None listed
Conditions
Brief summary
The aim of this clinical trial is to find out whether combination treatment with nivolumab and entinostat is safe and effective for children and adolescents with high-risk cancer. Who is it for? You may be eligible for this study if you are aged 2-21 years old and have been diagnosed with a relapsed or refractory high-risk cancer or high grade glioma with a repair defect of the genetic material. Study details: If you are eligible to participate, you will always receive the drugs nivolumab and entinostat in combination. There will be no placebo or control group with any other medication. Before treatment starts, there will be a screening phase. Molecular profiling (DNA sequencing of the tumour) will be performed and the molecular results will indicate if you are eligible for this study. You will be allocated to one of three biomarker groups and continue with screening. Routine tests will also be performed to confirm whether you are eligible for this study, and if you can start treatment. These include medical history, physical exam, CT or MRI scans of the tumour, ECG, blood tests and urine tests. During study treatment: Entinostat is a tablet or liquid taken once a week. Nivolumab is given at the hospital every two weeks, as an intravenous drip over 30 minutes. Routine tests will be performed during treatment to monitor your health. These include medical history, physical exam, CT or MRI scans of the tumour, ECG, blood tests and urine tests. Additional blood samples are collected for this study to measure the levels of drugs and examine how they are working the body. You will be in this study for up to 4 years. This includes the screening phase, study treatment (12 cycles for about 1 year), follow-up visits (every 4 weeks up to 100 days) and long term observation (every 3 months until the study closes).
Interventions
Use of nivolumab and entinostat in combination for the treatment of children and adolescents with refractory/relapsed/progressive high risk solid tumours or CNS tumours with no standard of care treatment available.
The study commenced in Phase I with two patient groups (12-21 years and 6-11 years) and evaluated the safety profile and recommended Phase II dose (RP2D) of the combination treatment.
The trial started with a dose escalation Phase I in the older cohort. Patients entering the trial
Use of nivolumab and entinostat in combination for the treatment of children and adolescents with refractory/relapsed/progressive high risk solid tumours or CNS tumours with no standard of care treatment available. The study commenced in Phase I with two patient groups (12-21 years and 6-11 years) and evaluated the safety profile and recommended Phase II dose (RP2D) of the combination treatment. The trial started with a dose escalation Phase I in the older cohort. Patients entering the trial on the RP2D in Phase I of the study can seamlessly enter Phase II. All groups in Phase II receive the RP2D. Dose de-escalation may occur intra-individually in response to toxicity in both phases of the trial. The trial is currently in Phase II for both the older cohort (12-21 years) and younger cohort (2-11 years). The trial is evaluating the safety and anti-tumour activity of the combination treatment in patients who have the following biomarkers in their tumour: (i) high mutational load, or (ii) focal MYC(N) amplification or ATRT-MYC subgroup, or (iii) high tumour-infiltrating lymphocytes (TILs) or tertiary lymphoid structures (TLS) Nivolumab is given at 3mg/kg body weight every 2 weeks, as a 30 minute intravenous (IV) infusion. Entinostat is given orally as a tablet or liquid suspension. The recommended dose of entinostat for Phase II of the trial is 2mg/m2 for the younger cohort and 4mg/m2 for the older cohort. There is one priming week (one dose of entinostat on day 1) followed by cycles of combination treatment. 12 cycles of treatment is planned and each cycle is 4 weeks. Entinostat is taken on days 1, 8, 15, 22, with IV administration of nivolumab on day 1 and 15.
Sponsors
Heidelberg University
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
2 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
- Children and adolescents with refractory/relapsed/progressive high-risk -- CNS tumours: medulloblastoma, ependymoma, ATRT, ETMR, paediatric high grade glioma (including DIPG) or other paediatric embryonal CNS tumours OR -- solid tumours: neuroblastoma, nephroblastoma, rhabdoid tumour, embryonal or alveolar rhabdomyosarcoma or other embryonal small round blue cell tumours including paediatric type (bone) sarcoma 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 - No standard of care treatment available - Age at registration greater than or equal to 2 years to less than or equal to 21 years - Molecular analysis for biomarker identification (SNV load, high TILs or TLS positive, MYC/N amplification) 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), IHC (high TILs or TLS positive) and whole genome sequencing (MYC/N amplification) - In case molecular analysis was not performed via INFORM molecular pipeline: transfer of molecular data (whole genome sequencing) - Time between biopsy/puncture/resection of the current refractory/relapsed/progressive tumour and registration less than or equal to 24 weeks - Disease that is measurable as defined by RANO criteria or RECIST v1.1. - Life expectancy > 3 months, sufficient general condition score (Lansky greater than or equal to 70 or Karnofsky greater than or equal to 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 greater than or equal to 1.0 × 10^9/L (unsupported), platelets greater than or equal to 100 × 10^9/L, hemoglobin greater than or equal to 8 g/dL or greater than or equal to 4.96 nmol/L -- Biochemistry: Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN) AST(SGOT) less than or equal to 3.0 x ULN, ALT(SGPT) less than or equal to 3.0 x ULN, serum creatinine less than or equal to 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 7 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 ATRT-MYC subgroup or -- Group E: High TILs or TLS positive (defined as cells per mm^2 > 600 or presence of tertiary lymphoid structure) based on IHC analysis
Exclusion criteria
- Patients with CNS tumours or metastases who are neurologically unstable despite adequate treatment (e.g. convulsions). - Patients with low-grade gliomas or tumours of unknown malignant potential are not eligible - Evidence of > Grade 1 recent CNS haemorrhage on the baseline MRI scan. - Participants with bulky CNS tumour on imaging are ineligible; bulky tumour is defined as: -- Tumour with any evidence of uncal herniation or severe midline shift -- Tumour with diameter of > 6 cm in one dimension on contrast-enhanced MRI -- Tumour 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, tumour 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 4 weeks or at least 5 half-lives (whichever is longer) of study drug administration. - Radiologically confirmed radiotherapy induced pseudoprogression in CNS tumours - 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 enrolment/informed consent procedures, the patient will be counselled 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. - 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 5mg/m^2/day prednisone equivalent) may be approved after consultation with the Sponsor. No patient will be allowed to enrol in this trial more than once.
Outcome results
None listed