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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT03838042




Registration number
NCT03838042
Ethics application status
Date submitted
1/12/2019
Date registered
8/02/2019
Date last updated
2/12/2019

Titles & IDs
Public title
INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies
Scientific title
INFORM2 Exploratory Multinational Phase I/II Combination Study of Nivolumab and Entinostat in Children and Adolescents With Refractory High-risk Malignancies
Secondary ID [1] 0 0
2018-000127-14
Secondary ID [2] 0 0
Final2, 09-01-2019
Universal Trial Number (UTN)
Trial acronym
INFORM2 NivEnt
Linked study record

Health condition
Health condition(s) or problem(s) studied:
CNS Tumor 0 0
Solid Tumor 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain
Cancer 0 0 0 0
Children's - Brain

Intervention/exposure
Study type
Interventional
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.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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).
Timepoint [1] 0 0
5 weeks
Primary outcome [2] 0 0
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.
Timepoint [2] 0 0
Change in 24 weeks
Secondary outcome [1] 0 0
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.
Timepoint [1] 0 0
Phase II: maximum of 48 weeks
Secondary outcome [2] 0 0
Disease Control Rate (DCR) - DCR will be evaluated in addition, also using iRECIST and iRANO.
Timepoint [2] 0 0
Phase II: maximum of 48 weeks
Secondary outcome [3] 0 0
Stable disease (SD) - SD will be evaluated in addition, also using iRECIST and iRANO.
Timepoint [3] 0 0
Phase II: maximum of 12 cycles (each cycle is 28 days)
Secondary outcome [4] 0 0
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.
Timepoint [4] 0 0
4 years
Secondary outcome [5] 0 0
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.
Timepoint [5] 0 0
Phase II: maximum of 12 cycles (each cycle is 28 days)
Secondary outcome [6] 0 0
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.
Timepoint [6] 0 0
Phase II: maximum of 48 weeks
Secondary outcome [7] 0 0
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.
Timepoint [7] 0 0
Phase II: maximum of 48 weeks
Secondary outcome [8] 0 0
Maximum Plasma Time (Tmax) - Time to reach the maximum concentration (hr).
Timepoint [8] 0 0
one week
Secondary outcome [9] 0 0
Maximum Plasma Concentration (Cmax) - The peak plasma concentration of a drug after Administration (ng/mL)
Timepoint [9] 0 0
one week
Secondary outcome [10] 0 0
Half-life - The time required for the concentration of the drug to reach half of its original value (hr)
Timepoint [10] 0 0
one week
Secondary outcome [11] 0 0
Area under the curve (AUC) - The integral of the concentration-time curve (ng/mL·hr)
Timepoint [11] 0 0
one week
Secondary outcome [12] 0 0
total Clearance (CI/F) - The total body clearance will be equal to the renal clearance + hepatic clearance + lung clearance (L/h/m²)
Timepoint [12] 0 0
one week

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 or other embryonal small round blue cell tumors including pediatric
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 ≥ 6 to ≤ 21 years

- Molecular analysis for biomarker identification (SNV load, PDL1 mRNA expression, 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), RNA-sequencing (PDL1
mRNA expression) and whole genome sequencing (MYC/N amplification)

- In case molecular analysis was not performed via INFORM Registry molecular pipeline:
transfer of molecular data (whole exome and RNA sequencing)

- Time between biopsy/puncture/resection of the current refractory/relapsed/progressive
tumor and registration ≤ 12 weeks

- 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 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
hemoglobin ≥ 8 g/dl or ≥ 5,6 nmol/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 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

- BSA ≥ 0.9m2

- Phase I: molecular analysis performed and biomarker status known (mutational load,
PD-L1 mRNA expression AND MYC(N) amplification status).

- Phase II: molecular analysis performed, biomarker status known (mutational load, PD-L1
mRNA expression 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 B: high PD-L1 mRNA expression (defined as reads per million total reads per
kilobase of exon model (RPKM) > 3) based on RNA sequencing OR

- Group C: Focal MYC(N) amplification based on whole genome sequencing OR

- Group D: Patients with biomarker low tumors according to the definitions of group A-C.
Minimum age
6 Years
Maximum age
21 Years
Gender
Both males and females
Can healthy volunteers participate?
No
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 4 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
Purpose of the study
Treatment
Allocation to intervention
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1/Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
Germany
State/province [1] 0 0
Berlin
Country [2] 0 0
Germany
State/province [2] 0 0
Essen
Country [3] 0 0
Germany
State/province [3] 0 0
Hannover
Country [4] 0 0
Germany
State/province [4] 0 0
Heidelberg
Country [5] 0 0
Germany
State/province [5] 0 0
Regensburg
Country [6] 0 0
Netherlands
State/province [6] 0 0
Utrecht

Funding & Sponsors
Primary sponsor type
Other
Name
University Hospital Heidelberg
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
German Cancer Research Center
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

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, high PD-L1 mRNA
expression or focal MYC(N) amplification and explore activity in biomarker low tumors (low
mutational load, low PD-L1 mRNA expression and non-MYC(N) amplified).
Trial website
https://clinicaltrials.gov/show/NCT03838042
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Melanie Heiss
Address 0 0
Country 0 0
Phone 0 0
+496221 56 7255
Fax 0 0
Email 0 0
melanie.heiss@kitz-heidelberg.de
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT03838042