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Trial details imported from ClinicalTrials.gov

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




Registration number
NCT03838042
Ethics application status
Date submitted
4/02/2019
Date registered
12/02/2019

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 (INFORM2-NivEnt)
Secondary ID [1] 0 0
2018-000127-14
Secondary ID [2] 0 0
Final4, 18-10-2023
Universal Trial Number (UTN)
Trial acronym
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.
Timepoint [1] 0 0
5 weeks
Primary outcome [2] 0 0
Phase II: Best response (CR or PR)
Timepoint [2] 0 0
Change in 24 weeks
Secondary outcome [1] 0 0
Duration of Response (DOR)
Timepoint [1] 0 0
Phase II: maximum of 48 weeks
Secondary outcome [2] 0 0
Disease Control Rate (DCR)
Timepoint [2] 0 0
Phase II: maximum of 48 weeks
Secondary outcome [3] 0 0
Stable disease (SD)
Timepoint [3] 0 0
Phase II: maximum of 12 cycles (each cycle is 28 days)
Secondary outcome [4] 0 0
Progression-free survival (PFS)
Timepoint [4] 0 0
4 years
Secondary outcome [5] 0 0
Time to Response (TTR)
Timepoint [5] 0 0
Phase II: maximum of 12 cycles (each cycle is 28 days)
Secondary outcome [6] 0 0
Overall Survival (OS)
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
Timepoint [7] 0 0
Phase II: maximum of 48 weeks
Secondary outcome [8] 0 0
Maximum Plasma Time (Tmax)
Timepoint [8] 0 0
one week
Secondary outcome [9] 0 0
Maximum Plasma Concentration (Cmax)
Timepoint [9] 0 0
one week
Secondary outcome [10] 0 0
Half-life
Timepoint [10] 0 0
one week
Secondary outcome [11] 0 0
Area under the curve (AUC)
Timepoint [11] 0 0
one week
Secondary outcome [12] 0 0
total Clearance (CI/F)
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, 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.
Minimum age
2 Years
Maximum age
21 Years
Sex
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 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Not applicable
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
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
26/05/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/06/2027
Actual
Sample size
Target
91
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC,WA
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 0 0
Children's Hospital at Westmead - Westmead
Recruitment hospital [3] 0 0
Royal Children's Hospital - Parkville
Recruitment hospital [4] 0 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
2145 - Westmead
Recruitment postcode(s) [3] 0 0
3052 - Parkville
Recruitment postcode(s) [4] 0 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 0 0
Austria
State/province [1] 0 0
Vienna
Country [2] 0 0
France
State/province [2] 0 0
Paris
Country [3] 0 0
Germany
State/province [3] 0 0
Augsburg
Country [4] 0 0
Germany
State/province [4] 0 0
Berlin
Country [5] 0 0
Germany
State/province [5] 0 0
Essen
Country [6] 0 0
Germany
State/province [6] 0 0
Hannover
Country [7] 0 0
Germany
State/province [7] 0 0
Heidelberg
Country [8] 0 0
Netherlands
State/province [8] 0 0
Utrecht
Country [9] 0 0
Sweden
State/province [9] 0 0
Stockholm
Country [10] 0 0
Switzerland
State/province [10] 0 0
Zurich

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
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Olaf Witt
Address 0 0
University Hospital Heidelberg
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Venukah Schäfer
Address 0 0
Country 0 0
Phone 0 0
+496221 56 7267
Fax 0 0
Email 0 0
venukah.schaefer@kitz-heidelberg.de
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
The pseudonymized data will be shared for transparency reasons in the context of publications and after publication with other physicians and scientists (national and international academia) to promote and accelerate research on causes and treatment development of oncological diseases.

Requests for access to pseudonymized patient data for non-INFORM-related scientific purposes will be reviewed by a Data Access Committee consisting of the INFORM Board, and the participating investigators. A positive statement of the respective ethic committee and a signed data protection commitment are requested. Requests should be addressed to the coordinating investigator Prof. Olaf Witt. Results of scientific research based on the INFORM2 NivEnt data may be used for academic teaching, research and scientific publications or presentations at scientific meetings.

Supporting document/s available: Clinical study report (CSR)
When will data be available (start and end dates)?
CSR will be available latest 1 year after the study is concluded.
Available to whom?
The CSR will be available via CTIS.
Available for what types of analyses?
How or where can data be obtained?


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT03838042