Study of Tozuleristide and the Canvas Imaging System in Pediatric Subjects With CNS Tumors Undergoing Surgery

PNOC012

Rationale for Study

There is an urgent unmet need for a tumor-targeted imaging agent to enable real-time intraoperative distinction between malignant and normal tissue to improve neurosurgical outcomes, either as increased chance of a gross total resection or decreased risk of inadvertent normal brain resection or both.

Trial Requirement/Treatment

Subjects randomized to Arm 1 (~9% of subjects) will not receive tozuleristide but will undergo standard of care neurosurgery and will have imaging performed with the Canvas System.

Subjects randomized to Arm 2 (~ 91% of subjects) will be administered tozuleristide at a dose of 15 mg/m^2 at least 1 hour and no more than 36 hours prior to surgery. They will undergo standard of care neurosurgery and will have imaging performed with the Canvas System. Surgery will be performed by a neurosurgeon and the Canvas will be operated by a designated Imaging Operator. Fluorescence of tumor and ambiguous tissue during surgery will be assessed and scored. Biopsy samples of these tumor and ambiguous tissues will be collected for pathology analysis.

All subjects will be monitored for safety during their participation in the study.

Primary Objectives

Sensitivity and specificity of tozuleristide imaged with the Canvas system to fluorescently identify tumor in equivocal tissue will be evaluated based on assessments made by the surgeon and imaging operator. These measures will be compared to the sensitivity and specificity of surgical designation of equivocal tissue without fluorescence.

Secondary Objectives

  • Safety - number of patients with adverse events
  • Extent of resection - extent of resection will be evaluated by the surgeon and by central review of post-operative magnetic resonance images (MRI). Extent of resection will be designated in the following categories: gross total resection (GTR; all tumor removed), near total resection (NTR; bulk of tumor removed), sub-total resection (STR; residual tumor present).
  • Concentration of tozuleristide in the blood (pharmacokinetics)
  • Performance of the Canvas system - The surgeon and imaging operator will complete a survey to evaluate the usability of the Canvas during surgery

 

Inclusion Criteria

Subjects must meet all of the following criteria to be included in this study:

  1. Subjects must be >1 month and ≤30 years of age at the time of study enrollment
  2. Subjects must have MRI obtained within 30 days of study enrollment documenting a measurable lesion consistent with a pediatric primary CNS tumor for which maximal safe resection is indicated
  3. Adequate renal function defined as:
    1. Serum creatinine within normal limits for age or calculated creatinine clearance ≥75 mL/min/1.73 m2 based on Schwartz equation or normal creatinine for age based on the following table:
      1. Age 1 to 2 years: 0.6 (male); 0.6 (female)
      2. Age 2 to <6 years: 0.8 (male); 0.8 (female)
      3. Age 6 to <10 years: 1 (male); 1 (female)
      4. Age 10 to <13 years: 1.2 (male); 1.2 (female)
      5. Age 13 to <16 years: 1.5 (male); 1.4 (female)
      6. Age ≥ 16 years: 1.7 (male); 1.4 (female)
  4. Adequate liver function defined as:
    1. Bilirubin <2 x upper limit of normal
    2. Alanine aminotransferase (ALT) < 3 x upper limit of normal
    3. Serum albumin >2 g/dL
  5. Prior therapy: Subjects with prior therapy are eligible provided they have recovered from any acute toxic effects of prior therapy and have sufficient time interval prior to enrollment:
  • Radiation therapy: subjects may not have had radiation therapy to the area of tumor planned to be resected within 28 days of study enrollment
  • Chemotherapy: at least 14 days from any myelosuppressive chemotherapy (28 days if prior nitrosourea) and if prior chemotherapy, must have an absolute neutrophil count recovery of ≥ 1000/mm3 following count nadir
  • Biologic: at least 7 days from any anti-neoplastic biologic agent (at least 3 half-lives since last administration of monoclonal antibodies)
  • Immunotherapy: at least 42 days after completion of any cellular immunotherapy, such as CAR-T cell therapy
  • Prior surgery for CNS tumors is allowed
  • Prior tozuleristide: at least 1 week after prior dose of tozuleristide if previously treated. NOTE: Subjects previously enrolled on PNOC012 study and randomized to Arm 1 (control) will be eligible for re-enrollment to the non-randomized re-treatment group in the event a second surgery is clinically indicated.
  • Written informed consent must be obtained from the subject or parent or legal guardian prior to the conduct of study activities. Routine clinical tests, e.g., MRI, clinical laboratory studies, may be used for screening requirements. Assent, when appropriate, will be obtained according to institutional guidelines.
  • The risks of treatment with tozuleristide during pregnancy have not been evaluated. Female subjects of child-bearing potential must agree not to attempt to become pregnant or undergo in vitro fertilization and, if participating in sexual activity that could lead to pregnancy, must use 2 reliable methods of contraception simultaneously for 30 days after surgery. Male subjects must agree not to attempt to father a child and, if participating in sexual activity that could lead to pregnancy, must use 2 reliable methods of contraception simultaneously for 30 days after surgery if their partner is of child-bearing potential.
  •  Exclusion Criteria

    1. Subjects meeting any of the following criteria will be considered ineligible for this study:
    2. Pregnancy and contraception: Subjects who are pregnant or breast-feeding or planning to conceive a child within 30 days are not eligible. Males and females of childbearing potential must agree to use 2 effective forms of contraception from the time of enrollment until 30 days post-surgery
    3. Subjects with on-going serious medical conditions (poorly controlled asthma, diabetes, heart disease) such that participation in the study could put the subject at increased risk of worsening their condition
    4. Subjects planned to undergo only a diagnostic biopsy procedure, without intent to resect tissue for therapeutic purposes (e.g., stereotactic pontine biopsy)
    5. Subjects who in the opinion of the investigator are not willing or able to comply with randomization procedures or other study-required study procedures and observations. Subjects previously enrolled and randomized to Arm 1 (control) are not eligible for re-enrollment unless a second surgery is required by standard of care.

    Important note: The eligibility criteria listed above are interpreted literally and cannot be waived.