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

NCT03838042 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: Final4, 18-10-20232018-000127-14NCT-2017-0516
• Study Type: interventional
• Target: 91
• Locations: 6 countries
• Sites: 10

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, focal MYC(N) amplification or ATRT-MYC subgroup as well as tumors with high tumor infiltrating lymphocytes (TILs) or a tertiary lymphoid structure (TLS).

Conditions

CNS Tumor; Solid Tumor

Keywords

high-risk solid tumors; high-risk CNS tumors

Outcome Measures

Primary Outcomes (2)

• 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).

  5 weeks

• 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.

  Change in 24 weeks

Secondary Outcomes (12)

• Duration of Response (DOR)

  Phase II: maximum of 48 weeks

• Disease Control Rate (DCR)

  Phase II: maximum of 48 weeks

• Stable disease (SD)

  Phase II: maximum of 12 cycles (each cycle is 28 days)

• Progression-free survival (PFS)

  4 years

• Time to Response (TTR)

  Phase II: maximum of 12 cycles (each cycle is 28 days)

Other Outcomes (7)

• Exploratory: circulating tumor DNA (ctDNA)

  At baseline and every odd cycle (Cycle 3 - 12) and every third cycle (Cycle 13 - 24) (each cycle is 28 days).

• Exploratory: Response prediction

  4 years

• Exploratory: Immune phenotyping (FACS Panel) and Luminex cytokine panel

  At baseline, after the priming week and after 5 weeks of initiation of therapy

Study Arms (1)

Nivolumab and Entinostat

EXPERIMENTAL

Combination Study of Nivolumab and Entinostat

Drug: Nivolumab and Entinostat

Interventions

Nivolumab and Entinostat DRUG

Patients entering phase I will receive one week entinostat without nivolumab (priming phase) before receiving the combination treatment of nivolumab and entinostat.

Also known as: Opdivo

Nivolumab and Entinostat

Eligibility Criteria

• Age: 2 Years - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• University Hospital Heidelberg: lead
• German Cancer Research Center: collaborator

Study Sites (14)

Sydney Children's Hospital

Randwick, New South Wales, 2031, Australia

RECRUITING

Children's Hospital at Westmead

Westmead, New South Wales, 2145, Australia

RECRUITING

Royal Children's Hospital

Parkville, Victoria, 3052, Australia

RECRUITING

Perth Children's Hospital

Nedlands, Western Australia, 6009, Australia

RECRUITING

St. Anna Children's Hospital

Vienna, 1090, Austria

RECRUITING

Institut Curie

Paris, 75005, France

RECRUITING

Augsburg University Hospital

Augsburg, 86156, Germany

RECRUITING

Charité University Medicine Berlin

Berlin, Germany

RECRUITING

Essen University Hospital

Essen, Germany

RECRUITING

Hannover Medical School

Hanover, Germany

RECRUITING

Hopp Children's Cancer Center Heidelberg (KiTZ)

Heidelberg, 69120, Germany

RECRUITING

Prinses Máxima Centrum

Utrecht, Netherlands

RECRUITING

Karolinska Institute

Stockholm, Sweden

RECRUITING

Children's Hospital Zurich

Zurich, 8032, Switzerland

RECRUITING

Related Publications (1)

• van Tilburg CM, Witt R, Heiss M, Pajtler KW, Plass C, Poschke I, Platten M, Harting I, Sedlaczek O, Freitag A, Meyrath D, Taylor L, Balasubramanian GP, Jager N, Pfaff E, Jones BC, Milde T, Pfister SM, Jones DTW, Kopp-Schneider A, Witt O. INFORM2 NivEnt: The first trial of the INFORM2 biomarker driven phase I/II trial series: the combination of nivolumab and entinostat in children and adolescents with refractory high-risk malignancies. BMC Cancer. 2020 Jun 5;20(1):523. doi: 10.1186/s12885-020-07008-8.

  PMID: 32503469 DERIVED

MeSH Terms

Conditions

Central Nervous System Neoplasms

Interventions

Nivolumab; entinostat

Condition Hierarchy (Ancestors)

Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Olaf Witt

  University Hospital Heidelberg

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Venukah Schäfer

CONTACT

+496221 56 7267; venukah.schaefer@kitz-heidelberg.de

Melanie Heiß

CONTACT

+496221 56 7255; melanie.heiss@kitz-heidelberg.de

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. Olaf Witt

Model Details: Phase I: 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 and safety of the combination treatment with nivolumab and entinostat in children and adolescents aged 2-21 years with refractory/relapsed/progressive high-risk solid tumors and CNS tumors with: Group A: a high mutational load (\> 100 somatic SNVs/exome), Group C: Focal MYC(N) amplification or ATRT-MYC subgroup, Group E: high TILs or TLS positive (\> 600 cells/mm² or presence of TLS).

Study Record Dates

• First Submitted: February 4, 2019
• First Posted: February 12, 2019
• Study Start: May 26, 2020
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2027
• Last Updated: February 7, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR
• Time Frame: CSR will be available latest 1 year after the study is concluded.
• Access Criteria: The CSR will be available via CTIS.

Locations

CH (1); AU (1); FR (1); DE (5); NL (1); SE (1)