A Phase 1 Study of SRN-101 Administered Prior to Surgical Resection in Adults With Recurrent High-Grade Glioma.

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of intratumoral administration of SRN-101 in participants with recurrent high-grade glioma (rHGG) undergoing resection.

II. To evaluate the biologic activity of SRN-101.

EXPOLORATORY OBJECTIVES:

I. To assess immunologic response to SRN-101. II. To identify potential pharmacodynamics biomarkers for SRN-101 activity.

OUTLINE: Participants will receive a single administration of SRN-101 during real-time magnetic resonance imaging (MRI)-guided convection-enhanced delivery (CED), followed by non-investigational surgical resection 7 to 21 days after SRN-101 administration. Participants will be followed for up to 5 years after surgical resection.

Inclusion criteria

• Male or female ≥ 18 years of age.
• Participants have received at least one prior line of standard-of-care treatment for high-grade glioma (HGG). Specifically, participants have received prior surgery that resulted in histopathologic diagnosis followed by treatment with radiation alone and/or radiation plus temozolomide.
• Participants with recurrent high-grade glioma (rHGG) for whom resection is planned, and with a lesion that is accessible to convection-enhanced delivery (CED) therapy. Eligible tumor types include central nervous system (CNS) World Health Organization (WHO) Grade 4 astrocytoma isocitrate dehydrogenase (IDH) wild-type (WT) (i.e., glioblastoma), WHO Grade 4 astrocytoma IDH mutated, WHO Grade 3 astrocytoma IDH WT or mutated, and WHO Grade 3 oligodendroglioma IDH mutated, 1p19q codeleted. Participants may have had multiple recurrences.
• Tumors must be supratentorial in location, and participants can only have a single lesion that is ≥ 1 centimeter and ≤ 4 centimeters in diameter.
• Performance Level using the Karnofsky score ≥ 70%. Note: Neurologic deficits in participants with CNS tumors must have been stable for at least 7 days with no new deficits prior to study enrollment. Participants who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the Karnofsky performance score.
• Predictable life expectancy of at least 3 months.
• Participants must have adequately recovered from the acute toxic effects of all prior anti-cancer chemotherapy and must be at least 3 weeks from previous cytotoxic chemotherapy, 4 weeks from prior radiation therapy, and at least 2 weeks from any major surgery, with evidence of adequate wound healing.
• Participants must have adequate organ function based on laboratory assessments obtained within 21 days prior to study treatment. Laboratory values obtained as part of standard of care within this timeframe may be used to satisfy eligibility criteria.

Adequate bone marrow function:

absolute neutrophil count ≥1,500/microliter (mcL) platelets ≥100,000/mcL

Adequate hepatic function:

total bilirubin ≤ 2x upper limit of normal (ULN) for their age Aspartate aminotransferase (AST)serum glutamic-oxaloacetic transaminase (SGOT) ≤2 X institutional upper limit of normal alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) ≤2 X institutional upper limit of normal Serum albumin ≥ 2 g/dL

Adequate renal function:

creatinine ≤ 1.5 x within institutional upper limit of normal OR creatinine clearance radioisotope (GFR) ≥ 70 mL/min/1.73 m2, calculated using the Cockcroft-Gault equation, unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m2

Adequate coagulation:

Prothrombin time and international normalized ratio ≤ 1.5x ULN

Note: Participants receiving anticoagulant therapy must be able to safely discontinue anticoagulation per institutional guidelines and the treating neurosurgeon's discretion prior to infusion of SRN-101.

• Participants with seizure disorders may be enrolled if on a stable anticonvulsant dose and not experiencing refractory seizures in the last 3 months.
• Agree to participate in the long-term safety follow-up.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• Disseminated disease or multifocal disease.
• Pregnant or breastfeeding. Participants of childbearing potential and male participants with female partners of childbearing potential must agree to always use highly effective forms of contraception during the course of the study and for at least 3 months after completion of study intervention. Contraceptive use by participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Participants of childbearing potential must have a negative blood pregnancy test within 21 days of commencement of study intervention. Participants must refrain from donating sperm during the course of the study and for at least 3 months after completion of study intervention.
• History of active liver disease, including Hepatitis B or Hepatitis C or human immunodeficiency virus (HIV).
• Another concurrent tumor immunotherapy.
• Initiation and/or escalation of systemic immunosuppressive therapy (including corticosteroids) within 7 days prior to study initiation, except protocol-required peri-procedural dexamethasone. Participants already on dexamethasone (at a maximum dose of 4 mg per day) are eligible.
• Known or suspected hypersensitivity to Gadoteridol, its excipients, or other gadolinium-based contrast agents.
• Recent onset of neurologic dysfunction or abnormality that is deemed by the Investigator to prevent patient participation.
• Inability, or potential inability, to comply with the safety monitoring requirements of the study, as determined by the Investigator's opinion.
• Other comorbidities that the Investigator believes will negatively impact the participant's ability to benefit from or tolerate this study.
• Inability to undergo an MRI.
• Radiographic evidence that the target lesion or an associated treatment or resection cavity directly communicates with the ventricular system, or determination by the treating neurosurgeon that adequate CED of the target lesion cannot be performed without clinically meaningful leakage of infusate into a cerebral spinal fluid (CSF) space.