INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies

Inclusion Criteria

• •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 ≥ 2 to ≤ 21 years
• •Molecular analysis for biomarker identification (SNV load, MYC/N amplification, high TILs or TLS positive) 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), whole genome- or whole exome sequencing (MYC/N amplification), IHC (high TILs or TLS positive)
• •In case molecular analysis was not performed via INFORM Registry molecular pipeline: transfer of molecular data (whole exome 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 requiring antibiotic treatments 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
• •Phase I: molecular analysis performed and biomarker status known (mutational load, high TILs or TLS positive AND MYC(N) amplification status).
• •Phase II: molecular analysis performed, biomarker status known (mutational load, high TILs or TLS positive 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 C: Focal MYC(N) amplification based on whole genome sequencing or whole exome sequencing ot ATRT-MYC subgroup OR
• •* Group E: high TILs or TLS positive (defined as cells per mm² \> 600 or presence of tertiary lymphoid structure) based on IHC analysis.