Safety and Efficacy of NEO212 in Patients With Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype or Brain Metastasis

Prior treatment

• Patient in Phase 1 concurrently receiving any other antitumor therapy.
• Patient in Phase 2a or 2b who is concurrently receiving any SOC therapy not listed in Appendix 1.
• Patient has received stereotactic or highly conformal radiotherapy to CNS lesions within 2 weeks before receipt of NEO212.
• Patient has prior history or new diagnosis of secondary cancer within five years prior to the date of informed consent, except for basal cell carcinoma or squamous cell carcinoma of the skin.
• Patient had surgery within 7 days prior to the date of informed consent.
• Patient has not recovered to Grade 1 from treatment related adverse events due to chemotherapy, immunotherapy, or radiation therapy.
• Patient had prior treatment with perillyl alcohol.

Other illness

• Patient with history of known leptomeningeal involvement.
• Patient has a history of allergic reactions attributed to perillyl alcohol.

Lab values

• Patient has a corrected QT interval (using Fridericia's correction formula) (QTcF) of \>470 msec, a history of additional risk factors for TdP (e.g. heart failure, hypokalemia), and/or the use of concomitant medications that prolong QT/QTc interval.

Other

• Patients with metastases to the spinal cord parenchyma.
• Patients with metastases to the meninges.
• Patients in Phase 2b with Astrocytoma IDH-mutant, or Glioblastoma IDH-wildtype who have had more than one recurrence or progression of his/her primary CNS tumor(s).

• Patient must be ≥ 18yrs of age.
• Patient must have the ability to understand, and the willingness to sign, a written informed consent form.
• Patient has been on a stable or decreasing dose of steroids for at least five days prior to the date of informed consent.
• Any toxicity from prior therapy must be resolved or at maximum Grade 1 prior to initiation of NEO212.
• If progression of disease occurs within 90 days or conformal radiation, the progression/recurrence must be outside of the radiation field or proven by biopsy/resection.
• Patient with Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype must have a Karnofsky Performance Status (KPS) of ≥ 60.
• Patient with select solid tumors must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Patient must have an expected survival or at least three months.
• Patient must have a baseline MRI of the brain with gadolinium within 14 days of administration of NEO212.
• Patient with select solid tumors must have a baseline CT scan with IV contrast and oral contrast of neck, chest, abdomen and pelvis within 14 days of administration of NEO212.
• Patients must be able to comply with all study assessments.
• If patient suffers from seizures (s)he must be controlled on a stable dose of anti-epileptics for 14-days prior to the date of informed consent.
• Patient must have adequate organ and marrow function as follows:
  • Absolute neutrophil count ≥ 1,500/microliter
  • Platelets ≥ 100,000/microliter
  • Total bilirubin within normal institutional limits
  • AST (SGOT) / ALT (SPGT) ≤ 2.5 x institutional upper limit of normal
  • Creatinine clearance (CrCl) of \>60 mL/min (using the Cockcroft-Gault formula or 24- hour urine collection).
• Female patients of child-bearing potential and male patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for 30 days prior to the first dose of NEO212, for the duration of study participation, and for 90 days following completion of therapy.
  • A female of child-bearing potential is any women (regardless of sexual orientation, not having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has not had menses at any time in the preceding 12 consecutive months).
• A negative serum pregnancy test will be required of all female patients of child-bearing potential within seven days prior to the receipt of NEO212.
• A serum pregnancy test will be repeated immediately if pregnancy is suspected.
  • Phase 1: (dose escalation)
• Patient must:
  • have radiographically confirmed Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype following previous radiation therapy or treatment with temozolomide and radiation, or
  • have select solid tumors with uncontrolled metastases to the brain (confirmed by cranial CT or MRI) that is not controlled by surgery or radiation therapy and receiving one of the protocol approved SOC regimens.
• Patients receiving prior systemic therapy must have a minimum wash-out period (defined as the period prior to receipt of the first dose of NEO212) of:
  • 28 days or 5 half-lives (whichever is shorter) elapsed from the administration from any experimental agent;
  • 2 weeks from administration of immunotherapies;
  • 28 days from administration of cytotoxic agents; and
  • 7 days from administration of non-cytotoxic agents (interferon, tamoxifen, thalidomide, cis-retinoic acid, and herbal medicine).
  • NOTE: No washout is necessary for alternating electrical fields.
  • Phase 2a: (safety run-in)
• Patient must have select solid tumors with uncontrolled metastases to the brain (confirmed by cranial CT or MRI) that is not controlled by surgery or radiation therapy and receiving one of the protocol approved SOC regimens.
• Patients receiving prior systemic therapy must be receiving one of the protocol approved Standard of Care (SOC) regimens.
• Patient must have measurable/evaluable CNS disease per RANO or RANO-BM criteria.
• Patient must have measurable/evaluable systemic disease per RECIST v1.1 criteria.
  • Phase 2b: (efficacy)
• Patient must:
  • have radiographically confirmed Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype following previous radiation therapy or treatment with temozolomide and radiation, or
  • have select solid tumors with uncontrolled metastases to the brain (confirmed by cranial CT or MRI) that is not controlled by surgery or radiation therapy and receiving one of the protocol approved SOC regimens.
• Patients receiving prior systemic therapy must be receiving one of the protocol approved Standard of Care (SOC) regimens.
• Patient must have measurable/evaluable CNS disease per RANO or RANO-BM criteria
• Patient with select solid tumors must have measurable/evaluable systemic disease per RECIST v1.1 criteria.
• Creatinine clearance (CrCl) of \>60 mL/min (using the Cockcroft-Gault formula or 24-hour urine collection). Female patients of child-bearing potential and male patients must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for 30 days prior to the first dose of NEO212, for the duration of study participation, and for 90 days following completion of therapy.