Phase I Study of APX005M in Pediatric CNS Tumors

Phase 1

Active, not recruiting

• Conditions: Glioblastoma Multiforme; High-grade Astrocytoma NOS; CNS Primary Tumor, Nos; Ependymoma, NOS; Diffuse Intrinsic Pontine Gliomas (DIPG); Medulloblastoma

• Registration Number: NCT03389802
• Lead Sponsor: Pediatric Brain Tumor Consortium

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2017-12-15
• Last Update Posted: 2 September 2024

Recruitment & Eligibility

• Status: Active, not recruiting
• Sex: All
• Target Recruitment: Not specified

Inclusion Criteria

Inclusion Criteria:<br><br> - Diagnosis -- Stratum 1: Recurrent or refractory primary malignant CNS tumor patients<br> Patients with a histologically confirmed diagnosis of a primary malignant<br> non-brainstem CNS tumor (excluding DIPG patients) that is recurrent, progressive, or<br> refractory. All tumors must have histologic verification at either the time of<br> diagnosis or recurrence except patients with marker (+) CNS germ cell tumors.<br><br>Stratum 2: Newly diagnosed DIPG patients (on-hold until pediatric RP2D has been<br>established in Stratum 1) Patients with diffuse intrinsic pontine gliomas (DIPGs) will be<br>eligible 6 to 14 weeks post-completion of radiation therapy if they do not have any<br>evidence of progression. Patients with newly diagnosed DIPGs, defined as tumors with a<br>pontine epicenter and diffuse involvement of 2/3 or more of the pons, are eligible<br>without histologic confirmation. Patients with pontine tumors that do not meet these<br>criteria or not considered to be typical intrinsic pontine gliomas will only be eligible<br>if the tumors have been biopsied and (1) are proven to be an anaplastic astrocytoma,<br>glioblastoma multiforme, gliosarcoma, anaplastic mixed glioma or fibrillary astrocytoma<br>or (2) have a histone mutation typically seen in DIPG. Patients with disseminated disease<br>are not eligible, and MRI of spine must be performed if disseminated disease is suspected<br>by the treating physician.<br><br> - Available Pre-trial Tumor Tissue -- Stratum 1: Recurrent or refractory primary<br> malignant CNS tumor patients must have adequate pre-trial frozen or FFPE tumor<br> material (minimum of 10 unstained slides) available for use in the tumor mutation<br> burden studies (section 9.1.5).<br><br>Stratum 2: Patients with DIPG who have pre-trial tumor tissue available are requested to<br>submit tissue; however, this is not required for eligibility.<br><br> - Age -- Patient must be = 1 and = 21 years of age at the time of enrollment.<br><br> - Prior Therapy -- Newly Diagnosed DIPG patients Patients must have not received any<br> prior therapy for treatment of their current CNS malignancy other than radiation<br> therapy.<br><br>Refractory/Recurrent patients Patients must have recovered from the acute treatment<br>related toxicities (defined as < grade 1) of all prior chemotherapy, immunotherapy,<br>radiotherapy or any other treatment modality prior to entering this study.<br><br>Myelosuppressive chemotherapy -- Patients must have received their last dose of known<br>myelosuppressive anticancer therapy at least 21 days prior to enrollment or at least 42<br>days if nitrosourea.<br><br>Biological agent: Patient must have recovered from any acute toxicity potentially related<br>to the agent and received their last dose of the biologic agent = 7 days prior to study<br>enrollment.<br><br>For agents that have known adverse events occurring beyond 7 days after administration,<br>this period must be extended beyond the time during which adverse events are known to<br>occur.<br><br>Monoclonal antibody treatment and agents with known prolonged half-lives: At least three<br>half-lives must have elapsed prior to enrollment.<br><br>Radiation --<br><br>Patients must have had their last fraction of:<br><br>Craniospinal irradiation (>24Gy) or total body irradiation or radiation to greater than<br>50% of pelvis > 3 months prior to enrollment.<br><br>Focal irradiation >6 weeks prior to enrollment Local palliative irradiation (small port)<br>=4 weeks<br><br>Autologous Stem Cell Transplant -- Patient must be = 6 months since autologous bone<br>marrow/stem cell transplant prior to enrollment and have CD4 counts above 200/mm3.<br><br>Surgery -- Patients must be at least 4 weeks (28 days) from major surgery and fully<br>recovered from all acute effects of prior surgical intervention.<br><br> - Inclusion of Women and Minorities -- Both males and females of all races and ethnic<br> groups are eligible for this study<br><br> - Neurologic Status -- Patients with neurological deficits should have deficits that<br> are stable for a minimum of 1 week prior to enrollment.<br><br>Patients with seizure disorders may be enrolled if seizures are well controlled.<br><br>• Performance Status -- Karnofsky Performance Scale (KPS for > 16 years of age) or Lansky<br>Performance Score (LPS for = 16 years of age) assessed within two weeks of enrollment<br>must be = 60. Patients who are unable to walk because of neurologic deficits, but who are<br>up in a wheelchair, will be considered ambulatory for the purpose of assessing the<br>performance score.<br><br>• Organ Function --<br><br>Patients must have adequate organ and bone marrow function as defined below:<br><br>Absolute Neutrophil Count (ANC) = 1.0 x 109 cells/ L Platelets = 100 x 109 cells/L<br>(unsupported, defined as no platelet transfusion within 7 days) Hemoglobin = 8 g/dL (may<br>receive transfusions) Total bilirubin =1.5 times institutional upper limit of normal<br>(ULN) AST(SGOT)/ALT(SGPT) = 3 x institutional upper limit of normal (ULN) Albumin = 3<br>g/dl Serum creatinine based on age/gender as noted below. Patients that do not meet the<br>criteria below but have a 24 hour Creatinine Clearance or GFR (radioisotope or<br>iothalamate) = 70 mL/min/1.73 m2 are eligible.<br><br>Age Maximum Serum Creatinine (mg/dL) 1 to < 2 years 0.6, 0.6 (M, F); 2 to < 6 years 0.8,<br>0.8 (M, F); 6 to < 10 years 1, 1 (M, F); 10 to < 13 years 1.2, 1.2 (M, F); 13 to < 16<br>years 1.5, 1.4 (M, F); = 16 years 1.7, 1.4 (M, F).<br><br>• Cardiac Function: Left Ventricular Ejection Fraction (LVEF) > 50% ECG QTc = 450 msec<br><br>• Pulmonary Function: Oxygen saturation as measured by pulse oximetry is > 93% on room<br>air and no evidence of dyspnea at rest<br><br>• Growth Factors -- Patients must be off all colony- forming growth factor(s) for at<br>least 1 week prior to enrollment (i.e., filgrastim, sargramostim or erythropoietin). 2<br>weeks must have elapsed if patients received PEG formulations.<br><br> - Pregnancy Status -- Female patients of childbearing potential must have a negative<br> serum or urine pregnancy test.<br><br> - Pregnancy Prevention -- Female subjects with childbearing potential and male<br> subjects should use effective contraception methods (or abstain from sexual<br> activity) while being treated with APX005M and for 30 days following treatment.<br><br> - Informed Consent -- The patient or parent/guardian is able to understand the consent<br> and is willing to sign a written informed consent document according to<br> institutional guidelines.<br><br>Exclusion Criteria:<br><br>• Concurrent Illness -- Patients with any clinically significant unrelated systemic<br>illness (serious infections Grade = 2 or significant cardiac, pulmonary, hepatic or other<br>organ dysfunction), that in the opinion of the investigator would compromise the<br>patient's ability to tolerate protocol therapy, put them at additional risk for toxicity<br>or would interfere with the study procedures or results.<br><br>Patients with a history of any other malignancy, except patients with a secondary brain<br>tumor if the patient's first malignancy has been in remission for at least 5 years from<br>the end of treatment.<br><br>• Concurrent Therapy -- Patients who are receiving any other anticancer or<br>investigational drug therapy.<br><br>Patients requiring systemic treatment with either corticosteroids (greater than<br>physiologic replacement, defined as dexamethasone 0.75 mg/m2/day) or other<br>immunosuppressive medications within 14 days of study drug administration will be<br>excluded. However, patients who require intermittent use of bronchodilators or local<br>steroid injections will not be excluded from

Exclusion Criteria

Not provided

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Number of patients who experienced dose-limiting toxicities (DLTs);Maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of APX005M in Stratum 1;Maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of APX005M in Stratum 2;Serum concentration of APX005M

Secondary Outcome Measures

Name	Time	Method
Overall survival for Stratum 2 (DIPG) patients;Progression-free survival for Stratum 2 (DIPG) patients;Overall response rate for Stratum 2 (DIPG) patients;Duration of response for Stratum 2 (DIPG) patients