refractory or progressive high-risk solide tumors or CNS tmors
Conditions
Interventions
Patients will receive nivolumab 3mg/kg body weight every 2 weeks as a 30-minute
IV infusion in both phase I and II of the trial.
Entinostat has 2 dose levels in the phase I part of the trial 2mg/m2
Sponsors
Heidelberg University Hospital, Hopp Children's Cancer Center Heidelberg (KiTZ)
Eligibility
Age
2 Years to 17 Years
Inclusion criteria
Inclusion criteria: - Children and adolescents with refractory/relapsed/progressive high-risk CNS tumors OR solid tumors OR with newly diagnosed high grade glioma. All specified in the protocol. - No standard of care treatment available - Age at registration >= 2 to 3 months, Lansky >= 70 or Karnofsky >= 70. -Laboratory requirements: - Hematology: absolute granulocytes >= 1.0 × 10^9/l (unsupported) platelets >= 100 × 10^9/l & stable hemoglobin >= 8 g/dl or >= 4,96 nmol/L - Biochemistry: Total bilirubin 100 somatic SNVs/exome) based on whole exome sequencing OR - Group B (enrolment closed): 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 exome sequencing or ATRT-MYC subgroup OR Group D (enrolment closed): Patients with biomarker low tumors according to the definitions of group A,C,E. OR Group E: high TILs or TLS positive (defined as cells per mm2 >600 or prescence of tertiary lymphoid strucure) based on IHC analysis
Exclusion criteria
Exclusion criteria: -Patients with CNS tumors or metastases who are neurologically unstable despite adequate treatment (e.g. convulsions). - Patients with low-grade gliomas or tumors of unknown malignant potential are not eligible - Evidence of > Grade 1 recent CNS hemorrhage on the baseline MRI scan. - Participants with bulky tumor on imaging are ineligible; bulky tumor are defined in the protocol - - 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, would preclude adequate absorption. - Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Known active hepatitis B or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection are eligible. Patients positive for hepatitis C antibody ar eliglible only if polymerase chain reaction is negative form HCV RNA. see details in protocol - Clinically significant, uncontrolled heart disease - Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48 hour interval must be maintained before the first dose of the investigational drug is administered. - Any anticancer therapy within 2 weeks or at least 5 half-lives (whichever is longer) of study drug administration. - Confirmed radiotherapy induced pseudoprogression - Traditional herbal medicines; these therapies are not fully studied and their use may result in unanticipated drug-drug interactions that may cause or confound the assessment of toxicity. - History of hypersensitivity to the investigational medicinal product or to any drug with 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 that in the opinion of the Investigator or Sponsor could adversely affect the ability of the subject to comply with or tolerate study procedures and/or study therapy, or confound the ability to interpret the tolerability of combned administration of entinostat and nivolumab in treated subjects. - Patients receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (up to 5 mg/m2/day prednisone equivalent) may be approved after consultation with the Sponsor.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Phase 1:Dose Limiting Toxicity (DLT) of the combination treatment. Phase 2: Best response (CR or PR) will be based on RANO criteria for all primary CNS tumors and RECIST for non-CSN tumors, defined for each patient as the best response under study combination therapy during the first 6 cycles. Calcified or intra-osseous (osteo)sarcoma target lesions which were progressive before initiation of treatment and show SD on response evaluation (confirmation through a subsequent scan at least 4 weeks later) will be considered as a responder | — |
Secondary
| Measure | Time frame |
|---|---|
| Duration of Response (DOR) Disease Control Rate (DCR) Stabel disease (SD) Progression-free survival (PFS) Time to Response (TTR) Overall survival (OS) Immune related Response Rate (RR) measured by iRECIST criteria and iRANO criteria Entinostat plasma PK | — |
Countries
Netherlands
Outcome results
None listed