An international Phase I/II combination study of Nivolumab and Entinostat in children and adolescents with recurrent (relapsing) or refractory (treatment-resistant) tumors (INFORM2 NivEnt)

Australia, Austria, France, Germany, Netherlands, Sweden, Switzerland (ICTRP)

Identifiant de l'essai ICTRP
NCT03838042 (ICTRP)

Titre officiel (approuvé par le comité d'éthique)
INFORM2 exploratory multinational phase I/II combination study of Nivolumab and Entinostat in children and adolescents with refractory high-risk malignancies (BASEC)

Titre académique
INFORM2 Exploratory Multinational Phase I/II Combination Study of Nivolumab and Entinostat in Children and Adolescents With Refractory High-risk Malignancies (INFORM2-NivEnt) (ICTRP)

Titre public
INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies (ICTRP)

Maladie en cours d'investigation
CNS Tumor;Solid Tumor (ICTRP)

Intervention étudiée
Drug: Nivolumab and Entinostat (ICTRP)

Type d'essai
Interventional (ICTRP)

Plan de l'étude
Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Critères d'inclusion/exclusion
Gender: All
Maximum age: 21 Years
Minimum age: 2 Years

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 mm? > 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. (ICTRP)

non disponible

Critères d'évaluation principaux et secondaires
Phase I: Dose Limiting Toxicity (DLT) of the combination treatment.;Phase II: Best response (CR or PR) (ICTRP)

Duration of Response (DOR);Disease Control Rate (DCR);Stable disease (SD);Progression-free survival (PFS);Time to Response (TTR);Overall Survival (OS);Immune related Response Rate (RR) measured by iRECIST criteria and iRANO criteria;Maximum Plasma Time (Tmax);Maximum Plasma Concentration (Cmax);Half-life;Area under the curve (AUC);total Clearance (CI/F) (ICTRP)

Date d'enregistrement
non disponible

Inclusion du premier participant
non disponible

Sponsors secondaires
German Cancer Research Center (ICTRP)

Contacts supplémentaires
Olaf Witt;Venukah Sch?fer;INFORM2 Team, venukah.schaefer@kitz-heidelberg.de; inform2@kitz-heidelberg.de, +496221 56 7267;, University Hospital Heidelberg, (ICTRP)

ID secondaires
2018-000127-14, NCT-2017-0516, Final4, 18-10-2023 (ICTRP)

Résultats-Données individuelles des participants
non disponible

Informations complémentaires sur l'essai
https://clinicaltrials.gov/ct2/show/NCT03838042 (ICTRP)