Prospective Pilot Trial to Assess a Multimodal Molecular Targeted Therapy in Children, Adolescent and Young Adults With Relapsed or Refractory High-grade Pineoblastoma

Inclusion Criteria:

Patients with relapsed and refractory high-grade pineoblastome (=rPB) and all of the following criteria will be considered for admission to the clinical trial:

* Children, adolescents and young adults 0 months to 25 years
* Signed written informed consent (patient or his/her parents/legal guardian)
* 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 months.
* 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:

  * patient is refractory or relapsed early after primary therapy

Exclusion Criteria:

Patients presenting with any of the following criteria will not be included in this clinical trial:

* Pregnancy, nursing
* Patients who suffered from a thrombotic event and need anticoagulation (i.e. coumadine 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")
* 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 interventional 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