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Trial registered on ANZCTR


Registration number
ACTRN12619001768189
Ethics application status
Approved
Date submitted
2/12/2019
Date registered
12/12/2019
Date last updated
15/09/2020
Date data sharing statement initially provided
12/12/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies (INFORM2 NivEnt)
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] 299764 0
NCT-2017-0516
Secondary ID [2] 299904 0
EudraCT 2018-000127-14
Secondary ID [3] 299905 0
ITCC-072
Secondary ID [4] 299906 0
SNDX-275-0209
Secondary ID [5] 299907 0
CA209-9JH
Universal Trial Number (UTN)
Trial acronym
INFORM2 NivEnt
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid tumour 315327 0
Central nervous system (CNS) tumour 315328 0
Condition category
Condition code
Cancer 313624 313624 0 0
Children's - Brain
Cancer 313625 313625 0 0
Brain
Cancer 313626 313626 0 0
Sarcoma (also see 'Bone') - soft tissue
Cancer 313627 313627 0 0
Bone
Cancer 313628 313628 0 0
Kidney
Cancer 313632 313632 0 0
Children's - Other

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Use of nivolumab and entinostat in combination for the treatment of children and adolescents with refractory/relapsed/progressive high risk solid tumours or CNS tumours with no standard of care treatment available.

Phase I has two patient groups (12-21 years and 6-11 years), and evaluates the safety profile and recommended Phase II dose (RP2D) of the combination treatment.

Phase II has four patient groups - 1) high mutational load, 2) high PD-L1 m RNA expression, 3) focal MYC(N) amplification, 4) low mutational load and low PD-L1 mRNA expression and no MYC(N) amplification - and evaluates the activity of the combination treatment.

The trial starts with a dose escalation Phase I in the 12-21 years cohort. Patients entering the trial on the RP2D in Phase I of the study can seamlessly enter Phase II. All groups in Phase II receive the RP2D. Dose de-escalation may occur intra-individually in response to toxicity in both phases of the trial.

Nivolumab is given at 3mg/kg body weight every 2 weeks, as a 30 minute intravenous (IV) infusion – in both Phase I and Phase II of the clinical trial.
Entinostat has two dose levels 2mg/m2 and 4mg/m2 and is taken orally. The recommended dose of entinostat for Phase II of the trial is determined in Phase I.

There is one priming week (one dose of entinostat on day 1) followed by cycles of combination treatment. 12 cycles of treatment is planned and each cycle is 4 weeks. Entinostat is taken on days 1, 8, 15, 22, with IV administration of nivolumab on day 1 and 15.
Intervention code [1] 316185 0
Treatment: Drugs
Comparator / control treatment
No comparator or control group.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 322076 0
Phase I: Dose Limiting Toxicity (DLT) of the combination treatment, by protocol defined drug-related adverse events
DLT is any AE, defined per protocol, 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.
Timepoint [1] 322076 0
5 weeks (priming week and first cycle of combination treatment)
Primary outcome [2] 322077 0
Phase II: Best response - complete response (CR) or partial response (PR), by RANO or RECIST
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).
Timepoint [2] 322077 0
Change in 24 weeks (first 6 cycles of combination treatment)
Secondary outcome [1] 377231 0
Duration of response (DOR), by RANO and iRANO or RECIST and iRECIST, evaluated for all patients who experienced (confirmed) response
Timepoint [1] 377231 0
Phase II: maximum of 48 weeks from time of start of treatment (starting time will be the time when best response was determined)
Secondary outcome [2] 377232 0
Disease control rate (DCR), evaluated in addition, also using iRECIST and iRANO
Timepoint [2] 377232 0
Phase II: maximum of 48 weeks from time of start of treatment
Secondary outcome [3] 377233 0
Stable disease (SD), evaluated in addition, also using iRECIST and iRANO
Timepoint [3] 377233 0
Phase II: maximum of 12 cycles (each cycle is 28 days) from time of start of treatment
Secondary outcome [4] 377234 0
Progression-free survival (PFS), using RECIST or RANO
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] 377234 0
4 years
Secondary outcome [5] 377235 0
Time to response (TTR), using RECIST or RANO
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] 377235 0
Phase II: maximum of 12 cycles (each cycle is 28 days), from time of start of treatment
Secondary outcome [6] 377236 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] 377236 0
Phase II: maximum of 48 weeks
Secondary outcome [7] 377237 0
Immune related Response Rate (RR) measured by iRECIST criteria and iRANO criteria
Timepoint [7] 377237 0
Phase II: maximum of 48 weeks, for patients who continued treatment beyond progression in case of clinical benefit
Secondary outcome [8] 377238 0
Maximum plasma time (Tmax) of entinostat
Timepoint [8] 377238 0
one week (priming week)
Secondary outcome [9] 377239 0
Maximum plasma concentration (Cmax) of entinostat
Timepoint [9] 377239 0
one week (priming week)
Secondary outcome [10] 377240 0
Half-life of entinostat
Timepoint [10] 377240 0
one week (priming week)
Secondary outcome [11] 377241 0
Area under the curve (AUC) of entinostat
Timepoint [11] 377241 0
one week (priming week)
Secondary outcome [12] 377242 0
Total clearance (CI/F) of entinostat
Timepoint [12] 377242 0
one week (priming week)

Eligibility
Key inclusion criteria
- Children and adolescents with refractory/relapsed/progressive high-risk
-- CNS tumours: medulloblastoma, ependymoma, ATRT, ETMR, paediatric high grade glioma (including DIPG) or other paediatric embryonal CNS tumours OR
-- solid tumours: neuroblastoma, nephroblastoma, rhabdoid tumour, embryonal or alveolar rhabdomyosarcoma or other embryonal small round blue cell tumours including paediatric 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 greater than or equal to 6 years to less than or equal 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 tumour and registration less than or equal to 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 greater than or equal to 70 or Karnofsky greater than or equal to 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 greater than or equal to 1.0 × 10^9/L (unsupported), platelets greater than or equal to 100 × 10^9/L, hemoglobin greater than or equal to 8 g/dL or greater than or equal to 5,6 nmol/L
-- Biochemistry: Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN) AST(SGOT) less than or equal to 3.0 x ULN, ALT(SGPT) less than or equal to 3.0 x ULN, serum creatinine less than or equal to 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 greater than or equal to 0.9m^2
- 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 tumours 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 tumours or metastases who are neurologically unstable despite adequate treatment (e.g. convulsions).
- Patients with low-grade gliomas or tumours of unknown malignant potential are not eligible
- Evidence of > Grade 1 recent CNS haemorrhage on the baseline MRI scan.
- Participants with bulky CNS tumour on imaging are ineligible; bulky tumour is defined as:
-- Tumour with any evidence of uncal herniation or severe midline shift
-- Tumour with diameter of > 6 cm in one dimension on contrast-enhanced MRI
-- Tumour 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, tumour 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 tumours
- 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 enrolment/informed consent procedures, the patient will be counselled 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.
- 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 5mg/m^2/day prednisone equivalent) may be approved after consultation with the Sponsor.
No patient will be allowed to enrol in this trial more than once.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
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
Who is / are masked / blinded?



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

Recruitment
Recruitment status
Recruiting
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)
NSW,WA,VIC
Recruitment hospital [1] 15325 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 15326 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [3] 15327 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 28634 0
2031 - Randwick
Recruitment postcode(s) [2] 28635 0
3052 - Parkville
Recruitment postcode(s) [3] 28636 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 22144 0
Germany
State/province [1] 22144 0
Country [2] 22145 0
Netherlands
State/province [2] 22145 0
Country [3] 22989 0
Sweden
State/province [3] 22989 0

Funding & Sponsors
Funding source category [1] 304231 0
Government body
Name [1] 304231 0
Luminesce Alliance - Innovation for Children’s Health, a not for profit cooperative with the support of the New South Wales Government.
Address [1] 304231 0
214 Hawkesbury Road
Westmead NSW 2145
Country [1] 304231 0
Australia
Funding source category [2] 304372 0
Charities/Societies/Foundations
Name [2] 304372 0
Minderoo Foundation
Address [2] 304372 0
PO Box 3155
Broadway
Nedlands WA 6009
Country [2] 304372 0
Australia
Funding source category [3] 304373 0
Government body
Name [3] 304373 0
Medical Research Future Fund
Address [3] 304373 0
Department of Health
GPO Box 9848
Canberra ACT 2601
Country [3] 304373 0
Australia
Primary sponsor type
University
Name
Heidelberg University
Address
Ruprecht-Karls-University Heidelberg
Im Neuenheimer Feld 672
69120 Heidelberg
Country
Germany
Secondary sponsor category [1] 304470 0
Other Collaborative groups
Name [1] 304470 0
Australian and New Zealand Children's Haematology/Oncology Group
Address [1] 304470 0
Hudson Institute of Medical Research
27-31 Wright Street
Clayton VIC 3168
Country [1] 304470 0
Australia
Other collaborator category [1] 281059 0
Other Collaborative groups
Name [1] 281059 0
Children’s Cancer Institute Australia
Address [1] 281059 0
Lowy Cancer Research Centre
C25/9 High Street
Kensington NSW 2750
Country [1] 281059 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304692 0
Sydney Children’s Hospitals Network Human Research Ethics Committee (SCHN HREC)
Ethics committee address [1] 304692 0
Cnr Hawkesbury Road and Hainsworth Street
Westmead NSW 2145
Ethics committee country [1] 304692 0
Australia
Date submitted for ethics approval [1] 304692 0
Approval date [1] 304692 0
27/09/2019
Ethics approval number [1] 304692 0

Summary
Brief summary
The aim of this clinical trial is to find out whether combination treatment with nivolumab and entinostat is safe and effective for children and adolescents with high-risk cancer.

Who is it for?

You may be eligible for this study if you are aged 6-21 years old and have been diagnosed with a relapsed or refractory high-risk cancer or high grade glioma with a repair defect of the genetic material.

Study details:

If you are eligible to participate, you will always receive the drugs nivolumab and entinostat in combination. There will be no placebo or control group with any other medication.

Before treatment starts, there will be a screening phase. Molecular profiling (DNA/RNA sequencing of the tumour) will be performed and the molecular results will indicate if you are eligible for this study. You will be allocated to one of four biomarker groups and continue with screening. Routine tests will also be performed to confirm whether you are eligible for this study, and if you can start treatment. These include medical history, physical exam, CT or MRI scans of the tumour, ECG, blood tests and urine tests.

During study treatment:

Entinostat is a tablet taken once a week. Nivolumab is given at the hospital every two weeks, as an intravenous drip over 30 minutes. Routine tests will be performed during treatment to monitor your health. These include medical history, physical exam, CT or MRI scans of the tumour, ECG, blood tests and urine tests. Additional blood samples are collected for this study to measure the levels of drugs and examine how they are working the body.

You will be in this study for up to 4 years. This includes the screening phase, study treatment (12 cycles for about 1 year), follow-up visits (every 4 weeks up to 100 days) and long term observation (every 3 months until the study closes).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 97886 0
Prof Dr. Olaf Witt
Address 97886 0
Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Department of Pediatric Oncology and Hematology
& Head of Division Clinical Cooperation Unit Pediatric Oncology
Heidelberg University Hospital and German Cancer Research Center (DKFZ)
Im Neuenheimer Feld 430
69120 Heidelberg
Country 97886 0
Germany
Phone 97886 0
+49 6221 42 3570
Fax 97886 0
Email 97886 0
inform2@kitz-heidelberg.de
Contact person for public queries
Name 97887 0
A/Prof David Ziegler
Address 97887 0
Kids Cancer Centre
Sydney Children's Hospital
High Street
Randwick NSW 2031
Country 97887 0
Australia
Phone 97887 0
+61 2 9382 3122
Fax 97887 0
Email 97887 0
SCHN-INFORM2@health.nsw.gov.au
Contact person for scientific queries
Name 97888 0
A/Prof David Ziegler
Address 97888 0
Kids Cancer Centre
Sydney Children's Hospital
High Street
Randwick NSW 2031
Country 97888 0
Australia
Phone 97888 0
+61 2 9382 3122
Fax 97888 0
Email 97888 0
SCHN-INFORM2@health.nsw.gov.au

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 pseudonymised data will be shared for transparency reasons in the context of publications, and after publication, with other physicians and scientists to promote and accelerate research on causes and treatment development of oncological diseases.
When will data be available (start and end dates)?
No start or end date determined.
Available to whom?
Physicians and scientists (national and international academia).
Available for what types of analyses?
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. A positive statement of the respective ethics committee and a signed data protection commitment are requested.
How or where can data be obtained?
Requests for access to pseudonymised data for other scientific purposes should be addressed to the Coordinating Investigator Prof. Dr. Olaf Witt (using Principal Investigator details on ANZCTR), and will be reviewed by the Data Access Committee.
What supporting documents are/will be available?
No other documents available
Summary results
No Results