Clinical Trials /

INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies

NCT03838042

Description:

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).

Related Conditions:
  • Alveolar Rhabdomyosarcoma
  • Atypical Teratoid/Rhabdoid Tumor
  • Childhood Central Nervous System Embryonal Carcinoma
  • Desmoplastic Small Round Cell Tumor
  • Diffuse Intrinsic Pontine Glioma
  • Embryonal Rhabdomyosarcoma
  • Embryonal Tumor with Multilayered Rosettes, C19MC-Altered
  • Ependymoma
  • Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor of Bone
  • Malignant Glioma
  • Medulloblastoma
  • Neuroblastoma
  • Rhabdoid Tumor
  • Synovial Sarcoma
  • Wilms Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: INFORM2 Study Uses Nivolumab and Entinostat in Children and Adolescents With High-risk Refractory Malignancies
  • Official Title: INFORM2 Exploratory Multinational Phase I/II Combination Study of Nivolumab and Entinostat in Children and Adolescents With Refractory High-risk Malignancies

Clinical Trial IDs

  • ORG STUDY ID: Final2, 09-01-2019
  • SECONDARY ID: 2018-000127-14
  • SECONDARY ID: NCT-2017-0516
  • NCT ID: NCT03838042

Conditions

  • CNS Tumor
  • Solid Tumor

Interventions

DrugSynonymsArms
Nivolumab and EntinostatNivolumab and Entinostat

Purpose

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).

Detailed Description

      Compared to adult cancers, most pediatric cancers carry a relatively low mutational burden.
      However, a small fraction of pediatric tumors in the INFORM registry cohort display a higher
      mutational burden. Truly hypermutated tumors, e.g. in the context of rare cancer
      predisposition syndromes, are reported to respond well to immune checkpoint inhibition. In
      addition to hypermutation, increased PD-L1 expression is associated with clinical responses
      to checkpoint inhibition. Increased PD-L1 mRNA expression is observed in a small fraction of
      pediatric patients in the INFORM registry cohort independent from mutational load. We
      hypothesize that pediatric tumors with a high mutational burden and/or high PD-L1 expression
      will respond to checkpoint inhibition.

      HDAC inhibition (HDACi) modifies T-cell regulation and can augment response to checkpoint
      inhibition by reducing the number of myeloid-derived suppressor cells and creating an
      immunogenic tumor microenvironment including induction of MHCI and neo-antigens. In vitro and
      in vivo models showed enhanced anti-tumor activity of the combination of checkpoint
      inhibition and HDACi compared to either agent alone. This provides a strong rationale to
      combine these drug classes.

      Furthermore, MYC- or NMYC-driven (referred to as MYC(N)) malignancies like very high-risk
      medulloblastomas or very high-risk neuroblastomas still have a dismal outcome. MYC is not
      only reported to upregulate PD-L1 and thereby a possible biomarker for checkpoint inhibition
      but also very compelling recent preclinical data strongly suggests that HDAC inhibitors are
      active against MYC amplified medulloblastoma in vitro and in vivo. In NMYC amplified
      neuroblastoma cell lines similar observations were made in vitro. Taken together, our results
      suggest that MYC(N)-driven tumors depend on HDAC and we hypothesize that MYC(N) status can
      serve as a biomarker for response prediction to a combinatorial treatment of checkpoint
      inhibition and HDAC inhibition.

      Pediatric patients aged 6-21 years with refractory/relapsed/progressive high-risk
      malignancies with a high mutational load (group A), with high PD-L1 mRNA expression (group
      B), with MYC(N) amplification (group C) and with a low mutational load, low PD-L1 mRNA
      expression and no MYC(N) amplification (Biomarker low group D) are eligible for this trial.
      Phase I determines the recommended phase 2 dose (RP2D) for the combination of the HDACi
      entinostat and the checkpoint inhibitor nivolumab for the age groups 6-11 and 12-21 years,
      respectively. Phase II investigates activity in 4 groups A, B, C, D. The duration of
      treatment is 12 cycles (1 cycle = 28 days), preceded by 1 priming week.

      In addition, a comprehensive accompanying research program investigates PD biomarkers for
      immune checkpoint and HDAC inhibition.

      Clinical trials investigating the combination of nivolumab and entinostat in children have
      not been reported so far.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab and EntinostatExperimentalCombination Study of Nivolumab and Entinostat
  • Nivolumab and Entinostat

Eligibility Criteria

        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.

        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.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:6 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Dose Limiting Toxicity (DLT) of the combination treatment.
Time Frame:5 weeks
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Duration of Response (DOR)
Time Frame:Phase II: maximum of 48 weeks
Safety Issue:
Description:DOR will be evaluated for all patients who experienced (confirmed) response. Starting time point will be the time when best response was determined.
Measure:Disease Control Rate (DCR)
Time Frame:Phase II: maximum of 48 weeks
Safety Issue:
Description:DCR will be evaluated in addition, also using iRECIST and iRANO.
Measure:Stable disease (SD)
Time Frame:Phase II: maximum of 12 cycles (each cycle is 28 days)
Safety Issue:
Description:SD will be evaluated in addition, also using iRECIST and iRANO.
Measure:Progression-free survival (PFS)
Time Frame:4 years
Safety Issue:
Description: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.
Measure:Time to Response (TTR)
Time Frame:Phase II: maximum of 12 cycles (each cycle is 28 days)
Safety Issue:
Description: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.
Measure:Overall Survival (OS)
Time Frame:Phase II: maximum of 48 weeks
Safety Issue:
Description: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.
Measure:Immune related Response Rate (RR) measured by iRECIST criteria and iRANO criteria
Time Frame:Phase II: maximum of 48 weeks
Safety Issue:
Description: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.
Measure:Maximum Plasma Time (Tmax)
Time Frame:one week
Safety Issue:
Description:Time to reach the maximum concentration (hr).
Measure:Maximum Plasma Concentration (Cmax)
Time Frame:one week
Safety Issue:
Description:The peak plasma concentration of a drug after Administration (ng/mL)
Measure:Half-life
Time Frame:one week
Safety Issue:
Description:The time required for the concentration of the drug to reach half of its original value (hr)
Measure:Area under the curve (AUC)
Time Frame:one week
Safety Issue:
Description:The integral of the concentration-time curve (ng/mL·hr)
Measure:total Clearance (CI/F)
Time Frame:one week
Safety Issue:
Description:The total body clearance will be equal to the renal clearance + hepatic clearance + lung clearance (L/h/m²)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University Hospital Heidelberg

Trial Keywords

  • high-risk solid tumors
  • high-risk CNS tumors

Last Updated

December 10, 2019