INFORM2 NivEnt: This study aims to analyse the effectiveness of combined treatment in children and adolescents with certain high risk refractory, relapsed or progressive cancerINFORM2 Exploratory Multinational Phase I/II Combination Study of Nivolumab and Entinostat in Children and Adolescents With Refractory High-risk Malignancies

Inclusion

• Children and adolescents with refractory/relapsed/progressive high-risk

  • CNS tumors: medulloblastoma, ependymoma, ATRT, ETMR, pediatric high grade glioma (including DIPG) or other pediatric embryonal CNS tumors OR
  • solid tumors: neuroblastoma, nephroblastoma, rhabdoid tumor, embryonal or alveolar rhabdomyosarcoma, other embryonal small round blue cell tumors including pediatric type (bone) sarcoma or other pediatric type solid tumors OR
  • Children and adolescents with newly diagnosed high grade glioma (HGG) in the context of a constitutional mismatch repair deficiency syndrome after maximum safe surgical resection with no established standard of care treatment option with curative intention available. In addition in France: ineligible to radiotherapy
• No standard of care treatment available
• Age at registration ≥ 6 to ≤ 21 years
• Molecular analysis for biomarker identification (SNV load, PDL1 mRNA expression, MYC/N amplification) in laboratories complying with DIN EN ISO/IEC 17025 or similar via INFORM molecular diagnostic platform or equivalently valid molecular pipeline
• Biomarker determined using whole exome sequencing (SNV load), RNA-sequencing (PDL1 mRNA expression), whole genome- or whole exome sequencing (MYC/N amplification)
• In case molecular analysis was not performed via INFORM Registry molecular pipeline: transfer of molecular data (whole exome and RNA sequencing)
• Time between biopsy/puncture/resection of the current refractory/relapsed/progressive tumor and registration ≤ 24 weeks. In patients receiving therapy not impacting biomarker stratification, time between biopsy/puncture/resection of the current refractory/relapsed/progressive tumor and registration of ≤ 36 weeks is allowed
• Disease that is measurable as defined by RANO criteria or RECIST v1.1 (as appropriate).
• Life expectancy > 3 months, sufficient general condition score (Lansky ≥ 70 or Karnofsky ≥ 70). Transient states like infections can be accepted, and also stable disabilities resulting from disease/surgery (hemiparesis, amputations etc.) can be accepted and will not be considered for Lansky/Karnofsky assessments.

• Laboratory requirements:

  • Hematology:

    • absolute granulocytes ≥ 1.0 × 109/l (unsupported)
    • platelets ≥ 100 × 109/l & stable
    • hemoglobin ≥ 8 g/dl or ≥ 4.96 mmol/L

  • Biochemistry:

    • Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
    • AST(SGOT) ≤ 3.0 x ULN
    • ALT(SGPT) ≤ 3.0 x ULN
    • serum creatinine ≤ 1.5 x ULN for age
• ECG: normal QTc interval according to Bazett formula < 440ms
• Patient is able to swallow oral study medication
• Ability of patient and/or legal representative(s) to understand the character and individual consequences of clinical trial
• Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment. Sexually active women of childbearing potential must agree to use acceptable and appropriate contraception during the study and for at least 6 months after the last study treatment administration. Sexually active male patients must agree to use a condom during the study and for at least 3 months after the last study treatment administration.
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• Before patient screening and registration, written informed consent, also concerning data and blood transfer, must be given according to ICH/GCP, and national/local regulations.
• No prior therapy with the combination of immune checkpoint inhibitors and HDACi
• BSA ≥ 0.9m2
• Phase I: molecular analysis performed and biomarker status known (mutational load, PD-L1 mRNA expression AND MYC(N) amplification status).

• Phase II: molecular analysis performed, biomarker status known (mutational load, PD-L1 mRNA expression AND MYC(N) amplification status) and stratification according to the following criteria:

  • Group A: high mutational load (defined as > 100 somatic SNVs/exome) based on whole exome sequencing OR
  • Group B: high PD-L1 mRNA expression (defined as reads per million total reads per kilobase of exon model (RPKM) > 3) based on RNA sequencing OR
  • Group C: Focal MYC(N) amplification based on whole genome sequencing or whole exome sequencing OR
  • Group D: Patients with biomarker low tumors according to the definitions of group A-C.