CD40 Agonistic Monoclonal Antibody APX005M in Treating Pediatric Patients with Recurrent or Refractory Brain Tumors
- Stratum 1: Recurrent or refractory primary malignant central nervous system (CNS) tumor patients * Patients with a histologically confirmed diagnosis of a primary malignant non-brainstem CNS tumor (excluding DIPG patients) that is recurrent, progressive, or refractory; all tumors must have histologic verification at either the time of diagnosis or recurrence except patients with marker (+) CNS germ cell tumors
- Stratum 2: Newly diagnosed DIPG patients * Patients with diffuse intrinsic pontine gliomas (DIPGs) will be eligible 6 to 14 weeks post-completion of radiation therapy if they do not have any evidence of progression; patients with newly diagnosed DIPGs, defined as tumors with a pontine epicenter and diffuse involvement of 2/3 or more of the pons, are eligible without histologic confirmation; patients with pontine tumors that do not meet these criteria or not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors have been biopsied and (1) are proven to be an anaplastic astrocytoma, glioblastoma multiforme, gliosarcoma, anaplastic mixed glioma or fibrillary astrocytoma or (2) have a histone mutation typically seen in DIPG; patients with disseminated disease are not eligible, and magnetic resonance imaging (MRI) of spine must be performed if disseminated disease is suspected by the treating physician
- Stratum 1: Recurrent or refractory primary malignant CNS tumor patients must have adequate pre-trial frozen or formalin-fixed paraffin-embedded (FFPE) tumor material (minimum of 10 unstained slides) available for use in the tumor mutation burden studies
- Stratum 2: Patients with DIPG who have pre-trial tumor tissue available are requested to submit tissue; however, this is not required for eligibility
- Prior therapy * Newly diagnosed DIPG patients ** Patients must have not received any prior therapy for treatment of their current CNS malignancy other than radiation therapy * Refractory/recurrent patients ** Patients must have recovered from the acute treatment related toxicities (defined as < grade 1) of all prior chemotherapy, immunotherapy, radiotherapy or any other treatment modality prior to entering this study * Myelosuppressive chemotherapy ** Patients must have received their last dose of known myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42 days if nitrosourea * Biological agent/monoclonal antibody **Biological agent: *** Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the biologic agent >= 7 days prior to study enrollment **** For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur * Monoclonal antibody treatment and agents with known prolonged half-lives: Patient must have recovered from any acute toxicity potentially related to the agent and received their last dose of the agent >= 28 days prior to study enrollment * Radiation ** Patients must have had their last fraction of: *** Craniospinal irradiation (> 24 Gy) or total body irradiation or radiation to >= 50% of pelvis >= 42 days prior to enrollment *** Focal irradiation >= 14 days prior to enrollment *** Local palliative irradiation (small port) >= 14 days prior to enrollment * Autologous stem cell transplant ** If the patient has previously received an autologous stem cell transplant, patient must be >= 6 months since autologous bone marrow/stem cell transplant prior to enrollment and have CD4 counts above 200/mm^3
- Patients must be at least 4 weeks (28 days) from major surgery and fully recovered from all acute effects of prior surgical intervention
- Neurologic status * Patients with neurological deficits should have deficits that are stable for a minimum of 1 week prior to enrollment * Patients with seizure disorders may be enrolled if seizures are well controlled
- Karnofsky performance scale (KPS for > 16 years of age) or Lansky performance score (LPS for =< 16 years of age) assessed within two weeks of enrollment must be >= 60; patients who are unable to walk because of neurologic deficits, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score
- Absolute Neutrophil Count (ANC) >= 1.0 x 10^9 cells/ L
- Platelets >= 100 x 10^9 cells/L (unsupported, defined as no platelet transfusion within 7 days)
- Hemoglobin >= 8 g/dL (may receive transfusions)
- Total bilirubin =< 1.5 times institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal (ULN)
- Albumin >= 3 g/dl
- Serum creatinine based on age/gender; patients that do not meet the criteria but have a 24 hour creatinine clearance or glomerular filtration rate (GFR) (radioisotope or iothalamate) >= 70 mL/min/1.73 m^2 are eligible * Age: maximum serum creatinine (mg/dL) ** 1 to < 2 years: 0.6 (male and female) ** 2 to < 6 years: 0.8 (male and female) ** 6 to < 10 years: 1 (male and female) ** 10 to < 13 years: 1.2 (male and female) ** 13 to < 16 years: 1.5 (male) 1.4 (female) ** >= 16 years: 1.7 (male) 1.4 (female)
- Left ventricular ejection fraction (LVEF) > 50%
- Electrocardiogram (ECG) corrected QT (QTc) =< 450 msec
- Oxygen saturation as measured by pulse oximetry is > 93% on room air and no evidence of dyspnea at rest
- Patients must be off all colony- forming growth factor(s) for at least 1 week prior to enrollment (i.e., filgrastim, sargramostim or erythropoietin); 2 weeks must have elapsed if patients received polyethylene glycol (PEG) formulations
- Female patients of childbearing potential must have a negative serum or urine pregnancy test
- Female subjects with childbearing potential and male subjects should use effective contraception methods (or abstain from sexual activity) while being treated with APX005M and for 30 days following treatment
- The patient or parent/guardian is able to understand the consent and is willing to sign a written informed consent document according to institutional guidelines
- Concurrent Illness * Patients with any clinically significant unrelated systemic illness (serious infections grade >= 2 or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the patient’s ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results * Patients with a history of any other malignancy, except patients with a secondary brain tumor if the patient’s first malignancy has been in remission for at least 5 years from the end of treatment
- Concurrent Therapy * Patients who are receiving any other anticancer or investigational drug therapy * Patients requiring systemic treatment with either corticosteroids (greater than dexamethasone 0.75 mg/m^2/day or the equivalent dose of other steroids) or other immunosuppressive medications within 14 days of study drug administration will be excluded; however, patients who require intermittent use of bronchodilators or local steroid injections will not be excluded from the study
- Patients with bulky tumor on imaging are ineligible; bulky tumor is defined as: * Tumor with any evidence of uncal herniation or midline shift * Tumor that in the opinion of the site investigator, shows significant mass effect ** Treating physicians are encouraged to contact the study chair to request a rapid central imaging review to confirm fulfilment of these eligibility criteria, if they have concerns
- Patients with a history of severe (grade >= 3) hypersensitivity reaction to a monoclonal antibody are ineligible
- Patients who have received allogeneic hematopoietic stem cell transplantation are ineligible
- Patients with active autoimmune disease or documented history of autoimmune disease/syndrome that requires ongoing systemic steroids or systemic immunosuppressive agents, except * Patients with vitiligo or well controlled asthma/atopy * Patients with hypothyroidism stable on hormone replacement or Sjogren’s syndrome
- Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions
- Patients with a known coagulopathy or bleeding diathesis or require the use of systemic anticoagulant medication are not eligible
- Female patients must not be pregnant or breast-feeding
District of Columbia
I. To evaluate the safety of CD40 agonistic monoclonal antibody APX005M (APX005M) administered intravenously every 3 weeks to children with central nervous system tumors.
II. To determine the maximum tolerated dose and/or the recommended phase II dose of APX005M.
III. To determine the pharmacokinetics of APX005M.
I. To make a preliminary assessment of efficacy via overall response rate, duration of response, progression-free survival and overall survival for diffuse intrinsic pontine glioma (DIPG) patients.
I. To assess the incidence of anti-drug antibodies.
II. To determine the immune pharmacodynamics of APX005M.
III. To identify tumor and blood efficacy and/or resistance biomarkers.
OUTLINE: This is a dose escalation study.
Patients receive CD40 agonistic monoclonal antibody APX005M intravenously (IV) over 60 minutes on day 1. Treatment repeats every 3 weeks for up to 36 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, then up to 3 years.
Trial Phase Phase I
Trial Type Treatment
Pediatric Brain Tumor Consortium
Ira J. Dunkel
- Primary ID PBTC-051
- Secondary IDs NCI-2017-01235
- Clinicaltrials.gov ID NCT03389802