CNS TumorPhase 1/2NCT03838042
INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies
A Phase 1/2 study testing Nivolumab and Entinostat in people with CNS Tumor and Solid Tumor, run by University Hospital Heidelberg at 14 sites in 7 countries.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 2 to 21 years
- Conditions the study is for
- CNS Tumor, Solid Tumor
- What is being tested?
- Nivolumab and Entinostat
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 91 participants
- Where
- 14 sitesin 7 countries
- Study dates
- 26 May 2020to 30 Jun 2027
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
- No standard of care treatment available
- Age at registration ≥ 2 to ≤ 21 years
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- Molecular analysis for biomarker identification (SNV load, MYC/N amplification, high TILs or TLS positive) in laboratories complying with DIN EN ISO/IEC 17025 or similar via INFORM molecular diagnostic platform or equivalently valid molecular pipeline
- Biomarker determined using whole exome sequencing (SNV load), whole genome- or whole exome 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/progressive tumor and registration ≤ 24 weeks. In patients receiving therapy not impacting biomarker stratification, time between biopsy/puncture/resection of the current refractory/relapsed/progressive tumor and registration of ≤ 36 weeks is allowed
- Disease that is measurable as defined by RANO criteria or RECIST v1.1 (as appropriate).
- Life expectancy > 3 months, sufficient general condition score (Lansky ≥ 70 or Karnofsky ≥ 70). Transient states like infections requiring antibiotic treatments can be accepted, and also stable disabilities resulting from disease/surgery (hemiparesis, amputations etc.) can be accepted and will not be considered for Lansky/Karnofsky assessments.
- 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 and individual consequences of clinical trial
- Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment. Sexually active women of childbearing potential must agree to use acceptable and appropriate contraception during the study and for at least 6 months after the last study treatment administration. Sexually active male patients must agree to use a condom during the study and for at least 3 months after the last study treatment administration.
- Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
- Before patient screening and registration, written informed consent, also concerning data and blood transfer, must be given according to ICH/GCP, and national/local regulations.
- 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, high TILs or TLS positive AND MYC(N) amplification status) and stratification according to the following criteria:
- Group A: high mutational load (defined as > 100 somatic SNVs/exome) based on whole exome sequencing OR
- Group C: Focal MYC(N) amplification based on whole genome sequencing or whole exome sequencing ot ATRT-MYC subgroup OR
- Group E: high TILs or TLS positive (defined as cells per mm² > 600 or presence of tertiary lymphoid structure) based on IHC analysis.
Who cannot join
- 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 CNS tumor on imaging are ineligible; bulky tumor is defined as:
- Tumor with any evidence of uncal herniation or severe midline shift
- Tumor with diameter of > 6 cm in one dimension on contrast-enhanced MRI
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- 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, would preclude adequate absorption.
- Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Known active hepatitis B (e.g., hepatitis B surface antigen-reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid [qualitative]). Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBc Ab] and absence of HBsAg) are eligible. HBV DNA test must be performed in these patients prior to study treatment. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
- 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 (e.g., chemotherapy, HDACi (including valproic acid), DNA methyltransferase inhibitors, other immunotherapy, targeted therapy, biological response modifiers, endocrine anticancer therapy or radiotherapy) within 2 weeks or at least 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 may result in unanticipated drug-drug interactions that may cause or confound the assessment of toxicity. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the- counter medicine or herbal product. For information on CYP substrates and P-gp inhibitors or inducers see section 5.8.
- 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 (e.g. gastrointestinal disorders or electrolyte disturbances) 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 combined 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. No patient will be allowed to enroll in this trial more than once.
Trial locations and contacts
14 sites in 7 countries. Contact the study team or a site near you to ask about taking part.
14 sites in 7 countries
Germany5 sites, 5 recruiting
- Recruiting
Augsburg University Hospital
Augsburg, 86156
Michael Frühwald, Prof.Dr.Dr.
- Recruiting
Charité University Medicine Berlin
Berlin
Anne Thorwarth, Dr. med.
- Recruiting
Essen University Hospital
Essen
Uta Dirksen, Prof.Dr.med.
- Recruiting
Hannover Medical School
Hanover
Andreas Beilken, Dr. med.
- Recruiting
Hopp Children's Cancer Center Heidelberg (KiTZ)
Heidelberg, 69120
INFORM2 Team, inform2@kitz-heidelberg.de
Olaf Witt, Prof.Dr.med.
Australia4 sites, 4 recruiting
- Recruiting
Perth Children's Hospital
Nedlands, Western Australia, 6009
Nick Gottardo
- Recruiting
Royal Children's Hospital
Parkville, Victoria, 3052
Dong Anh Khuong Quang
- Recruiting
Sydney Children's Hospital
Randwick, New South Wales, 2031
David Ziegler
- Recruiting
Children's Hospital at Westmead
Westmead, New South Wales, 2145
Dinisha Govender
Austria1 site, 1 recruiting
- Recruiting
St. Anna Children's Hospital
Vienna, 1090
Caroline Hutter
France1 site, 1 recruiting
- Recruiting
Institut Curie
Paris, 75005
Gudrun Schleiermacher
Netherlands1 site, 1 recruiting
- Recruiting
Prinses Máxima Centrum
Utrecht
Jasper van der Lugt
Sweden1 site, 1 recruiting
- Recruiting
Karolinska Institute
Stockholm
Anna Nilsson
Switzerland1 site, 1 recruiting
- Recruiting
Children's Hospital Zurich
Zurich, 8032
Nicolas Gerber
About this study
Official title: INFORM2 Exploratory Multinational Phase I/II Combination Study of Nivolumab and Entinostat in Children and Adolescents With Refractory High-risk Malignancies (INFORM2-NivEnt)
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).
Read the detailed description
Compared to adult cancers, most pediatric cancers carry a relatively low mutational burden. 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. Checkpoint inhibition results in activation of tumor-associated T cells. It is now becoming increasingly evident that patients with tumors with a high number of tumor infiltrating T cells at baseline show an increased response rate. Additionally, recent clinical data on immune checkpoint inhibition (ICI) for melanoma patients detected tertiary lymphoid structures (TLS) as indicators of an activated adaptive immune response. Their presence has been linked to objective treatment responses in patients with different cancer entities receiving ICI.
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. In addition, it has been shown recently that the molecular MYC subgroup of atypical teratoid rhabdoid tumors (ATRT) exhibit a strong T-cell infiltrate in contrast to the SHH-ATRT subtype and are considered immunological "hot" tumors. 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 2-21 years with refractory/relapsed/progressive high-risk malignancies with a high mutational load (group A), with MYC(N) amplification or from the ATRT-MYC subgroup (group C) as well as patients with high TILs and/or TLS positive (group E) 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 3 groups A, C, E for patients in the two age cohorts 2-11 and 12-21 years. 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.
- Conditions
- CNS Tumor, Solid Tumor
- Being tested
- Nivolumab and Entinostat
- Keywords
- high-risk solid tumors, high-risk CNS tumors
- Medical subject headings
- Central Nervous System Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nivolumab and EntinostatDrug
Also called Opdivo
Patients entering phase I will receive one week entinostat without nivolumab (priming phase) before receiving the combination treatment of nivolumab and entinostat.
| Study group | Role | What they receive |
|---|---|---|
| Nivolumab and Entinostat | Experimental | Combination Study of Nivolumab and Entinostat Receives: Drug: Nivolumab and Entinostat |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 5 weeks
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.
Measured: Change in 24 weeks
Secondary outcomes (12)
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.
Measured: Phase II: maximum of 48 weeks
Disease Control Rate (DCR)
DCR will be evaluated in addition, also using iRECIST and iRANO.
Measured: Phase II: maximum of 48 weeks
Stable disease (SD)
SD will be evaluated in addition, also using iRECIST and iRANO.
Measured: Phase II: maximum of 12 cycles (each cycle is 28 days)
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.
Measured: 4 years
Time to Response (TTR)
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.
Measured: Phase II: maximum of 12 cycles (each cycle is 28 days)
Overall Survival (OS)
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.
Measured: Phase II: maximum of 48 weeks
Immune related Response Rate (RR) measured by iRECIST criteria and iRANO criteria
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.
Measured: Phase II: maximum of 48 weeks
Maximum Plasma Time (Tmax)
Time to reach the maximum concentration (hr).
Measured: one week
Maximum Plasma Concentration (Cmax)
The peak plasma concentration of a drug after Administration (ng/mL)
Measured: one week
Half-life
The time required for the concentration of the drug to reach half of its original value (hr)
Measured: one week
Area under the curve (AUC)
The integral of the concentration-time curve (ng/mL·hr)
Measured: one week
total Clearance (CI/F)
The total body clearance will be equal to the renal clearance + hepatic clearance + lung clearance (L/h/m²)
Measured: one week
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Feb 2019
- Study start26 May 2020
- Primary completion30 Jun 2026 (estimated)
- Study completion30 Jun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for CNS TumorStudies of the same condition, open and under way.
- More trials run by University Hospital HeidelbergThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Phase I: 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 Phase II: To evaluate activity and safety of the combination treatment with nivolumab and entinostat in children and adolescents aged 2-21 years with refractory/relapsed/progressive high-risk solid tumors and CNS tumors with: Group A: a high mutational load (\> 100 somatic SNVs/exome), Group C: Focal MYC(N) amplification or ATRT-MYC subgroup, Group E: high TILs or TLS positive (\> 600 cells/mm² or presence of TLS).
- Masking
- None (open label)
- Enrolment
- 91 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital Heidelberg
- Sponsor type
- University, hospital or other
- Collaborators
- German Cancer Research Center
- Responsible party
- Principal investigator, Olaf Witt, MD, University Hospital Heidelberg
- Investigators
- Olaf Witt, Principal investigator, University Hospital Heidelberg
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03838042
- Sponsor's protocol ID
- Final4, 18-10-2023
- Other IDs
- 2018-000127-14, NCT-2017-0516, 2018
- Status last verified
- Feb 2024
- First submitted
- 4 Feb 2019
- Last updated
- 7 Feb 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: The pseudonymized data will be shared for transparency reasons in the context of publications and after publication with other physicians and scientists (national and international academia) to promote and accelerate research on causes and treatment development of oncological diseases. Requests for access to pseudonymized patient data for non-INFORM-related scientific purposes will be reviewed by a Data Access Committee consisting of the INFORM Board, and the participating investigators. A positive statement of the respective ethic committee and a signed data protection commitment are requested. Requests should be addressed to the coordinating investigator Prof. Olaf Witt. Results of scientific research based on the INFORM2 NivEnt data may be used for academic teaching, research and scientific publications or presentations at scientific meetings.
Publications
van Tilburg CM, Witt R, Heiss M, Pajtler KW, Plass C, Poschke I, Platten M, Harting I, Sedlaczek O, Freitag A, Meyrath D, Taylor L, Balasubramanian GP, Jager N, Pfaff E, Jones BC, Milde T, Pfister SM, Jones DTW, Kopp-Schneider A, Witt O. INFORM2 NivEnt: The first trial of the INFORM2 biomarker driven phase I/II trial series: the combination of nivolumab and entinostat in children and adolescents with refractory high-risk malignancies. BMC Cancer. 2020 Jun 5;20(1):523. doi: 10.1186/s12885-020-07008-8.
PubMed 32503469
Study at a glance
From the registry record, last updated by the sponsor on 7 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- INFORM2 Exploratory Multinational Phase I/II Combination Study of Nivolumab and Entinostat in Children and Adolescents With Refractory High-risk Malignancies (INFORM2-NivEnt)
- ClinicalTrials.gov ID
- NCT03838042
- Acronym / sponsor ID
- Final4, 18-10-2023
- Conditions
- CNS Tumor, Solid Tumor
- Keywords
- high-risk solid tumors, high-risk CNS tumors
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 91 participants (estimated)
- Lead sponsor
- University Hospital HeidelbergUniversity, hospital or other
- Collaborators
- German Cancer Research Center
- Study start
- 26 May 2020 (actual)
- Primary completion
- 30 Jun 2026 (estimated)
- Study completion
- 30 Jun 2027 (estimated)
- First posted
- 12 Feb 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Detailed description
Compared to adult cancers, most pediatric cancers carry a relatively low mutational burden. 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. Checkpoint inhibition results in activation of tumor-associated T cells. It is now becoming increasingly evident that patients with tumors with a high number of tumor infiltrating T cells at baseline show an increased response rate. Additionally, recent clinical data on immune checkpoint inhibition (ICI) for melanoma patients detected tertiary lymphoid structures (TLS) as indicators of an activated adaptive immune response. Their presence has been linked to objective treatment responses in patients with different cancer entities receiving ICI.
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. In addition, it has been shown recently that the molecular MYC subgroup of atypical teratoid rhabdoid tumors (ATRT) exhibit a strong T-cell infiltrate in contrast to the SHH-ATRT subtype and are considered immunological "hot" tumors. 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 2-21 years with refractory/relapsed/progressive high-risk malignancies with a high mutational load (group A), with MYC(N) amplification or from the ATRT-MYC subgroup (group C) as well as patients with high TILs and/or TLS positive (group E) 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 3 groups A, C, E for patients in the two age cohorts 2-11 and 12-21 years. 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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Phase I: 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 Phase II: To evaluate activity and safety of the combination treatment with nivolumab and entinostat in children and adolescents aged 2-21 years with refractory/relapsed/progressive high-risk solid tumors and CNS tumors with: Group A: a high mutational load (> 100 somatic SNVs/exome), Group C: Focal MYC(N) amplification or ATRT-MYC subgroup, Group E: high TILs or TLS positive (> 600 cells/mm² or presence of TLS).
| Arm | Type | Receives |
|---|---|---|
| Nivolumab and Entinostat | Experimental | Drug: Nivolumab and EntinostatCombination Study of Nivolumab and Entinostat |
Who may qualify
- Ages
- 2 to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (34 listed)
- Children and adolescents with refractory/relapsed/progressive high-risk
- No standard of care treatment available
- Age at registration ≥ 2 to ≤ 21 years
- Molecular analysis for biomarker identification (SNV load, MYC/N amplification, high TILs or TLS positive) in laboratories complying with DIN EN ISO/IEC 17025 or similar via INFORM molecular diagnostic platform or equivalently valid molecular pipeline
- Biomarker determined using whole exome sequencing (SNV load), whole genome- or whole exome sequencing (MYC/N amplification), IHC (high TILs or TLS positive)
Key exclusion criteria (23 listed)
- 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 CNS tumor on imaging are ineligible; bulky tumor is defined as:
- Previous allogeneic bone marrow, stem cell or organ transplantation
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nivolumab and EntinostatAlso: OpdivoPatients entering phase I will receive one week entinostat without nivolumab (priming phase) before receiving the combination treatment of nivolumab and entinostat. | Drug | Nivolumab and Entinostat |
Primary outcome
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.
12 secondary outcomes
Duration of Response (DOR)
Time frame: Phase II: maximum of 48 weeks
Disease Control Rate (DCR)
Time frame: Phase II: maximum of 48 weeks
Stable disease (SD)
Time frame: Phase II: maximum of 12 cycles (each cycle is 28 days)
Progression-free survival (PFS)
Time frame: 4 years
Time to Response (TTR)
Time frame: Phase II: maximum of 12 cycles (each cycle is 28 days)
Overall Survival (OS)
Time frame: Phase II: maximum of 48 weeks
Immune related Response Rate (RR) measured by iRECIST criteria and iRANO criteria
Time frame: Phase II: maximum of 48 weeks
Maximum Plasma Time (Tmax)
Time frame: one week
Maximum Plasma Concentration (Cmax)
Time frame: one week
Half-life
Time frame: one week
Area under the curve (AUC)
Time frame: one week
total Clearance (CI/F)
Time frame: one week
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Feb 2024.
- Derived from this study: PubMed 32503469van Tilburg CM, Witt R, Heiss M, Pajtler KW, Plass C, Poschke I, Platten M, Harting I, Sedlaczek O, Freitag A, Meyrath D, Taylor L, Balasubramanian GP, Jager N, Pfaff E, Jones BC, Milde T, Pfister SM, Jones DTW, Kopp-Schneider A, Witt O. INFORM2 NivEnt: The first trial of the INFORM2 biomarker driven phase I/II trial series: the combination of nivolumab and entinostat in children and adolescents with refractory high-risk malignancies. BMC Cancer. 2020 Jun 5;20(1):523. doi: 10.1186/s12885-020-07008-8.
- Individual participant dataSharing planned: Yes. The pseudonymized data will be shared for transparency reasons in the context of publications and after publication with other physicians and scientists (national and international academia) to promote and accelerate research on causes and treatment development of oncological diseases. Requests for access to pseudonymized patient data for non-INFORM-related scientific purposes will be reviewed by a Data Access Committee consisting of the INFORM Board, and the participating investigators. A positive statement of the respective ethic committee and a signed data protection commitment are requested. Requests should be addressed to the coordinating investigator Prof. Olaf Witt. Results of scientific research based on the INFORM2 NivEnt data may be used for academic teaching, research and scientific publications or presentations at scientific meetings.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Olaf Witt principal investigator
University Hospital Heidelberg
14 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Nivolumab and Entinostat in people with CNS Tumor and Solid Tumor, run by University Hospital Heidelberg at 14 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 34 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 7 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 14 sites in Germany, Australia, Austria, France, Netherlands and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Venukah Schäfer (+496221 56 7267, venukah.schaefer@kitz-heidelberg.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase I: Dose Limiting Toxicity (DLT) of the combination treatment. (time frame: 5 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03838042, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Feb 2024.