INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies (INFORM2 NivEnt)
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|ClinicalTrials.gov Identifier: NCT03838042|
Recruitment Status : Recruiting
First Posted : February 12, 2019
Last Update Posted : April 19, 2021
|Condition or disease||Intervention/treatment||Phase|
|CNS Tumor Solid Tumor||Drug: Nivolumab and Entinostat||Phase 1 Phase 2|
Compared to adult cancers, most pediatric cancers carry a relatively low mutational burden. However, a small fraction of pediatric tumors in the INFORM registry cohort display a higher mutational burden. Truly hypermutated tumors, e.g. in the context of rare cancer predisposition syndromes, are reported to respond well to immune checkpoint inhibition. In addition to hypermutation, increased PD-L1 expression is associated with clinical responses to checkpoint inhibition. Increased PD-L1 mRNA expression is observed in a small fraction of pediatric patients in the INFORM registry cohort independent from mutational load. We hypothesize that pediatric tumors with a high mutational burden and/or high PD-L1 expression will respond to checkpoint inhibition.
HDAC inhibition (HDACi) modifies T-cell regulation and can augment response to checkpoint inhibition by reducing the number of myeloid-derived suppressor cells and creating an immunogenic tumor microenvironment including induction of MHCI and neo-antigens. In vitro and in vivo models showed enhanced anti-tumor activity of the combination of checkpoint inhibition and HDACi compared to either agent alone. This provides a strong rationale to combine these drug classes.
Furthermore, MYC- or NMYC-driven (referred to as MYC(N)) malignancies like very high-risk medulloblastomas or very high-risk neuroblastomas still have a dismal outcome. MYC is not only reported to upregulate PD-L1 and thereby a possible biomarker for checkpoint inhibition but also very compelling recent preclinical data strongly suggests that HDAC inhibitors are active against MYC amplified medulloblastoma in vitro and in vivo. In NMYC amplified neuroblastoma cell lines similar observations were made in vitro. Taken together, our results suggest that MYC(N)-driven tumors depend on HDAC and we hypothesize that MYC(N) status can serve as a biomarker for response prediction to a combinatorial treatment of checkpoint inhibition and HDAC inhibition.
Pediatric patients aged 6-21 years with refractory/relapsed/progressive high-risk malignancies with a high mutational load (group A), with high PD-L1 mRNA expression (group B), with MYC(N) amplification (group C) and with a low mutational load, low PD-L1 mRNA expression and no MYC(N) amplification (Biomarker low group D) are eligible for this trial. Phase I determines the recommended phase 2 dose (RP2D) for the combination of the HDACi entinostat and the checkpoint inhibitor nivolumab for the age groups 6-11 and 12-21 years, respectively. Phase II investigates activity in 4 groups A, B, C, D. The duration of treatment is 12 cycles (1 cycle = 28 days), preceded by 1 priming week.
In addition, a comprehensive accompanying research program investigates PD biomarkers for immune checkpoint and HDAC inhibition.
Clinical trials investigating the combination of nivolumab and entinostat in children have not been reported so far.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||128 participants|
|Intervention Model:||Single Group Assignment|
|Intervention Model Description:||
To determine the recommended phase II dose (RP2D) of the combination treatment with nivolumab and entinostat administered to adolescents 12-21 years with progressive, relapsed, refractory high-risk solid tumors and CNS tumors To determine the recommended phase II dose (RP2D) of the combination treatment with nivolumab and entinostat administered to children 6-11 years with progressive, relapsed, refractory high-risk solid tumors and CNS Tumors
To evaluate activity and safety of the combination treatment with nivolumab and entinostat in children and adolescents with refractory/relapsed/progressive high-risk solid tumors and CNS tumors with:
Group A: a high mutational load (> 100 somatic SNVs/exome) Group B: high PD-L1 mRNA expression (RPKM by RNA-Seq > 3) Group C: Focal MYC(N) amplification Group D: Patients with biomarker low tumors according to the definitions of group A-C.
|Masking:||None (Open Label)|
|Official Title:||INFORM2 Exploratory Multinational Phase I/II Combination Study of Nivolumab and Entinostat in Children and Adolescents With Refractory High-risk Malignancies|
|Actual Study Start Date :||July 26, 2019|
|Estimated Primary Completion Date :||September 2022|
|Estimated Study Completion Date :||March 2023|
Experimental: Nivolumab and Entinostat
Combination Study of Nivolumab and Entinostat
Drug: Nivolumab and Entinostat
Patients 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. [ 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).
- 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.
- 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.
- Disease Control Rate (DCR) [ Time Frame: Phase II: maximum of 48 weeks ]DCR will be evaluated in addition, also using iRECIST and iRANO.
- 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.
- 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.
- 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.
- 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.
- 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.
- Maximum Plasma Time (Tmax) [ Time Frame: one week ]Time to reach the maximum concentration (hr).
- Maximum Plasma Concentration (Cmax) [ Time Frame: one week ]The peak plasma concentration of a drug after Administration (ng/mL)
- Half-life [ Time Frame: one week ]The time required for the concentration of the drug to reach half of its original value (hr)
- Area under the curve (AUC) [ Time Frame: one week ]The integral of the concentration-time curve (ng/mL·hr)
- 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)
- Exploratory: circulating tumor DNA (ctDNA) [ Time Frame: At baseline and every odd cycle (Cycle 3 - 12) and every third cycle (Cycle 13 - 24) (each cycle is 28 days). ]Assessment of circulating Tumor DNA in peripheral blood.
- Exploratory: Response prediction [ Time Frame: 4 years ]Response prediction in a co-clinical PDX model and drug testing program
- Exploratory: Immune phenotyping (FACS Panel) and Luminex cytokine panel [ Time Frame: At baseline, after the priming week and after 5 weeks of initiation of therapy ]Immune phenotyping (FACS Panel) and Luminex cytokine panel in peripheral blood.
- Exploratory: mRNA expression [ Time Frame: 4 years ]Analyze mRNA Expression data for Tumor infiltrating immune cell populations
- Exploratory: gene signatures [ Time Frame: 4 years ]Analyze gene signature in whole exome data
- Exploratory: cryptic transcription start sites [ Time Frame: At baseline, after priming week and after 5 weeks of initiation of therapy ]Test induction of cryptic transcription start sites
- Exploratory: Single nucleotide variant (SNV) load [ Time Frame: 4 years ]Determination of SNV load by different methods (WES, Panel-Seq)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03838042
|Contact: Melanie Heiss||+496221 56 email@example.com|
|Contact: Ruth Wittfirstname.lastname@example.org|
|Australia, New South Wales|
|Sydney Children's Hospital||Recruiting|
|Randwick, New South Wales, Australia, 2031|
|Principal Investigator: David Ziegler|
|Royal Children's Hospital||Recruiting|
|Parkville, Victoria, Australia, 3052|
|Principal Investigator: Jordan Hansford|
|Australia, Western Australia|
|Perth Children's Hospital||Recruiting|
|Nedlands, Western Australia, Australia, 6009|
|Principal Investigator: Nick Gottardo|
|St. Anna Children's Hospital||Recruiting|
|Vienna, Austria, 1090|
|Principal Investigator: Caroline Hutter|
|Paris, France, 75005|
|Principal Investigator: Gudrun Schleiermacher|
|Charité University Medicine Berlin||Recruiting|
|Principal Investigator: Anne Thorwarth, Dr. med.|
|Essen University Hospital||Recruiting|
|Principal Investigator: Uta Dirksen, Prof. Dr. med.|
|Hannover Medical School||Recruiting|
|Principal Investigator: Andreas Beilken, Dr. med.|
|Hopp Children's Cancer Center Heidelberg (KiTZ)||Recruiting|
|Heidelberg, Germany, 69120|
|Contact: INFORM2 Team email@example.com|
|Principal Investigator: Olaf Witt, Prof. Dr. med.|
|University Hospital Regensburg||Recruiting|
|Regensburg, Germany, 93053|
|Principal Investigator: Marcus Jakob, Dr.|
|Prinses Máxima Centrum||Recruiting|
|Principal Investigator: Jasper van der Lugt|
|Principal Investigator: Ingrid Ora|