An Open-Label, Phase 1/2A Dose Escalation Study of Safety and Efficacy of NEO100 in Recurrent or Progressive Grade III or Grade IV Gliomas With IDH1 Mutation
This multi-site, Phase 1/2a clinical trial is an open-label study to identify the safety, pharmacokinetics, and efficacy of a repeated dose regimen of NEO100 (perillyl alcohol) for the treatment of patients with radiographically-confirmed progression of Grade IV glioma or recurrent primary or secondary Grade IV glioma. The study will have two phases, Phase 1 and Phase 2a. Phase 1 is a standard cohort dose escalation 3+3 design used to determine the maximum tolerated dose for Phase 2a. There will be up to 24 patients enrolled in Phase 1. There will be 25 patients enrolled in Phase 2a. For both phases of the study, NEO100 will be self-administered four times daily for a 28-day treatment cycles until disease progression, death or patient withdraw from study for any reason, whichever occurs first. Version 10 of the protocol changed the inclusion criteria for Phase 2a to limit inclusion to those patients with progressive or recurrent primary or secondary Grade IV gliomas expressing IDH1 mutations. Prior to the protocol amendment, 4 patients were enrolled who were IDH1 wild-type. Therefore, an additional 28 patients will be recruited for a total of 32 patients enrolled into Phase 2a of this study to have 35 evaluable cases. Version 12 of the protocol expanded the inclusion criteria for Phase 2a to include those patients with progressive or recurrent Grade III Astrocytoma expressing IDH1 mutations. Review of the literature specific to these patients found the same expected time to progression and death. As a result, the number of patients to enroll remains 32 to have 35 evaluable cases.
∙ Patient must:
• Have radiographically-confirmed progression of, or recurrent, primary or
• secondary Grade IV glioma, including infratentorial (brainstem, cerebellar) glioma (confirmed by biopsy) and subcortical glioma.
• Have radiographically-confirmed progression of, recurrent, primary or secondary Grade III astrocytoma.
• All patients must be on a stable or decreasing dose of steroids for at least five days prior to the date of informed consent.
∙ Patient must have failed previous radiation treatment or combined treatment with temozolomide and radiation.
∙ If progression of disease occurs within 90 days of conformal radiation, the progression/recurrence must be outside of the radiation field or proven by biopsy/resection.
∙ Patient must be ≥ 18 years of age. Patient must have an ECOG performance status of 0-2 or KPS ≥ 60 (the latter for Phase 1 only).
∙ Patient must have an expected survival of at least three months. Patient must have a baseline MRI with gadolinium within 14 days of first administration of study drug.
∙ 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 defined below:
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• Total bilirubin within normal institutional limits
• AST (SGOT)/ALT (SPGT)≤ 2.5 × institutional upper limit of normal
• Creatinine within normal institutional limits 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 administration of study drug, for the duration of study participation, and for 90 days following completion of therapy. Should a female patient become pregnant, or suspect she is pregnant, while participating in this study, she should inform her treating physician immediately.
• A female of child-bearing potential is any woman (regardless of sexual orientation, 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 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 initiating study drug.
⁃ A serum pregnancy test will be repeated immediately if pregnancy is suspected. Patient must have the ability to understand, and the willingness to sign, a written informed consent.
• Phase 2a
• In addition to meeting Inclusion Criteria for the Phase I portion of the study, patients eligible for participation in the Phase 2a portion of the study must additionally meet the following
• criteria: Patients must have a confirmed IDH1 mutation by reverse transcription polymerase chain reaction (rtPCR) or immunohistochemistry (unless continuing into the Phase 2a portion of the study from the Phase I portion of the study).