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

This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 alone for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH- mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled metastases to the brain.

The study will have three phases, Phase 1, Phase 2a and Phase 2b.

This multi-site, Phase 1/2 clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO212 for the treatment of patients with radiographically-confirmed progression of Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype, and the safety, pharmacokinetics and efficacy of a repeated dose regimen of NEO212 when given with select SOC for the treatment of solid tumor patients with radiographically confirmed uncontrolled brain metastasis. The study will have three phases, Phase 1, Phase 2a and Phase 2b.

Phase 1 is a standard cohort dose escalation 3+3 design with a modified Fibonacci dose escalation used to determine the maximum tolerated dose to select a recommended Phase 2 dose (RP2D) of NEO212 for Phase 2a and Phase 2b. The initial dose of NEO212 will be 170 mg and the dose will increase in successive cohorts (220, 400, 610, 810, and 1,000 mg) until a MTD is reached and a RP2D is selected. There will be up to 42 patients enrolled in Phase 1. In the event two DLTs are experienced in any cohort, a dose de- escalation cohort will be followed (with half of the dose increase from the previous cohort) to determine the MTD/RP2D.

Phase 2a is a safety run-in study with a standard 3+3 design used to confirm the safety of the MTD/RP2D of NEO212 when given in combination with select SOC regimens (as defined in Appendix 1) for patients with uncontrolled metastases to the brain (see Appendix 2). There will be up to 12 patients enrolled into each combination regimen to confirm safety. One dose below the NEO212 MTD/RP2D Cohort Dose will be administered as a starting dose to establish safety (3+3), before moving to Phase 2b with the MTD/RP2D (3+3). In the event that two DLTs are experienced for patients receiving the MTD/RP2D in combination with SOC, the dose de-escalation cohort will be expanded to determine the MTD for a newly established Phase 2b Treatment Group.

Phase 2b is a dose expansion study to assess efficacy of NEO212 alone, at the MTD/RP2D in patients with Astrocytoma IDH-mutant, Glioblastoma IDH-wildtype as a single Treatment Group. A second Treatment Group to study the MTD/RP2D of NEO212 in combination with select SOC regimens in patients with solid tumors and uncontrolled metastases to the brain established in Phase 2a will be evaluated. Phase 2b will be initiated for patients with Astrocytoma IDH-mutant or Glioblastoma IDH-wildtype alongside Phase 2a. There will be up to 28 patients enrolled to have 27 evaluable patients enrolled in each Phase 2b Treatment Group.

For all phases of the study, NEO212 will be self-administered daily for days 1-5 of a 28- day treatment cycle.

Eligibility Criteria:
To be eligible to participate in the study, a patient must meet all of the following inclusion criteria:

* 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 (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 of the brain with gadolinium within 14 days of administration of NEO212.
* Patient with select solid tumors (see Appendix 2) 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 (see Appendix 2) 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 (see Appendix 2) 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 listed on Appendix 1.
* 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 (see Appendix 2) 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 listed on Appendix 1.
* Patient must have measurable/evaluable CNS disease per RANO or RANO-BM criteria
* Patient with select solid tumors (see Appendix 2) 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.

9.2 Exclusion Criteria: (all Phases)

* 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.
* Patients with metastases to the spinal cord parenchyma.
* Patients with metastases to the meninges.
* 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 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).