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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03838042
Registration number
NCT03838042
Ethics application status
Date submitted
4/02/2019
Date registered
12/02/2019
Date last updated
7/02/2024
Titles & IDs
Public title
INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies
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Scientific title
INFORM2 Exploratory Multinational Phase I/II Combination Study of Nivolumab and Entinostat in Children and Adolescents With Refractory High-risk Malignancies (INFORM2-NivEnt)
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Secondary ID [1]
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2018-000127-14
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Secondary ID [2]
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Final4, 18-10-2023
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
CNS Tumor
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Solid Tumor
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Condition category
Condition code
Cancer
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Brain
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Cancer
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Children's - Brain
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Nivolumab and Entinostat
Experimental: Nivolumab and Entinostat - Combination Study of Nivolumab and Entinostat
Treatment: Drugs: 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.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Phase I: Dose Limiting Toxicity (DLT) of the combination treatment.
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Assessment method [1]
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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).
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Timepoint [1]
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5 weeks
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Primary outcome [2]
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Phase II: Best response (CR or PR)
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Assessment method [2]
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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.
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Timepoint [2]
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Change in 24 weeks
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Secondary outcome [1]
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Duration of Response (DOR)
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Assessment method [1]
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DOR will be evaluated for all patients who experienced (confirmed) response. Starting time point will be the time when best response was determined.
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Timepoint [1]
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Phase II: maximum of 48 weeks
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Secondary outcome [2]
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Disease Control Rate (DCR)
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Assessment method [2]
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DCR will be evaluated in addition, also using iRECIST and iRANO.
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Timepoint [2]
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Phase II: maximum of 48 weeks
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Secondary outcome [3]
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Stable disease (SD)
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Assessment method [3]
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SD will be evaluated in addition, also using iRECIST and iRANO.
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Timepoint [3]
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Phase II: maximum of 12 cycles (each cycle is 28 days)
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Secondary outcome [4]
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Progression-free survival (PFS)
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Assessment method [4]
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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.
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Timepoint [4]
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4 years
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Secondary outcome [5]
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Time to Response (TTR)
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Assessment method [5]
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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.
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Timepoint [5]
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Phase II: maximum of 12 cycles (each cycle is 28 days)
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Secondary outcome [6]
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Overall Survival (OS)
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Assessment method [6]
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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.
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Timepoint [6]
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Phase II: maximum of 48 weeks
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Secondary outcome [7]
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Immune related Response Rate (RR) measured by iRECIST criteria and iRANO criteria
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Assessment method [7]
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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.
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Timepoint [7]
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Phase II: maximum of 48 weeks
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Secondary outcome [8]
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Maximum Plasma Time (Tmax)
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Assessment method [8]
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Time to reach the maximum concentration (hr).
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Timepoint [8]
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one week
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Secondary outcome [9]
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Maximum Plasma Concentration (Cmax)
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Assessment method [9]
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The peak plasma concentration of a drug after Administration (ng/mL)
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Timepoint [9]
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one week
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Secondary outcome [10]
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Half-life
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Assessment method [10]
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The time required for the concentration of the drug to reach half of its original value (hr)
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Timepoint [10]
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one week
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Secondary outcome [11]
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Area under the curve (AUC)
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Assessment method [11]
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The integral of the concentration-time curve (ng/mL·hr)
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Timepoint [11]
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one week
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Secondary outcome [12]
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total Clearance (CI/F)
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Assessment method [12]
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The total body clearance will be equal to the renal clearance + hepatic clearance + lung clearance (L/h/m²)
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Timepoint [12]
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one week
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Eligibility
Key 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.
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Minimum age
2
Years
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Maximum age
21
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
N/A
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1/Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
26/05/2020
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
30/06/2027
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Actual
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Sample size
Target
91
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW,VIC,WA
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Recruitment hospital [1]
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Sydney Children's Hospital - Randwick
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Recruitment hospital [2]
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Children's Hospital at Westmead - Westmead
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Recruitment hospital [3]
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Royal Children's Hospital - Parkville
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Recruitment hospital [4]
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Perth Children's Hospital - Nedlands
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Recruitment postcode(s) [1]
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2031 - Randwick
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Recruitment postcode(s) [2]
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2145 - Westmead
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Recruitment postcode(s) [3]
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3052 - Parkville
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Recruitment postcode(s) [4]
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6009 - Nedlands
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Recruitment outside Australia
Country [1]
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Austria
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State/province [1]
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Vienna
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Country [2]
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France
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State/province [2]
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Paris
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Country [3]
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Germany
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State/province [3]
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Augsburg
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Country [4]
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Germany
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State/province [4]
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Berlin
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Country [5]
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Germany
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State/province [5]
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Essen
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Country [6]
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Germany
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State/province [6]
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Hannover
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Country [7]
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Germany
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State/province [7]
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Heidelberg
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Country [8]
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Netherlands
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State/province [8]
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Utrecht
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Country [9]
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Sweden
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State/province [9]
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Stockholm
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Country [10]
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Switzerland
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State/province [10]
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Zurich
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Funding & Sponsors
Primary sponsor type
Other
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Name
University Hospital Heidelberg
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Address
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Country
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Other collaborator category [1]
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Other
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Name [1]
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German Cancer Research Center
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Address [1]
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Country [1]
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Ethics approval
Ethics application status
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Summary
Brief 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).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03838042
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Olaf Witt
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Address
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University Hospital Heidelberg
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Venukah Schäfer
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Address
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Country
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Phone
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+496221 56 7267
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Fax
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Email
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[email protected]
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT03838042
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