Informations générales (source: ClinicalTrials.gov)
INFORM2 Exploratory Multinational Phase I/II Combination Study of Nivolumab and Entinostat in Children and Adolescents With Refractory High-risk Malignancies (INFORM2-NivEnt)
Interventional
Phase 1/Phase 2
University Hospital Heidelberg (Voir sur ClinicalTrials)
mai 2020
juin 2027
29 juin 2024
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).
Etablissements
| Les établissements d'Île-de-France ayant mis à jour leurs données Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CLCC INSTITUT CURIE | 04/09/2024 13:49:45 | Contact (sur clinicalTrials) | |||
Critères
Tous
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.
- 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.
- 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.