Children, adolescents and young adults with high risk relapsed or treatment refractory neuroblastoma (rNB) represent a group of patients with dismal prognosis for whom a recommended standard salvage therapy is currently not available.

The multimodal metronomic approach combining molecular targeted drugs (rapamycin and dasatinib) with conventional chemotherapy (irinotecan and temozolomide) will be investigated in a randomized fashion as new treatment strategy for patients with rNB. The intention is to assess the therapeutic benefit of molecular targeted drugs for the treatment of rNB.

The combination of irinotecan and temozolomide showed activity in the treatment of several solid organ tumors, brain tumors and neuroblastoma. In one study rNB patients received a median of 5 courses of 5 days irinotecan and temozolomide every 3 to 4 weeks with a cumulative dose of 35% lower than in the RIST design. 33% had disease regression with 8% CR or PR. A phase II study in rNB also using irinotecan and temozolomide with a substantially lower intensity showed a response rate of 15%.

The combination of a mTOR inhibitor with a multi-kinase inhibitor demonstrated in preclinical studies a synergistic effect on cell cycle arrest, apoptosis and sensitization for radio- and chemotherapy. It is assumed that this combination of molecular targeted drugs with a tolerable conventional chemotherapy consisting of irinotecan and temozolomide can substantially improve the outcome of this patient population. A group of 20 rNB patients treated with the RIST therapy approach in a compassionate use setting showed an overall survival of 55% at a median of 80 weeks with a tolerable adverse event profile.

Inclusion Criteria:Patients with relapsed high-risk neuroblastoma (stage IV and all MYCN pos. stages) or progressive disease during primary treatment (=rNB) and all of the following criteria will be considered for admission to the clinical trial:

• Children, adolescents and young adults less than 25 years

• Signed written informed consent

• Females of childbearing age must have a negative urine pregnancy test prior to starting the study drug. The first pregnancy test must be performed within 10-14 days prior to the start of the study drug and the second pregnancy test must be performed within 24 hours prior to the start of study drug. The subject may not receive the study drug until the investigator has verified that the results of these pregnancy tests are negative.

• Females of childbearing age must comply with the institutional standards of birth control with a pearl index <1%. Contraception must be started at least four weeks before the start of the investigational therapy.

• Females of childbearing age must be willing to abstain from breastfeeding for the duration of the clinical trial and for at least 30 days after discontinuation of the clinical trial.

• Males must agree not to father a child and must use latex condom during any sexual contact with women of childbearing age during and for 6 months after therapy ends or is stopped, even if they have undergone successful vasectomy.

• Willing and able to complete the clinical trial procedures, as described in the protocol

• Non-smoker for at least the previous 3 months. Smoking is not allowed during the entire study period

• Abstain from alcohol within the last 24 hours before screening and before admission to the clinical trial center as well as during the entire clinical trial. The regular daily ethanol intake has to be less than 20g/day for at least the previous three month.

• Patients are required to have an absolute neutrophil count (ANC) ≥ 500/µL, hemoglobin ≥8g/dL (transfusion permitted), and an unsupported platelet count ≥30,000/µL unless:

  1. extensive bone marrow involvement was documented
  2. patient is refractory or relapsed early after primary therapy

Exclusion Criteria:

• Pregnancy, nursing
• Patients who suffered from a thrombotic event and need anticoagulation (i.e. coumadin derivatives or low molecular weight heparin derivatives, LMWH)
• Patients with cardiac arrhythmias especially prolonged QT
• Patients with chronic inflammatory bowel diseases and/or bowel obstruction
• Patients with bilirubin serum levels 1,5 fold above the upper normal limit
• Vaccination with a live virus vaccine during the clinical trial
• Impaired liver function and/or impaired renal function (hepatic and renal index parameter two times above normal range; see below)
• Potentially unreliable subjects, probably non compliant subjects and those judged by the investigator to be unsuitable for the study
• Doubts about the patient's cooperation
• Any contraindications or known hypersensitivity to the IMPs or to any of the other components: (see SPC ("Fachinformation", appendix)
• Known allergic reactions to the treatment medication
• Patients who were treated with radiation and/or chemotherapy for any other oncological condition
• Participation in any other phase I to III trial
• Sexually active patients who refuse to use contraception according to the institutional requirements
• Patients with extremely poor general condition (Karnofsky or Lansky score <50%)
• Neutrophil count (ANC) <500/µL, hemoglobin <8g/dL (transfusion permitted), and an unsupported platelet count <30 000/µL
• 12-lead ECG with QTc>500 msec / QTc>60 msec baseline
• Patients with hepatitis B reactivation