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

Recruiting now · Phase 1/Phase 2

Conditions studied: CNS Tumor, Solid Tumor

In brief

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).

Key facts

Study ID

NCT03838042

Run by

University Hospital Heidelberg

People needed

91

Starts

2020-05-26

Expected to finish

2027-06-30

Last updated by the study team

2024-02-07

Who can join

Age: 2 and older, up to 21. Sex: any. Healthy volunteers: not accepted.

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)
• 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

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.
• 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.

Where it is running

• Sydney Children's Hospital — Randwick, New South Wales, Australia (enrolling)
• Children's Hospital at Westmead — Westmead, New South Wales, Australia (enrolling)
• Royal Children's Hospital — Parkville, Victoria, Australia (enrolling)
• Perth Children's Hospital — Nedlands, Western Australia, Australia (enrolling)
• St. Anna Children's Hospital — Vienna, Austria (enrolling)
• Institut Curie — Paris, France (enrolling)
• Augsburg University Hospital — Augsburg, Germany (enrolling)
• Charité University Medicine Berlin — Berlin, Germany (enrolling)
• Essen University Hospital — Essen, Germany (enrolling)
• Hannover Medical School — Hanover, Germany (enrolling)
• Hopp Children's Cancer Center Heidelberg (KiTZ) — Heidelberg, Germany (enrolling)
• Prinses Máxima Centrum — Utrecht, Netherlands (enrolling)
• Karolinska Institute — Stockholm, Sweden (enrolling)
• Children's Hospital Zurich — Zurich, Switzerland (enrolling)

Full record on ClinicalTrials.gov

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