Targeted LSAM-Cisplatin Infusion in Gliomas, Evaluation of Response

Large Surface Area Microparticle (LSAM)-Cisplatin consists of large surface area microparticles of the chemotherapy drug cisplatin. These microparticles are administered as a single-magnetic resonance imaging (MRI) guided infusion directly into the tumor to target cancer at the site of the disease with less systemic exposure than intravenously administered chemotherapy. In this study, all participants with diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), will receive LSAM-Cisplatin and will be evaluated to determine whether it is safe and has an effect on the tumor.

• LSAM-Cisplatin (Drug): Participants with diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), will receive a single intratumoral infusion of LSAM-Cisplatin 6 mg/mL via MRI-guided delivery at an infusion rate of 5 µL/min. Phase 1 (Dose Escalation): Participants will be enrolled sequentially into one of six dose levels. Volumes being delivered will range from 27 to 296 µL over a time period of 5 to 59 minutes. Phase 2 (Dose Expansion): Participants will receive LSAM-Cisplatin 6 mg/mL at the recommended Phase 2 dose (RP2D) selected based on the safety and tolerability findings from the dose-escalation phase.

Primary outcomes

• Number of Participants With Treatment Emergent Adverse Events (Safety and Tolerability) [Day 1 to Week 24]: Treatment Emergent Adverse Events will be assessed by changes in adverse events, changes in concomitant medications, changes in laboratory values, and physical exams.

Secondary outcomes

• Objective Response Rate (ORR) [Weeks 4, 12, and 24]: The proportion of participants with overall confirmed response of complete response (CR) or partial response (PR) as determined using Response Assessment in Pediatric Neuro-Oncology (RAPNO)/Response Assessment in Pediatric Neuro-Oncology for Diffuse Intrinsic Pontine Glioma (RAPNO-DIPG) criteria.
• Progression-Free Survival (PFS) [Day 1 to Week 24]: Progression-Free survival (PFS) as assessed using Response Assessment in Pediatric Neuro-Oncology (RAPNO)/Response Assessment in Pediatric Neuro-Oncology for Diffuse Intrinsic Pontine Glioma (RAPNO-DIPG) criteria.
• Overall Survival (OS) [Day 1 to Week 24]: Overall survival (OS) as determined by survival time post-infusion of LSAM-Cisplatin.
• Concentration of Cisplatin in the Systemic Circulation Post-infusion [Day 1 to Week 8]: Cisplatin concentrations in plasma samples collected pre-infusion of LSAM-Cisplatin, and at 1, 2, 24, and 48 hours after completion of the LSAM-Cisplatin infusion, and at Weeks 1, 2, 3, 4, and 8.
• Concentration of Cisplatin in the Cerebrospinal Fluid (CSF) Post-infusion [Prior to infusion to Week 24]: Cisplatin concentrations in cerebrospinal fluid (CSF) samples collected prior to infusion of LSAM-Cisplatin, prior to discharge from the hospital post-infusion; and at Weeks 4, 12, and 24.

Sex: All, ages: 3 Years to 21 Years

Inclusion Criteria:

* Aged 3 to ≤ 21 years.
* Diagnosis of diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG), based on characteristic magnetic resonance imaging (MRI) findings and/or histopathologic confirmation.
* Prior radiation treatment must have included focal radiation therapy per institutional standard of care and must have been initiated within 6 weeks of diagnosis.
* At least 4 weeks, but no more than 12 weeks, post-completion of radiotherapy treatment.
* A standard of care post-radiation magnetic resonance imaging (MRI) performed 4 to 6 weeks after radiation therapy is required for confirmation of eligibility.
* Performance status \[Karnofsky Performance Scale or Lansky Performance Score\] within 14 days of Day 1 ≥ 60.
* Absence of other significant medical condition.
* A legal parent/guardian and/or participant must be able to understand and be willing to sign a written informed consent and/or assent document, as appropriate.

Exclusion Criteria:

* Untreated symptomatic hydrocephalus at the time of consent, has metastatic or disseminated disease, or leptomeningeal disease.
* Magnetic resonance imaging (MRI) findings that preclude stereotactic procedure.
* Intercurrent illnesses or conditions which preclude participation: active systemic infections, autoimmune disease requiring systemic immunomodulation, active or uncontrolled seizure disorder, central nervous system (CNS) vasculopathy or aneurysms, Grade ≥3 cardiac dysfunction, Fridericia-corrected QT interval (QTcF) ≥470 ms.
* Abnormal organ function:

  * Renal insufficiency: glomerular filtration rate (GFR) ≤ 60 mL/min/1.73m² (with Schwartz equation)
  * Hepatic dysfunction: aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 1.5 x upper limit of normal (ULN) and 3 x upper limit of normal (ULN) in the presence of liver metastases; or bilirubin ≤ 1.5 x upper limit of normal (ULN) and 3 x upper limit of normal (ULN) in the presence of Gilbert disease
  * Bone marrow suppression:

    * absolute neutrophil count (ANC) < 1,000/μL
    * platelets < 100,000/μL
  * Coagulopathy or international normalized ratio (INR) > 1.5
* Receiving any anticoagulants or antiplatelet drugs; any drugs known to cause ototoxicity and nephrotoxicity; receiving any other tumor-directed therapy.
* Known allergy or hypersensitivity to the study agent (including cisplatin and diluent components).
* Female participants of childbearing potential must not be pregnant or breast-feeding.