THIOTEPA for Neuroblastoma | High-risk neuroblastoma

Inclusion criteria

• {"criterion_text":"- HR-NBL2 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. ** see section 8 (Biology) for details 2) No previous chemotherapy or up to 21 days after one cycle of Carboplatin-Etoposidechemotherapy for patients with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN amplification or patients with metastatic neuroblastoma treated in emergency or up to 21 days after one course of the current protocol for low/intermediate risk neuroblastoma in Germany/Netherlands for patients with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN amplification OR after the first cycle A of Rapid COJEC and before the beginning of cycle B (2nd course) of Rapid COJEC induction regimen 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 HR-NBL2 study 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” (Appendix 11). Female patients who are lactating must agree to stop breast-feeding. 4) Written informed consent to enter the HR-NBL2 protocol 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"}
• {"criterion_text":"- 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 and no further treatment. OR - L2, M or Ms neuroblastoma, any age, with MYCN amplification, or focal high level MYC or MYCL amplification** ** see section 8 (Biology) for details 2) Age < 21 years at the time of randomization 3) Complete response (CR) or partial response (PR) at metastatic sites:  Bone disease: mIBG uptake 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 tumours).  Bone marrow disease: CR and/or minimal disease (MD) according to International Neuroblastoma Response Criteria  Other metastatic sites: CR. (after induction chemotherapy +/- surgery), except For distant lymph nodes for which PR is accepted with a possible secondary surgery 4) Acceptable organ function and performance status:  Performance status ≥ 50%.  Hematological status: ANC>0.5x109/L, platelets > 20x 109/L  Cardiac function: (< grade 2)  Normal chest X-Ray and oxygen saturation.  Absence of any toxicity ≥ grade 3. 4) Sufficient collected stem cells available; a total harvest of at least 6 x 106/kg CD34+ cells, to be stored in at least 4 separate bags to administer at least 3 x 106/kg CD34+ cells per rescue. 5) Written informed consent, including agreement of patient or parents/legal guardian for minors, to enter the R-HDC randomisation. 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, 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 organ toxicity, HDC will consist on the standard HD Bu-Mel and patients will be eligible for the subsequent randomisation.5) Cellules souches autologues collectées ≥ 6 x 106 CD34+ cellules/kg et stockées avec un minimum de 4 fractions distinctes. 6) Consentement signé par le patient ou les parents / représentants légaux et accord de l'enfant en fonction de son âge pour l'entrée dans la randomisation R-HDC. 7) Les patients doivent être affiliés à un régime de sécurité sociale ou l'équivalent selon les exigences locales. 8) Les patients doivent être capables et disposés à participer aux visites d'étude et aux procédures conformément au protocole. Dans le cas d’un refus de participation des parents ou du patient à la randomisation R-HDC, ou d’un nombre insuffisant de cellules souches autologues collectées pour la double greffe mais avec un minimum de 3 x 106 CD34+ cellules/kg de poids corporel, ou en cas de patient âgés de plus de 21 ans, ou en cas de toxicités viscérales alors la CHD sera réalisée avec le traitement standard par Bu-Mel et les patients pourront être choisis pour une randomisation ultérieure."}
• {"criterion_text":"- R-RTx eligibility criteria: 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 21,6-Gy radiotherapy to the pre-operative tumour 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 randomisation. 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 randomisation, the patient will receive 21.6 Gy radiotherapy to the pre-operative tumour bed."}
• {"criterion_text":"- Chemoimmunotherapy arm eligibility criteria: 1. Insufficient metastatic response at the end of induction chemotherapy, defined as:  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) OR  Bone marrow disease: SD according to International Neuroblastoma Response Criteria OR  Other metastatic sites: PR or SD. For distant lymph nodes: PR and not resectable or SD. 2. Performance status ≥ 50%. 3. Hematological status: ANC>0.75x109/L without G-CSF for at least 48 hours (or ANC ≥ 0.50 x 109 /L in case of bone marrow involvement), platelets > 50x 109/L and rising, without platelets transfusion for 72 hours. 4. AST or ALT ≤7.5 ULN and total bilirubin ≤1.5 ULN. In patients with liver metastases, total bilirubin ≤2.5 ULN is allowed. 5. No active infection; 6. No grade >2 gastrointestinal toxicity. 7. No grade ≥ 3 toxicity related to previous treatment. 8. Oxygen saturation > 94%."}

Exclusion criteria

• {"criterion_text":"- Non-inclusion criteria for HR-NBL2: 1. Any negative answer concerning the HR-NLB2 inclusion criteria 2. Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving his consent.Participating in another clinical study with an IMP while on study treatment. 4. Chronic inflammatory bowel disease and/or bowel obstruction. 5. Pregnant or breastfeeding women. 6. Known hypersensitivity to the active substance or to any of the excipients of the study drugs 7. Concomitant self-medication medicine that in the investigator opinion could interact with study treatments, including herbal medicine (e.g. St John’s Wort (Hypericum Perforatum))"}
• {"criterion_text":"- Non-inclusion criteria common to all randomisations R-HDC, and R-RTx : 1. Any negative answer concerning the inclusion criteria of R- HDC or R-RTx will render the patient ineligible for the corresponding therapy phase randomisation. 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 randomisations. 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 study coordinator to discuss about the treatment. 4. Dyspnea at rest and/or pulse oximetry <95% in air (only for R-HDC, and R-RTx) 5. Any uncontrolled intercurrent illness or infection that in the investigator opinion would impair study participation. 6. Concomittant use with yellow fever vaccine and with live virus or bacterial vaccines."}
• {"criterion_text":"- Non-inclusion criteria to chemoimmunotherapy arm: Any negative answer concerning the inclusion criteria of chemoimmunotherapy arm."}

Primary endpoints

• {"endpoint_text":"- R-HDC: 3-year EFS from the date of R-HDC randomisation","definition_or_measurement_approach":"Event-free survival (EFS) at 3 years from R-HDC randomisation; primary analyses will be intention-to-treat and controlled for stratification factors per protocol."}
• {"endpoint_text":"- R-RTx: 3-year EFS from the date of RTx randomization","definition_or_measurement_approach":"Event-free survival (EFS) at 3 years from RTx randomisation; primary analyses will be intention-to-treat and controlled for stratification factors per protocol."}
• {"endpoint_text":"- Chemoimmunotherapy arm: Metastatic response rate after 4 cycles of TEMIRI/DB.","definition_or_measurement_approach":"Metastatic response rate assessed after 4 courses of irinotecan-temozolomide combined with dinutuximab beta, using International Neuroblastoma Response Criteria (INRC); analyses by intention-to-treat and adjusted for stratification factors as stated."}

Secondary endpoints

• {"endpoint_text":"- For the whole population of high-risk neuroblastoma: - 3- and 5-year EFS, PFS and OS calculated from diagnosis","definition_or_measurement_approach":"EFS, PFS and OS at 3 and 5 years calculated from diagnosis across the whole high-risk population; standard survival analysis methods."}
• {"endpoint_text":"- For each randomized treatment: -5-year EFS, 3- and 5-year PFS and OS calculated from the date of each randomisation/ arm inclusion - Cumulative incidence of relapse/progression -Cumulative incidence of treatment related mortality and of disease related mortality - Overall and metastatic response as per the new INRG response criteria (including primary tumour after induction), skeletal response on mIBG, bone marrow response, local control - Therapy-related toxicity","definition_or_measurement_approach":"Survival endpoints (EFS/PFS/OS) calculated from date of randomisation/arm inclusion; cumulative incidence analyses for relapse/progression and cause-specific mortality; responses assessed per INRG/INRC criteria and mIBG/bone marrow assessments; toxicity graded per protocol-specified CTCAE or equivalent."}
• {"endpoint_text":"- For patients in the chemoimmunotherapy arm: - Metastatic reponse rate after 2 cycles TEMIRI/DB and 3- and 5- year EFS/PFS/OS from the date of initial diagnosis","definition_or_measurement_approach":"Metastatic response after 2 cycles of TEMIRI/DB assessed by INRC; longer-term EFS/PFS/OS measured from initial diagnosis according to protocol definitions."}

Primary sponsor

Full Name

Institut Gustave Roussy

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

France

Third parties

• {"country":"Denmark","full_name":"Frederiksberg Hospital","duties_or_roles":"sponsorDuties codes: [1,5]","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Greece","full_name":"Coronis Research S.A.","duties_or_roles":"sponsorDuties codes: [1,12,8]","organisation_type":"Pharmaceutical company"}