Informations générales (source: ClinicalTrials.gov)
High-Risk Neuroblastoma Study 2 of SIOP-Europa-Neuroblastoma (SIOPEN) (HR-NBL2)
Interventional
Phase 3
Gustave Roussy, Cancer Campus, Grand Paris (Voir sur ClinicalTrials)
novembre 2019
novembre 2032
29 juin 2024
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.
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT CURIE | 04/09/2024 13:49:46 | Contacter | |||
| CLCC INSTITUT GUSTAVE ROUSSY | Dominique VALTEAU COUANET | 23/05/2024 13:27:02 | Contacter | ||
| Les établissements d'Île-de-France dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| AP-HP - Hôpital Armand Trousseau-La Roche Guyon | Arnaud Petit, MD | Contact (sur clinicalTrials) | |||
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
| Centre Antoine Lacassagne - Nice - France | Contact (sur clinicalTrials) | ||||
| Centre Eugène Marquis - Rennes - France | Contact (sur clinicalTrials) | ||||
| Centre François Baclesse - Caen - France | Contact (sur clinicalTrials) | ||||
| Centre Georges-François Leclerc - Dijon - France | Contact (sur clinicalTrials) | ||||
| Centre Léon Berard - Lyon - France | Benoit Dumond, MD | Contact (sur clinicalTrials) | |||
| centre Oscar lambert - Lille - France | Anne-Sophie DEFACHELLES | Contact (sur clinicalTrials) | |||
| CHRU Nancy-Hôpital Brabois Enfant - Nancy - France | Ludovic Mansuy, MD | Contact (sur clinicalTrials) | |||
| CHU angers - Angers - France | Stéphanie Proust, MD | Contact (sur clinicalTrials) | |||
| CHU Bordeaux - 33600 - Bordeaux - France | Ayemeri Huchet, MD | Contact (sur clinicalTrials) | |||
| CHU Brest - 29609 - Brest - France | Liana Carausu, MD | Contact (sur clinicalTrials) | |||
| CHU Brest - Hôpital du Morvan - Brest - France | Liana CARAUSU, MD | Contact (sur clinicalTrials) | |||
| CHU d'AMIENS - 80054 - Amiens - France | Leslie Andry, MD | Contact (sur clinicalTrials) | |||
| CHU de Caen - Caen - France | Damien Bodet, MD | Contact (sur clinicalTrials) | |||
| Chu de La Reunion - St Denis - La Réunion - France | Yves REGUERRE, MD | Contact (sur clinicalTrials) | |||
| CHU Estaing - Clermont-Ferrand - France | justyna KANOLD, MD | Contact (sur clinicalTrials) | |||
| CHU Haute Pierre - Strasbourg - France | catherine PAILLARD, MD | Contact (sur clinicalTrials) | |||
| CHU Nice-Hôpital d'Archet - Nice - France | Joy Benadiba | Contact (sur clinicalTrials) | |||
| CHU Poitiers - Poitiers - France | Frederic Millot, MD | Contact (sur clinicalTrials) | |||
| CHU Rennes - Rennes - France | sophie taque, MD | Contact (sur clinicalTrials) | |||
| CHU Saint Etienne - Saint-Étienne - France | sandrine THOUVENIN-DOULET, MD | Contact (sur clinicalTrials) | |||
| CHU Tours Hôpital Clocheville - Tours - France | Pascal Blouin, MD | Contact (sur clinicalTrials) | |||
| CHU-Pôle Médico-Chirurgical de l'Enfant et l'Adolescant - Besançon - France | Veronique LAITHIER, MD | Contact (sur clinicalTrials) | |||
| Groupe Hospitalier Pellegrin - Chu - Bordeaux - Bordeaux - France | Julie Tandonnet, MD | Contact (sur clinicalTrials) | |||
| Hôpital Américain -CHU Reims - Reims - France | Claire PLUCHART, MD | Contact (sur clinicalTrials) | |||
| Hôpital Couple-Enfant CHU de Grenoble - Grenoble - France | Dominique Plantaz, MD | Contact (sur clinicalTrials) | |||
| Hôpital de la Mère et de l'Enfant - CHU Limoges - Limoges - France | christophe PIGUET, MD | Contact (sur clinicalTrials) | |||
| Hopital d'enfants Marechal de lattre - Dijon - France | claire BRIANDET, MD | Contact (sur clinicalTrials) | |||
| Hôpital des Enfants - CHU Rouen - Rouen - France | cecile DUMESNIL DE MAURICOURT, MD | Contact (sur clinicalTrials) | |||
| Hopital des enfants-CHU Toulouse - Toulouse - France | Marion Gambart, MD | Contact (sur clinicalTrials) | |||
| hopital la Timone - Marseille - France | carole coze, MD | Contact (sur clinicalTrials) | |||
| Institut de cancérologie de Loraine - Nancy - France | Contact (sur clinicalTrials) | ||||
| Institut de cancérologie de l'Ouest - Sité René Gauducheau - Saint-Herblain - France | Contact (sur clinicalTrials) | ||||
| Institut de Cancérologie Strasbourg - Strasbourg - France | Contact (sur clinicalTrials) | ||||
| IUCT Oncopole - Toulouse - France | Contact (sur clinicalTrials) | ||||
Critères
Tous
Inclusion Criteria:
Enrollment in HR-NBL2 will be performed:
- at diagnosis before the beginning of chemotherapy or
- up to 21 days after one course of Carboplatin-Etoposide 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 R-I randomisation (RAPID
COJEC/GPOH) low/intermediate risk neuroblastoma in Germany/Netherlands for patients
with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN
amplification
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.
2. No previous chemotherapy or up to 21 days after one cycle of Carboplatin-Etoposide
chemotherapy 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
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
R-I eligibility criteria:
- Written informed consent to enter the R-I randomisation from patient or
parents/legal representative, patient, and age- appropriate assent.
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 before or within 3 weeks from the beginning of chemotherapy
R-HDC randomisation (Single HDC Bu-Mel/ Tandem HDC Thiotepa+Bu-Mel) Etoposide or one
course of the current protocol for low/intermediate risk neuroblastoma in
Germany/Netherlands). Patients will be treated with the standard induction regimen per
country (Rapid COJEC or GPOH) and will be potentially eligible for subsequent
randomisations.
Randomisation for HDC strategy will be performed at the end of induction after the
disease evaluation and after surgery of the primary tumour 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 and no further treatment.
OR
- L2, M or Ms neuroblastoma, any age, with MYCN amplification, or focal high
level MYC or MYCL amplification
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.
R-RTx randomisation (Local Radiotherapy) Chemoimmunotherapy arm
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.
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%
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.
3. 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).
Non-inclusion criteria specific to the R-I randomisation (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 randomisations (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 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. Concomitant use with yellow fever vaccine and with live virus or bacterial vaccines.
7. Patient allergic to peanut or soya.
Non-inclusion criteria to R-HDC:
- Any negative answer concerning the R-HDC inclusion criteria
Non-inclusion criteria to chemoimmunotherapy arm:
- Any negative answer concerning the inclusion criteria of chemoimmunotherapy arm.
Enrollment in HR-NBL2 will be performed:
- at diagnosis before the beginning of chemotherapy or
- up to 21 days after one course of Carboplatin-Etoposide 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 R-I randomisation (RAPID
COJEC/GPOH) low/intermediate risk neuroblastoma in Germany/Netherlands for patients
with localized neuroblastoma or infants with metastatic neuroblastoma with MYCN
amplification
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.
2. No previous chemotherapy or up to 21 days after one cycle of Carboplatin-Etoposide
chemotherapy 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
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
R-I eligibility criteria:
- Written informed consent to enter the R-I randomisation from patient or
parents/legal representative, patient, and age- appropriate assent.
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 before or within 3 weeks from the beginning of chemotherapy
R-HDC randomisation (Single HDC Bu-Mel/ Tandem HDC Thiotepa+Bu-Mel) Etoposide or one
course of the current protocol for low/intermediate risk neuroblastoma in
Germany/Netherlands). Patients will be treated with the standard induction regimen per
country (Rapid COJEC or GPOH) and will be potentially eligible for subsequent
randomisations.
Randomisation for HDC strategy will be performed at the end of induction after the
disease evaluation and after surgery of the primary tumour 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 and no further treatment.
OR
- L2, M or Ms neuroblastoma, any age, with MYCN amplification, or focal high
level MYC or MYCL amplification
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.
R-RTx randomisation (Local Radiotherapy) Chemoimmunotherapy arm
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.
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%
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.
3. 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).
Non-inclusion criteria specific to the R-I randomisation (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 randomisations (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 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. Concomitant use with yellow fever vaccine and with live virus or bacterial vaccines.
7. Patient allergic to peanut or soya.
Non-inclusion criteria to R-HDC:
- Any negative answer concerning the R-HDC inclusion criteria
Non-inclusion criteria to chemoimmunotherapy arm:
- Any negative answer concerning the inclusion criteria of chemoimmunotherapy arm.