This study has been transitioned to CTIS with ID 2024-514409-78-01 check the CTIS register for the current data. Primary objectivePhase I (Phase I of the younger cohort was concluded in May 2023): To determine the recommended phase II dose (RP2D) of…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase 1:Dose Limiting Toxicity (DLT) of the combination treatment.
Phase 2: Best response (CR or PR) will be based on RANO criteria for all
primary CNS tumors and RECIST for non-CSN tumors, defined for each patient as
the best response under study combination therapy during the first 6 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
Secondary outcome
Duration of Response (DOR)
Disease Control Rate (DCR)
Stabel disease (SD)
Progression-free survival (PFS)
Time to Response (TTR)
Overall survival (OS)
Immune related Response Rate (RR) measured by iRECIST criteria and iRANO
criteria
Entinostat plasma PK
Background summary
Children and adolescents with relapsed or refractory malignant disease of a
high-risk entity have a particularly poor prognosis and well-established
treatment protocols are rare in this setting. Survival rates of less than 20%
after recurrence imply an urgent need for innovative treatment strategies for
these patients. The aim of the INFORM (INdividualized Therapy FOr Relapsed
Malignancies in Childhood) program is to translate next generation molecular
diagnostics into a personalized, biomarker driven treatment strategy for this
patient cohort. The program consists of two major foundations: the INFORM2
series of biomarker driven phase I/II trials within a common framework and the
INFORM registry [http://www.dkfz.de/en/inform] providing a molecular screening
platform (Worst et al., 2016).
The current trial is based on the rationale that tumors with high mutational
load or high PD-L1 expression are susceptible to treatment with immune
checkpoint inhibition, which can be augmented by HDAC inhibition (HDACi)
through induction of an immunogenic tumor microenvironment.
However, and in contrast to our assumption at the start of this study, in the
meantime it has become clear that PD-L1 mRNA expression is no longer considered
a consistent predictive biomarker for tumor response to immune checkpoint based
therapy.
Checkpoint inhibition results in activation of tumor-associated T cells. It is
now becoming increasingly evident that patients with tumors with a high number
of tumor infiltrating T cells at baseline show an increased response rate.
Additionally, recent clinical data on immune checkpoint inhibition (ICI) for
melanoma patients detected tertiary lymphoid structures (TLS) as indicators of
an activated adaptive immune response. Their presence has been linked to
objective treatment responses in patients with different cancer entities
receiving ICI.
Furthermore, recent preclinical data strongly show that HDAC inhibitors show
activity in MYC amplified medulloblastoma in vitro and in vivo which is the
rationale to explore the combination of nivolumab and entinostat in patients
with MYC(N) driven tumors. Lastly, because of the potential immune priming
effect of HDAC-inhibitors, efficacy of the combination treatment in patients
with low mutational burden and PD-L1 expression and no MYC(N) amplification
will also be explored.
Study objective
This study has been transitioned to CTIS with ID 2024-514409-78-01 check the CTIS register for the current data.
Primary objective
Phase I (Phase I of the younger cohort was concluded in May 2023): To determine
the recommended phase II dose (RP2D) of the combination treatment with
nivolumab and entinostat administered to adolescents 12-21 years with
progressive, relapsed , refractory high-risk solid tumors and CNS tumors.
To determine the recommended phase II dose (RP2D) of the combination treatment
with nivolumab and entinostat administered to children 6-11 years with
progressive, relapsed , refractory high-risk solid tumors and CNS tumors.
Phase II: To evaluate activity of the combination treatment of nivolumab and
entionstat in children and adolescents with refractory/relapsed/progressive
high-risk solid tumors and CNS tumors in four different groups:
Group A: a high mutational load (> 100 somatic SNVs/exome), Group B (closed per
30 Nov 2023) high PD-L1 mRNA expression (RPKM >3), Group C Focal MYC(N)
amplifaction, Group D (closed per 22-01-2024) Patients with biomarker low
tumors according to the definitions of group A,C, E.
Secondary objectives:
- Comparison of patient outcomes in group D (biomarker low) with all biomarker
positive groups A, B and C (pooled and separately)
- Comparison of patient outcomes in group A-D with matching groups of the
INFORM registry (pooled and separately)
- Evaluation of somatic SNV count as a predictive biomarker: relation of
patient outcomes to the level of somatic SNVs
- Evaluation of PD-L1 mRNA expression as a predictive biomarker: relation of
patient outcomes to the level of PD-L1 mRNA expression
- Evaluation of the level of MYC(N) amplification as a predictive biomarker:
relation to patient outcomes
- Evaluate activity using immune related response evaluation methods
- Entinostat plasma PK (CSF if appropriate)
See protocol 2.3 page 33 for exploratory objectives
Study design
INFORM2 NivEnt is an exploratory, nonrandomized, open-label, multinational and
multicenter seamless phase I/II trial of nivolumab and entinostat in children
and adolescents with relapsed / refractory or progressive high-risk solid
tumors and CNS tumors. Two group phase I evaluating safety profile and
determination of RP2D of combination treatment. Four group phase II basket
trial evaluating activity of the combination treatment.
The two age cohorts will run independently and follow a 3+3 design with two
dose levels. RP2D is the dose at which up to 1 of 6 patients experiences DLT.
Patients treated at the RP2D in the Phase I part of the trial will be included
for evaluation of activity in Phase II.
A Bayesian adaptive design will be used with the objective of stopping cohorts
early which are showing evidence of no activity. Recruitment will not be
suspended during the interim analysis.
Intervention
Patients will receive nivolumab 3mg/kg body weight every 2 weeks as a 30-minute
IV infusion in both phase I and II of the trial.
Entinostat has 2 dose levels in the phase I part of the trial 2mg/m2 and
4mg/m2. After one priming week with 1 dose of entinostat on day 1, cycles of 4
weeks each will start with entinostat (orally) on day 1, 8, 15 and 22 and
intravenous administration of nivolumab on day 1 and 15. Thereafter, every
cycle follows the same schedule. There is no pause between cycles. Dose level 2
is the maximum dose level. If an unexpected high level of toxicity is
encountered in dose level 2, the sponsor may initiate opening entinostat dose
level 1a: 3mg/m2 according to the same regimen and rules as dose levels 1 and 2
following discussion with the DMC.
Study burden and risks
Biopsy/punction or resection needs to be done during screening if it is not
been done 12 weeks before registration of the study. A pregnancy test could be
seen as a burden. Imaging (MRI/CTscan) needs to be done extra during the study.
Patients visit the site every week for the first 2 cycles and after that every
other week. Patients receive nivolumab 30 minutes intravenous on day 1 and 15
of every cycle.
Im Neuenheimer Feld 672
Heidelberg 69120
DE
Im Neuenheimer Feld 672
Heidelberg 69120
DE
Listed location countries
Age
Inclusion criteria
- Children and adolescents with refractory/relapsed/progressive high-risk CNS
tumors OR solid tumors OR with newly diagnosed high grade glioma. All specified
in the protocol.
- No standard of care treatment available
- Age at registration >= 2 to <= 21 years.
- Molecular analysis for biomarker identification (SNV load, high TILs or TLS
positive, 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), IHC (high TILs
or TLS
positive), whole genome- or whole exome 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 <= 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, Lansky >= 70 or Karnofsky >= 70.
-Laboratory requirements:
- Hematology: absolute granulocytes >= 1.0 × 10^9/l (unsupported)
platelets >= 100 × 10^9/l & stable
hemoglobin >= 8 g/dl or >= 4,96 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
- Females of childbearing potential must have a negative serum or urine
pregnancy test within 7 days prior to initiation of treatment.
- 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
- 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 B (enrolment closed): 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 exome sequencing or
ATRT-MYC subgroup
OR
Group D (enrolment closed): Patients with biomarker low tumors according to the
definitions of group A,C,E.
OR
Group E: high TILs or TLS positive (defined as cells per mm2 >600 or prescence
of tertiary lymphoid strucure) based on IHC analysis
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 tumor on imaging are ineligible; bulky tumor are
defined in the protocol -
- 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 or hepatitis C. Patients with past hepatitis B virus
(HBV) infection or resolved HBV infection are eligible. Patients positive for
hepatitis C antibody ar eliglible only if polymerase chain reaction is negative
form HCV RNA. see details in protocol
- 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 within 2 weeks or at least 5 half-lives (whichever is
longer) of study drug administration.
- Confirmed radiotherapy induced pseudoprogression
- 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.
- 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 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 combned 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-514409-78-01 |
| EudraCT | EUCTR2018-000127-14-NL |
| CCMO | NL67122.000.19 |