A Pilot Study of Intratumorally and Intraparenchymally Administered OS2966 using Convection-enhanced Delivery in Patients with Recurrent/Progressive High-grade Glioma Undergoing a Clinically-indicated Surgical Resection
The primary goal of this Phase 1 study is to determine if a new investigational drug, OS2966, when delivered directly to the brain of adult participants with recurrent/progressive high-grade glioma (HGG) is safe and well tolerated.
6.1. Primary Objective
-To determine the safety and tolerability of OS2966 when delivered both intratumorally (to the bulk, contrast-enhancing tumor) and intraparenchymally (to the surrounding nonenhancing tumor-infiltrated brain) by CED using the ICMC and real-time imaging in patients with recurrent/progressive HGG.
-To determine the optimal biological dose (OBD) of OS2966 when delivered intratumorally and intraparenchymally by CED.
6.2. Secondary Objectives
Secondary objectives are as follows:
- To determine the optimal CED infusion parameters with use of the ICMC, including infusion rate and duration, to maximize the Vd of OS2966 in the brain.
- To determine if OS2966 reaches the systemic circulation after direct delivery to the brain.
- To assess the preliminary efficacy of OS2966 when delivered directly to the tumor-infiltrated brain by CED using the ICMC.
6.3. Exploratory Objectives
- To further characterize the pharmacokinetics (PK) and to characterize the pharmacodynamic (PD) effects of OS2966 after intratumoral administration.
- To assess the following additional safety parameters:
- AEs by system organ class (SOC), severity, and seriousness
- Clinical laboratory assessments, including hematology, coagulation, chemistry, immunogenicity (anti-drug antibodies [ADAs]), as well as proportions of each that are out-of-normal range
- Vital signs, including blood pressure (BP), heart rate (HR), and respiratory rate (RR)
- 12-lead ECG, characterized as normal or abnormal
- Physical examination by system and characterized as normal or abnormal
- Karnofsky Performance Status (KPS) scores
6.4. Evaluation of Objectives
Study objectives will be evaluated throughout the study as defined in Table 2.
Male and female patients aged 18 years or older with histologically confirmed diagnosis of a stereotactically accessible, supratentorial, contrast-enhancing WHO Grade III or IV glioma (HGG) with a maximum volume between 2 and 20 cm3. NOTE: Only patients with a histologically confirmed diagnosis of WHO Grade IV glioma (glioblastoma) meeting the above criteria will be eligible for enrollment in the first 3 dose cohorts (ie, dose concentration levels).
Patient must have completed standard of care chemoradiation (ie, treatment with temozolomide and radiation) and have evidence of tumor recurrence or progression based on imaging studies within the previous 21 days that supports a clinically-indicated resection.
Patient understands the procedures and investigational nature of the study drug and agrees to comply with study requirements by providing written informed consent.
Patient must have KPS equal to or greater than 70.
At the time of study treatment, patients must have recovered from the toxic effects of prior therapy or meet the following criteria, or both:
More than 1 week from last noncytotoxic therapy
More than 4 weeks from last cytotoxic therapy, radiation, or treatment with bevacizumab
Patient must have adequate bone marrow and organ function as specified per protocol.
Women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control) before study entry, for the duration of the study, and for a minimum of 6 months after study completion.
Women of child-bearing potential must have a negative beta-human chorionic gonadoptropin (hCG) serum pregnancy test within 21 days, and a negative urine pregnancy test within 24 hours, before receiving study treatment.
Patients must be able to undergo contrast and noncontrast MRI studies.
Patient has any significant medical illness that, in the investigator's opinion, may compromise the patient's ability to participate in the study.
Patient has participated in another investigational therapeutic drug study in the previous 4 weeks.
Patient has any of the following tumor characteristics:
Multicentric disease - defined as tumors that have multiple discrete areas of contrast enhancement separated by intervening brain and not connected by T2-weighted-Fluid- attenuated Inversion Recovery (FLAIR) abnormality
Contrast-enhancing tumor that extends into the opposite cerebral hemisphere
Nonparenchymal tumor dissemination (subependymal or leptomeningeal)
Tumor located in the posterior fossa
Significant mass effect requiring urgent resection.
Patient has a history of hypersensitivity reaction to gadolinium contrast agents.
Patient is unable to undergo MRI.
Patient has a known history of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS).
Patient has an active infection (requiring treatment) or an unexplained febrile illness.
Patient is receiving anticoagulants, antiplatelets, or nonsteroidal anti-inflammatory drugs (NSAIDs) that cannot be stopped for surgery.
Patient is receiving escalating doses of steroids to treat mass effect. Note: patients on stable corticosteroid doses ≤ 4 mg of dexamethasone (or the equivalent of another corticosteroid) daily are eligible for the study.
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