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 oralveolar rhabdomyosarcoma, other embryonal small round blue cell tumors includingpediatric type (bone) sarcoma or other pediatric type solid tumors OR
• Children and adolescents with newly diagnosed high grade glioma (HGG) in thecontext of a constitutional mismatch repair deficiency syndrome after maximumsafe surgical resection with no established standard of care treatment optionwith curative intention available. In addition in France: ineligible toradiotherapy
• No standard of care treatment available
• Age at registration ≥ 2 to ≤ 21 years
• Molecular analysis for biomarker identification (SNV load, MYC/N amplification, highTILs or TLS positive) in laboratories complying with DIN EN ISO/IEC 17025 or similarvia INFORM molecular diagnostic platform or equivalently valid molecular pipeline
• Biomarker determined using whole exome sequencing (SNV load), whole genome- or wholeexome 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/progressivetumor and registration ≤ 24 weeks. In patients receiving therapy not impactingbiomarker stratification, time between biopsy/puncture/resection of the currentrefractory/relapsed/progressive tumor and registration of ≤ 36 weeks is allowed
• Disease that is measurable as defined by RANO criteria or RECIST v1.1 (asappropriate).
• Life expectancy > 3 months, sufficient general condition score (Lansky ≥ 70 orKarnofsky ≥ 70). Transient states like infections requiring antibiotic treatments canbe accepted, and also stable disabilities resulting from disease/surgery (hemiparesis,amputations etc.) can be accepted and will not be considered for Lansky/Karnofskyassessments.
• 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 andindividual consequences of clinical trial
• Females of childbearing potential must have a negative serum or urine pregnancy testwithin 7 days prior to initiation of treatment. Sexually active women of childbearingpotential must agree to use acceptable and appropriate contraception during the studyand for at least 6 months after the last study treatment administration. Sexuallyactive male patients must agree to use a condom during the study and for at least 3months after the last study treatment administration.
• Absence of any psychological, familial, sociological or geographical conditionpotentially hampering compliance with the study protocol and follow-up schedule; thoseconditions should be discussed with the patient before registration in the trial
• Before patient screening and registration, written informed consent, also concerningdata and blood transfer, must be given according to ICH/GCP, and national/localregulations.
• 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, highTILs or TLS positive AND MYC(N) amplification status) and stratification according tothe following criteria:
• Group A: high mutational load (defined as > 100 somatic SNVs/exome) based onwhole exome sequencing OR
• Group C: Focal MYC(N) amplification based on whole genome sequencing or wholeexome sequencing ot ATRT-MYC subgroup OR
• Group E: high TILs or TLS positive (defined as cells per mm² > 600 or presence oftertiary lymphoid structure) based on IHC analysis.

Exclusion Criteria:

• Patients with CNS tumors or metastases who are neurologically unstable despiteadequate treatment (e.g. convulsions).
• Patients with low-grade gliomas or tumors of unknown malignant potential are noteligible
• Evidence of > Grade 1 recent CNS hemorrhage on the baseline MRI scan.
• Participants with bulky CNS tumor on imaging are ineligible; bulky tumor is definedas:
• Tumor with any evidence of uncal herniation or severe midline shift
• Tumor with diameter of > 6 cm in one dimension on contrast-enhanced MRI
• Tumor that in the opinion of the investigator, shows significant mass effect
• Previous allogeneic bone marrow, stem cell or organ transplantation
• Diagnosis of immunodeficiency
• Diagnosis of prior or active autoimmune disease
• Evidence of interstitial lung disease
• Any contraindication to oral agents or significant nausea and vomiting, malabsorption,or significant small bowel resection that, in the opinion of the investigator, wouldpreclude adequate absorption.
• Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Known activehepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g.,hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis Bvirus (HBV) infection or resolved HBV infection (defined as the presence of hepatitisB core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA test must beperformed in these patients prior to study treatment. Patients positive for hepatitisC virus (HCV) antibody are eligible only if polymerase chain reaction is negative forHCV RNA.
• Clinically significant, uncontrolled heart disease
• Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritonealshunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous accessdevices are not considered major surgery, but for these procedures, a 48 hour intervalmust be maintained before the first dose of the investigational drug is administered.
• Any anticancer therapy (e.g., chemotherapy, HDACi (including valproic acid), DNAmethyltransferase inhibitors, other immunotherapy, targeted therapy, biologicalresponse modifiers, endocrine anticancer therapy or radiotherapy) within 2 weeks or atleast 5 half- lives (whichever is longer) of study drug administration.
• Radiologically confirmed radiotherapy induced pseudoprogression in CNS tumors
• Traditional herbal medicines; these therapies are not fully studied and their use mayresult in unanticipated drug-drug interactions that may cause or confound theassessment of toxicity. As part of the enrollment/informed consent procedures, thepatient will be counseled on the risk of interactions with other agents, and what todo if new medications need to be prescribed or if the patient is considering a newover-the- counter medicine or herbal product. For information on CYP substrates andP-gp inhibitors or inducers see section 5.8.
• History of hypersensitivity to the investigational medicinal product or to any drugwith similar chemical structure or to any excipient present in the pharmaceutical form (including benzamide) of the investigational medicinal product
• Participation in other ongoing clinical trials.
• Pregnant or lactating females.
• Presence of underlying medical condition (e.g. gastrointestinal disorders orelectrolyte disturbances) that in the opinion of the Investigator or Sponsor couldadversely affect the ability of the subject to comply with or tolerate studyprocedures and/or study therapy, or confound the ability to interpret the tolerabilityof combined administration of entinostat and nivolumab in treated subjects
• Patients receiving systemic steroid therapy or any other form of immunosuppressivetherapy within 7 days prior to the first dose of study treatment. The use ofphysiologic doses of corticosteroids (up to 5 mg/m2/day prednisone equivalent) may beapproved after consultation with the Sponsor. No patient will be allowed to enroll inthis trial more than once.