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

Inclusion Criteria: Phase 1: (dose escalation) Patient must be ≥ 18yrs of age. Patient must have the ability to understand, and the willingness to sign, a written informed consent form. 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 (see Appendix 2) with uncontrolled brain metastasis (confirmed by cranial CT or MRI) that is not controlled by surgery or radiation therapy and receiving one of the protocol approved SOC regimens. Patient has been on a stable or decreasing dose of steroids for at least five days prior to the date of informed consent. 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). 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 (see Appendix 2) 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 with gadolinium within 14 days of administration of NEO212. Patient 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. Patient 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. Patient must be willing to provide blood samples for pharmacokinetic study. 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 • Serum creatinine ≤ x ULN and creatinine clearance (CrCl) of >50 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: o Has not undergone a hysterectomy or bilateral oophorectomy; or o 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 2a: (safety run-in) Patient must be ≥ 18yrs of age. Patient must have the ability to understand, and the willingness to sign, a written informed consent form. Patient must have select solid tumors (see Appendix 2) with uncontrolled brain metastasis (confirmed by cranial CT or MRI) that is not controlled by surgery or radiation therapy and receiving one of the protocol approved SOC regimens. Patient been on a stable or decreasing dose of steroids for at least five days prior to the date of informed consent. Patients receiving prior systemic therapy must be receiving one of the protocol approved Standard of Care (SOC) regimens listed on Appendix 1. Any toxicity attributed to 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 select solid tumors (see Appendix 2) must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patient must have an expected life-expectancy of at least three months. Patient must have a baseline MRI with gadolinium within 14 days of administration of NEO212. Patient 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. Patient must have measurable/evaluable CNS disease per RANO criteria. Patient must have measurable/evaluable systemic disease per RECIST v1.1 criteria. Patient must be willing to provide blood samples for pharmacokinetic study. 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 Serum creatinine ≤ x ULN and creatinine clearance (CrCL) of >50 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: o Has not undergone a hysterectomy or bilateral oophorectomy; or Has 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 2b: (efficacy) Patient must be ≥ 18yrs of age. Patient must have the ability to understand, and the willingness to sign, a written informed consent form. 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 (see Appendix 2) with uncontrolled brain metastasis (confirmed by cranial CT or MRI) that is not controlled by surgery or radiation therapy and receiving one of the protocol approved SOC regimens. 3. Patient has been on a stable or decreasing dose of steroids for at least five days prior to the date of informed consent. 4. Patients receiving prior systemic therapy must be receiving one of the protocol approved Standard of Care (SOC) regimens listed on Appendix 1. 5. Any toxicity attributed to prior therapy must be resolved or at maximum Grade 1 prior to initiation of NEO212. 6. 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. 7. Patient with select solid tumors (see Appendix 2) must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 8. Patient must have an expected survival or at least three months. 9. Patient must have a baseline MRI with gadolinium within 14 days of administration of 10. Patient 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. 11. Patient must have measurable/evaluable CNS disease per RANO criteria. 12. Patient must have measurable/evaluable systemic disease per RECIST v1.1 criteria. 13. Patient must be willing to provide blood samples for pharmacokinetic study. 14. If patient suffers from seizures (s)he must be controlled on a stable dose of antiepileptics for 14-days prior to the date of informed consent. 15. 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 16. Serum creatinine ≤ x ULN and creatinine clearance (CrCl) of >50 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. Exclusion Criteria: 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 had more than one recurrence or progression of his/her CNS tumor(s). Patient has received stereotactic or highly conformal radiotherapy to CNS lesions within 2 weeks before receipt of NEO212. Patient with history of known leptomeningeal involvement. 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 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. 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. Patient has a history of allergic reactions attributed to perillyl alcohol. Patients with an autoimmune disease that required systemic therapy or a medical condition that requires immunosuppression.