Acceptable organ function and performance status

    • Performance status ≥ 50%.
    • Hematological status: ANC > 0.5x10^9/L, platelets > 20x 10^9/L
    • Cardiac function (< grade 2)
    • Normal chest X-ray and oxygen saturation.
    • Absence of any toxicity ≥ grade 3.
  5. Sufficient collected stem cells available; minimum required: 6 x 10^6 CD34+ cells/kg body weight stored in 3 separate fractions.
  6. Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-HDC randomization.
  7. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
  8. Patients should be able and willing to comply with study visits and procedures as per protocol.

In case of parents'/patient's refusal, or insufficient stem cells, collection for tandem HDC but with a minimum of 3 x 10^6 CD34+ cells/kg body weight, or in case of patients older than 21 years, or organ toxicity, HDC will consist on the standard HD Bu-Mel and will be eligible for subsequent randomization.

An evaluation of the local disease will be performed after HDC/ASCR and surgery:

  • In case of no local macroscopic disease, all patients will receive 21-Gy radiotherapy to the pre-operative tumor bed
  • In case of local macroscopic residual disease, patients will be eligible to R-RTx if the following criteria are met:

    1. No evidence of disease progression after HDC/ASCR.
    2. Interval between the last ASCR and radiotherapy start between 60 and 90 days.
    3. Performance status greater or equal 50%.
    4. Hematological status: ANC > 0.5x10^9/L, platelets > 20x10^9/L.
    5. Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-RTx randomization.
    6. Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
    7. Patients should be able and willing to comply with study visits and procedures as per protocol.

In case of parents'/patient's refusal of the randomization, the patient will receive 21.6 Gy radiotherapy to the pre-operative tumor bed

Exclusion

Non-inclusion criteria specific to the R-I randomization (RAPID COJEC/GPOH) :

  1. Urinary tract obstruction ≥ grade 3
  2. Heart failure or myocarditis ≥ grade 2, any arrhythmia or myocardial infection
  3. Peripheral motor or sensory neuropathy ≥ grade 3
  4. demyelinating form of Charcot-Marie-Tooth syndrome
  5. hearing impairment ≥ grade 2
  6. Concurrent prophylactic use of phenytoin
  7. cardiorespiratory disease that contraindicates hyperhydration

Non-inclusion criteria common to all randomizations (R-I, R-HDC and R-RTx) :

  1. Any negative answer concerning the inclusion criteria of R-I or R-HDC or R-RTx will render the patient ineligible for the corresponding therapy phase randomization. However, these patients may remain on study and be considered to receive standard treatment of the respective therapy phase, and may be potentially eligible for subsequent randomizations.
  2. Liver function: Alanine aminotransferase (ALT) > 3.0 x ULN and blood bilirubin > 1.5 x ULN (toxicity ≥ grade 2). In case of toxicity ≥ grade 2, call national principal investigator study coordinator to discuss the feasibility.
  3. Renal function: Creatinine clearance and/or GFR < 60 ml/min/1.73m^2 (toxicity ≥ grade 2). If GFR < 60 ml/min/1.73m^2, call national principal investigator to discuss about the treatment
  4. Dyspnea at rest and/or pulse oximetry < 95% in air.
  5. Any uncontrolled intercurrent illness or infection that in the investigator opinion would impair study participation.
  6. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving his consent.
  7. Participating in another clinical study with an IMP while on study treatment.
  8. Concomitant use with yellow fever vaccine and with live virus or bacterial vaccines.
  9. Patient allergic to peanut or soya.
  10. Chronic inflammatory bowel disease and/or bowel obstruction.
  11. Pregnant or breastfeeding women.
  12. Known hypersensitivity to the active substance or to any of the excipients of study drugs known
  13. Concomitant use with St John's Wort (Hypericum Perforatum).

Non-inclusion criteria to R-HDC:

Patients with insufficient metastatic response at the end of induction SIOPEN score > 3 or less than 50% reduction in mIBG score or > 3 bone lesions or less 50% reduction in number of FDG-PET-avid bone lesions for mIBG-non avid tumours, will not be eligible for RHDC

Inclusion

  • You have been diagnosed with cancer, but have not received any treatment.
  • You have had a certain type of treatment or surgical procedure.
  • Your cancer has not spread to other parts of the body.
  • Your cancer has spread to other parts of the body.

Exclusion

  • You have certain types of non-cancer medical conditions.
  • You have had certain treatments, surgical procedures or drugs.
  • You have previously been treated (or are currently being treated) on a clinical trial.
Message

Clinical trials have complex eligibility criteria.

Ask your doctor if this trial could be right for you.

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