Clinical Trials Logo

Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT03838042
Other study ID # Final4, 18-10-2023
Secondary ID 2018-000127-14NC
Status Recruiting
Phase Phase 1/Phase 2
First received
Last updated
Start date May 26, 2020
Est. completion date June 30, 2027

Study information

Verified date February 2024
Source University Hospital Heidelberg
Contact Venukah Schäfer
Phone +496221 56 7267
Email venukah.schaefer@kitz-heidelberg.de
Is FDA regulated No
Health authority
Study type Interventional

Clinical 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 infiltrating lymphocytes (TILs) or a tertiary lymphoid structure (TLS).


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.


Recruitment information / eligibility

Status Recruiting
Enrollment 91
Est. completion date June 30, 2027
Est. primary completion date June 30, 2026
Accepts healthy volunteers No
Gender All
Age group 2 Years to 21 Years
Eligibility Inclusion Criteria: - 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 - 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. 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 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 - 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.

Study Design


Intervention

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.

Locations

Country Name City State
Australia Perth Children's Hospital Nedlands Western Australia
Australia Royal Children's Hospital Parkville Victoria
Australia Sydney Children's Hospital Randwick New South Wales
Australia Children's Hospital at Westmead Westmead New South Wales
Austria St. Anna Children's Hospital Vienna
France Institut Curie Paris
Germany Augsburg University Hospital Augsburg
Germany Charité University Medicine Berlin Berlin
Germany Essen University Hospital Essen
Germany Hannover Medical School Hannover
Germany Hopp Children's Cancer Center Heidelberg (KiTZ) Heidelberg
Netherlands Prinses Máxima Centrum Utrecht
Sweden Karolinska Institute Stockholm
Switzerland Children's Hospital Zurich Zurich

Sponsors (2)

Lead Sponsor Collaborator
University Hospital Heidelberg German Cancer Research Center

Countries where clinical trial is conducted

Australia,  Austria,  France,  Germany,  Netherlands,  Sweden,  Switzerland, 

Outcome

Type Measure Description Time frame Safety issue
Other Exploratory: circulating tumor DNA (ctDNA) Assessment of circulating Tumor DNA in peripheral blood. At baseline and every odd cycle (Cycle 3 - 12) and every third cycle (Cycle 13 - 24) (each cycle is 28 days).
Other Exploratory: Response prediction Response prediction in a co-clinical PDX model and drug testing program 4 years
Other Exploratory: Immune phenotyping (FACS Panel) and Luminex cytokine panel Immune phenotyping (FACS Panel) and Luminex cytokine panel in peripheral blood. At baseline, after the priming week and after 5 weeks of initiation of therapy
Other Exploratory: mRNA expression Analyze mRNA Expression data for Tumor infiltrating immune cell populations 4 years
Other Exploratory: gene signatures Analyze gene signature in whole exome data 4 years
Other Exploratory: cryptic transcription start sites Test induction of cryptic transcription start sites At baseline, after priming week and after 5 weeks of initiation of therapy
Other Exploratory: Single nucleotide variant (SNV) load Determination of SNV load by different methods (WES, Panel-Seq) 4 years
Primary 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).
5 weeks
Primary 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.
Change in 24 weeks
Secondary 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. Phase II: maximum of 48 weeks
Secondary Disease Control Rate (DCR) DCR will be evaluated in addition, also using iRECIST and iRANO. Phase II: maximum of 48 weeks
Secondary Stable disease (SD) SD will be evaluated in addition, also using iRECIST and iRANO. Phase II: maximum of 12 cycles (each cycle is 28 days)
Secondary 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. 4 years
Secondary 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. Phase II: maximum of 12 cycles (each cycle is 28 days)
Secondary 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. Phase II: maximum of 48 weeks
Secondary 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. Phase II: maximum of 48 weeks
Secondary Maximum Plasma Time (Tmax) Time to reach the maximum concentration (hr). one week
Secondary Maximum Plasma Concentration (Cmax) The peak plasma concentration of a drug after Administration (ng/mL) one week
Secondary Half-life The time required for the concentration of the drug to reach half of its original value (hr) one week
Secondary Area under the curve (AUC) The integral of the concentration-time curve (ng/mL·hr) one week
Secondary total Clearance (CI/F) The total body clearance will be equal to the renal clearance + hepatic clearance + lung clearance (L/h/m²) one week
See also
  Status Clinical Trial Phase
Recruiting NCT05580991 - Intratumoral CAN1012(Selective TLR7 Agonist) in Subjects With Solid Tumors Phase 1
Recruiting NCT05691608 - MoleculAr Profiling for Pediatric and Young Adult Cancer Treatment Stratification 2 N/A
Active, not recruiting NCT02846038 - Understanding Communication in Healthcare to Achieve Trust (U-CHAT)
Recruiting NCT05159388 - A Study of PRS-344/S095012 (PD-L1x4-1BB Bispecific Antibody-Anticalin Fusion) in Patients With Solid Tumors Phase 1/Phase 2
Completed NCT03181854 - Randomized Controlled Trial of Integrated Early Palliative Care N/A
Recruiting NCT06014502 - Study to Evaluate IMGS-001 Treatment in Patients With Relapsed or Refractory Advanced Solid Tumors Phase 1
Recruiting NCT05981703 - A Study Investigating BGB-26808 Alone or in Combination With Tislelizumab in Participants With Advanced Solid Tumors Phase 1
Recruiting NCT04107311 - Prospective Analysis of Intestinal Microbiome and Autoimmune Panels as Predictors of Toxicity in ImmunOncology Patients
Active, not recruiting NCT04078152 - Durvalumab Long-Term Safety and Efficacy Study Phase 4
Completed NCT02250157 - A Dose-regimen Finding Study to Evaluate Safety, Tolerability, Pharmacokinetics and Activity of Oratecan in Subjects With Advanced Malignancies Phase 1
Recruiting NCT05566574 - A Study of RP-3500 in Combination With Standard Radiation Therapy in People With Solid Tumor Cancer Phase 1/Phase 2
Recruiting NCT03943004 - Trial of DFP-14927 in Advanced Solid Tumors Phase 1
Recruiting NCT06036836 - Study of Favezelimab Coformulated With Pembrolizumab (MK-4280A) in Participants With Selected Solid Tumors (MK-4280A-010) Phase 2
Recruiting NCT05525858 - KPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II
Recruiting NCT05798546 - Treatment of Advanced Solid Tumors With Neo-T(GI-NeoT-02) Phase 1
Terminated NCT04586335 - Study of CYH33 in Combination With Olaparib an Oral PARP Inhibitor in Patients With Advanced Solid Tumors. Phase 1
Active, not recruiting NCT00479128 - Bortezomib With Gemcitabine/Doxorubicin in Patients With Urothelial Cancer and Other Solid Tumors Phase 1
Recruiting NCT04143789 - Evaluation of AP-002 in Patients With Solid Tumors Phase 1/Phase 2
Not yet recruiting NCT04550663 - NKG2D CAR-T(KD-025) in the Treatment of Relapsed or Refractory NKG2DL+ Tumors Phase 1
Completed NCT03980041 - Study to Evaluate the Efficacy/Safety of IPI-549 in Combination With Nivolumab in Patients With Advanced Urothelial Carcinoma (MARIO-275) Phase 2