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High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN) (HR-NBL2)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04221035
Recruitment Status : Recruiting
First Posted : January 9, 2020
Last Update Posted : January 9, 2020
Sponsor:
Information provided by (Responsible Party):
Gustave Roussy, Cancer Campus, Grand Paris

Brief Summary:
This is an international multicenter, open-label, randomized phase III trial including three sequential randomizations to assess efficacy of induction and consolidation chemotherapies and radiotherapy for patients with high-risk neuroblastoma.

Condition or disease Intervention/treatment Phase
High-Risk Neuroblastoma Drug: Vincristine Drug: Carboplatin Drug: Etoposide Drug: Cyclophosphamide Drug: Vindesine Drug: Dacarbazine Drug: Ifosfamide Drug: Doxorubicin Drug: Busulfan Drug: Melphalan Drug: Thiotepa Radiation: Radiotherapy Drug: Dinutuximab Beta Drug: Cisplatin Phase 3

Detailed Description:

This is an international multicenter, open-label, randomized phase III trial including three sequential randomizations to assess efficacy of induction and consolidation chemotherapies and radiotherapy for patients with high-risk neuroblastoma.

The first randomization (R-I) will compare the efficacy of two induction chemotherapies (RAPID COJEC and GPOH regimens) in a phase III setting. The primary endpoint will be the 3-year EFS from date of randomization . The R-I randomization will be stratified on age, stage, MYCN status and countries.

The second randomization (R-HDC) will compare the efficacy of single HDC with Bu-Mel versus tandem HDC with Thiotepa followed by Bu-Mel. The primary endpoint is 3-year EFS calculated from the date of the R-HDC randomization. The R-HDC randomization will be stratified on the age, stage, MYCN status, induction chemotherapy regimen, response to induction phase and countries.

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 radiotherapy to the preoperative tumor bed will be randomized (R-RTx) versus the same treatment plus a sequential boost of additional 14.4 Gy to the residual tumor. The primary endpoint of R-RTx is 3-year EFS from the date of the R-RTx randomization. The R-RTx randomization will be stratified on age, stage, MYCN status, induction chemotherapy regimen, HDC regimen and countries.

In case of no macroscopic residual disease, 21.6 Gy radiotherapy will be delivered to the preoperative tumor bed.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 800 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN)
Actual Study Start Date : November 5, 2019
Estimated Primary Completion Date : November 2026
Estimated Study Completion Date : November 2032

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Neuroblastoma

Arm Intervention/treatment
Experimental: R-I
R-I: induction regimens RAPID COJEC vs GPOH Assuming a baseline 3-year EFS of 40%, with a sample size of 686 patients (343 in each arm) and a two-sided alpha=5% this trial will have 90% power to demonstrate an improvement of 12% in 3-year EFS, within a recruitment period of 3 years and a minimum follow up of 1.5 years.
Drug: Vincristine
1.5 mg/m2 (max dose 2 mg)

Drug: Carboplatin
750 mg/m2

Drug: Etoposide
175 mg/m2

Drug: Cyclophosphamide
1050 mg/m²

Drug: Vindesine
3 mg/m2/day (max dose 6 mg)

Drug: Dacarbazine
200 mg/m2/day

Drug: Ifosfamide
1500 mg/m2/day

Drug: Doxorubicin
30 mg/m²/dose

Drug: Cisplatin
80 mg/m²/24h

Experimental: R-HDC
R-HDC: consolidation regimen Bu-Mel vs Thiotepa + Bu-Mel The 3-year EFS in the Bu-Mel arm (with immunotherapy) is estimated to be 55%. This study aims to show an improvement of 12% for the Thiotepa + Bu-Mel arm (3-year EFS of 67%). With a recruitment of 448 patients (224 in each arm) over a period of 3 years and a minimum follow-up of 2 years, the power to show a 12% difference is 80% (two-sided logrank test and α=5%).
Drug: Busulfan
< 9kg: 1.0 mg/kg/dose 9 kg to < 16 kg : 1.2 mg/kg/dose 16 kg to 23 kg : 1.1 mg/kg/dose >23 kg to 34 kg: 0.95 mg/kg/dose >34 kg: 0.8 mg/kg/dose Infusion IV over 2 hours Administration every 6 hours for a total of 16 doses

Drug: Melphalan
140 mg/m2/dose IV short infusion (15'), at least24 h after the last busulfan dose

Drug: Thiotepa
300 mg/m2/day over 2 hours

Experimental: R-RTx
R-RTx: 21.6 Gy radiotherapy vs 21.6 Gy + 14.4 Gy boost in patients with macroscopic residual disease
Radiation: Radiotherapy
21.6 Gy 21.6 Gy + boost de 14.4 Gy

Drug: Dinutuximab Beta
Patients >12 kg are dosed based on the BSA: 10 mg/m2/day Patients ≤ 12 kg are dosed according to their body weight: 0.33 mg/kg/day




Primary Outcome Measures :
  1. Event free survival (EFS) [ Time Frame: Assessed at each end of randomization sequences up to one year ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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 nternational 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 with MYCN amplification, any age * 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 (except one cycle of Etoposide-Carboplatin or, in Germany and Nertherlands, one course of the current protocol for low/intermediate risk neuroblastoma).
  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 study drug and for one year after stopping the study drug. Acceptable contraception is defined in CTFG Guidelines "Recommendations related to contraception and pregnancy testing in clinical trials" (Appendix 11). 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 requrements.
  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 renal or liver toxicity, 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 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 with MYCN 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>0.5x109/L, platelets > 20x 109/L
    • Cardiac function: Shortening fraction ≥ 28% or ejection fraction ≥ 55% by echocardiogram, no clinical congestive heart failure. Normal pulmonary artery pressure.
    • Normal chest X-ray and oxygen saturation.
    • Absence of any toxicity ≥ grade 3.
  5. Sufficient collected stem cells available; minimum required: 6 x 106 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 106 CD34+ cells/kg body weight, or in case of patients older than 21 years, or liver or renal 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 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 >0.5x109/L, platelets > 20x109/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 and pursue the next step of the trial.

Exclusion Criteria:

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

  1. Urinary outflow obstruction
  2. severe arrhythmia, heart failure, previous cardiac infarct, acute inflammatory heart disease
  3. severe peripheral neuropathy
  4. demyelinating form of Charcot-Marie-Tooth syndrome
  5. hearing impairment
  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/1.73m² (toxicity ≥ grade 2). If GFR < 60ml/min/1.73m², call national principal investigator to discuss.the feasibility.
  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. Concomittant 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04221035


Contacts
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Contact: Dominique Valteau, MD 0142114211 ext +33 dominique.valteau@gustaveroussy.fr
Contact: Benhamou Jessica 0142114211 ext +33 jessica.benhamou@gustaveroussy.fr

Locations
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France
Gustave Roussy Recruiting
Villejuif, Val De Marne, France, 94800
Contact: Dominique Valteau, MD    0142114211 ext +33    dominique.valteau@gustaveroussy.fr   
Contact: Benhamou Jessica    0142114211 ext +33    jessica.benhamou@gustaveroussy.fr   
Sponsors and Collaborators
Gustave Roussy, Cancer Campus, Grand Paris
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Responsible Party: Gustave Roussy, Cancer Campus, Grand Paris
ClinicalTrials.gov Identifier: NCT04221035    
Other Study ID Numbers: 2019-001068-31
2019/2894 ( Other Identifier: CSET number )
First Posted: January 9, 2020    Key Record Dates
Last Update Posted: January 9, 2020
Last Verified: January 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neuroblastoma
Neuroectodermal Tumors, Primitive, Peripheral
Neuroectodermal Tumors, Primitive
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Cyclophosphamide
Melphalan
Busulfan
Ifosfamide
Thiotepa
Dacarbazine
Carboplatin
Doxorubicin
Etoposide
Vincristine
Vindesine
Ch14.18 monoclonal antibody
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents