Augsburg University Hospital 86156 Augsburg (Bayern) GermanyRekrutierend» Google-MapsCharité University Medicine Berlin Berlin (Berlin) GermanyRekrutierend» Google-MapsEssen University Hospital Essen (Nordrhein-Westfalen) GermanyRekrutierend» Google-Maps
Hannover Medical School Hannover (Niedersachsen) GermanyRekrutierend» Google-MapsHopp Children's Cancer Center Heidelberg (KiTZ) 69120 Heidelberg (Baden-Württemberg) GermanyRekrutierend» Google-Maps Ansprechpartner: INFORM2 Team E-Mail: inform2@kitz-heidelberg.de» Ansprechpartner anzeigenSydney Children's Hospital 2031 Randwick AustraliaRekrutierend» Google-MapsChildren's Hospital at Westmead 2145 Westmead AustraliaRekrutierend» Google-MapsRoyal Children's Hospital 3052 Parkville AustraliaRekrutierend» Google-MapsPerth Children's Hospital 6009 Nedlands AustraliaRekrutierend» Google-MapsSt. Anna Children's Hospital 1090 Vienna AustriaRekrutierend» Google-MapsInstitut Curie 75005 Paris FranceRekrutierend» Google-MapsPrinses Máxima Centrum Utrecht NetherlandsRekrutierend» Google-MapsKarolinska Institute Stockholm SwedenRekrutierend» Google-MapsChildren's Hospital Zurich 8032 Zurich SwitzerlandRekrutierend» Google-Maps
1. Phase I: Dose Limiting Toxicity (DLT) of the combination treatment. (Time Frame - 5 weeks): 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).
2. Phase II: Best response (CR or PR) (Time Frame - Change in 24 weeks): 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.
Secondary outcome:
1. Duration of Response (DOR) (Time Frame - Phase II: maximum of 48 weeks): DOR will be evaluated for all patients who experienced (confirmed) response. Starting time point will be the time when best response was determined.
2. Disease Control Rate (DCR) (Time Frame - Phase II: maximum of 48 weeks): DCR will be evaluated in addition, also using iRECIST and iRANO.
3. Stable disease (SD) (Time Frame - Phase II: maximum of 12 cycles (each cycle is 28 days)): SD will be evaluated in addition, also using iRECIST and iRANO.
4. Progression-free survival (PFS) (Time Frame - 4 years): 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.
5. Time to Response (TTR) (Time Frame - Phase II: maximum of 12 cycles (each cycle is 28 days)): The event-time endpoint TTR 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.
6. Overall Survival (OS) (Time Frame - Phase II: maximum of 48 weeks): The event-time endpoint OS 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.
7. Immune related Response Rate (RR) measured by iRECIST criteria and iRANO criteria (Time Frame - Phase II: maximum of 48 weeks): As a secondary endpoint for patients who continued treatment beyond progression in case of clinical benefit, response as assessed by iRECIST or iRANO will be performed.
8. Maximum Plasma Time (Tmax) (Time Frame - one week): Time to reach the maximum concentration (hr).
9. Maximum Plasma Concentration (Cmax) (Time Frame - one week): The peak plasma concentration of a drug after Administration (ng/mL)
10. Half-life (Time Frame - one week): The time required for the concentration of the drug to reach half of its original value (hr)
11. Area under the curve (AUC) (Time Frame - one week): The integral of the concentration-time curve (ng/mL·hr)
12. total Clearance (CI/F) (Time Frame - one week): The total body clearance will be equal to the renal clearance + hepatic clearance + lung clearance (L/h/m²)
Nivolumab and Entinostat (Opdivo): Patients entering phase I will receive one week entinostat without nivolumab (priming phase) before receiving the combination treatment of nivolumab and entinostat.
Quelle: ClinicalTrials.gov
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"INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies"
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