The aim of this trial is to determine preliminary activity of the combination treatment with nivolumab and entinostat in children and adolescents with high risk refractory/relapsed/progressive tumors harboring a high mutational load, focal MYC(N) amplification or ATRT-MYC subgroup as well as tumors with high tumor infiltrating lymphocytes (TILs) or a tertiary lymphoid structure (TLS).
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
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.
Tumor with any evidence of uncal herniation or severe midline shift
Single group
Nivolumab and Entinostat
DrugPatients entering phase I will receive one week entinostat without nivolumab (priming phase) before receiving the combination treatment of nivolumab and entinostat.
Phase I: Dose Limiting Toxicity (DLT) of the combination treatment.
A dose limiting toxicity (DLT) is defined as any AE according to the definitions and exceptions listed below that is related to the administration of the combination of investigational agents occurring during the priming week and first cycle of combination treatment (first 5 weeks) in phase I of the trial. A study participant will be considered evaluable for a DLT if at least 2 doses of nivolumab and 4 doses of entinostat were administered during the first 5 weeks (5 weeks normally incorporate the priming week and 1 cycle of planned combination treatment). Participants who discontinue treatment or have treatment delays preventing them from receiving the above defined minimal amount of treatment in the first cycle of combination treatment for reasons unrelated to study drug toxicity, are not evaluable for DLT and will be replaced in enrollment (maximum number of replacement subjects will be 3 per dose level).
Phase II: Best response (CR or PR)
Best response (CR or PR) will be based on RANO criteria for all primary CNS tumors and RECIST for non-CNS tumors, defined for each patient as the best response under study combination therapy during the first 6 cycles (assessment every 2 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.
Duration of Response (DOR)
DOR will be evaluated for all patients who experienced (confirmed) response. Starting time point will be the time when best response was determined.
Disease Control Rate (DCR)
DCR will be evaluated in addition, also using iRECIST and iRANO.
Stable disease (SD)
SD will be evaluated in addition, also using iRECIST and iRANO.
Progression-free survival (PFS)
The event-time endpoint PFS will be estimated using the Kaplan-Meier method, considering all the patients who started the treatment, whatever their compliance to treatment, including if the treatment was stopped prematurely for a reason other than disease progression. 95%-Confidence intervals will be provided for the Kaplan-Meier estimates.
Exploratory: circulating tumor DNA (ctDNA)
Assessment of circulating Tumor DNA in peripheral blood.
Exploratory: Response prediction
Response prediction in a co-clinical PDX model and drug testing program
Exploratory: Immune phenotyping (FACS Panel) and Luminex cytokine panel
Immune phenotyping (FACS Panel) and Luminex cytokine panel in peripheral blood.
Exploratory: mRNA expression
Analyze mRNA Expression data for Tumor infiltrating immune cell populations
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University Hospital Heidelberg
Lead sponsor
German Cancer Research Center
Collaborator
