Safety and Efficacy Study in Recurrent or Progressive Grade III or IV Glioma

Study Overview
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Brief Summary
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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 Grdae III or Grade IV glioma with IDH1 mutation or recurrent primary or secondary Grade III or Grade IV glioma with IDH1 mutation. 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 cycle up to six cycles until disease progression or death, whichever occurs first. At the completion of cycle six, patients will be given the option to continue receiving compassionate use treatment cycles.This is the first nasal administration in the US, after prior oral studies with perillyl alcohol proved ineffective. Nasal administration of perillyl alcohol is on-going in Brazil.

Detailed Description
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Perillyl alcohol has previously been tested in 15 clinical studies in > 600 subjects This includes 13 studies in 255 subjects using oral administration sponsored by the National Cancer Institute and two studies in > 350 subjects using intranasal administration in Brazil. NEO100 is a highly purified (>99%) form of perillyl alcohol. Studies in Brazil suggest improved survival for patients with recurrent glioblastoma. Doses of 96 mg qid, 144mg qid, 192mg qid, and 288 mg qid administered intranasally to patients with recurrent GBM for up to 6 months, disease progression or death. From 3 to 6 patients will be evaluated after first cycle (28 days) until MTD is reached. MRI with gadolinium will be at base line, and at the beginning of even cycles. A total of 25 patients will be treated at the MTD. PK studies will be conducted during Phase 1 at first dosing, and after first dose of 3rd cycle.

Official Title
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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

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Perillyl alcohol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Radiographically-confirmed progression of, or recurrent, primary or secondary Grade III or Grade IV glioma, and must be on a stable or decreasing dose of steroid for at least five days prior to the date of informed consent. Must have failed previous radiation treatment or combined treatment with temozolomide and radiation. If progression of disease occurs within three months of conformal radiation, it must be outside of the radiation field or proven by biopsy/resection. Must have an ECOG performance status of 0 - 2, or KPS ≥ 60. Must have an expected survival of at least three months. Must be willing to provide blood samples for pharmacokinetic study Must have adequate organ and marrow function Female patients of child-bearing potential and male patients must agree to use adequate contraception Must have the ability to understand, and the willingness to sign, a written informed consent. Phase 2a: Patient must have a confirmed IDH1 mutation 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). Exclusion Criteria: The size of the glioma tumor is multi-focal and > 30mm in size, as assessed at the baseline (pre-study) MRI evaluation. Patient has completed chemo-radiation within the last three months, unless new contrast enhancement is outside of radiation field, or there is tissue proven recurrence or progression. Patient has had surgery within seven days prior to the date of informed consent. Patient has had chemotherapy within 28 days prior to first administration of study drug. Patient has not recovered from adverse events due to chemotherapy, immunotherapy, or radiation therapy administered more than 28 days prior to first administration of study drug. Patient has had prior treatment with bevacizumab, a chemotherapy wafer implant (Gliadel), or any other FDA- approved chemotherapy except temozolomide. Patient has had more than one recurrence or progression of their tumors. Patient is receiving any other investigational agents. Patient has a history of allergic reactions attributed to perillyl alcohol. Patient has uncontrolled intercurrent illness Patient has a history of new diagnosis or treatment of cancer other than malignant glioma within five years prior to start of the study, except for basal cell carcinoma or squamous cell carcinoma.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NEO100 Phase 1<br>Intranasal delivery of NEO100 (perillyl alcohol) four times a day, escalation up to four different doses to determine maximum tolerated dose. | Drug: Perillyl alcohol<br>* Intranasal administration<br>* Other names: NEO100;|
| Experimental: NEO100 Phase 2A<br>Intranasal delivery of NEO100 (perillyl alcohol) four times a day. Treatment of total of 25 patients at maximum tolerated dose. | Drug: Perillyl alcohol<br>* Intranasal administration<br>* Other names: NEO100;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1 Primary Outcome: Number of Participants with Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment |  | Up to 6 months | 
| Phase 2 Primary Outcome: Number of Participants Who Are Alive Each Month For 6 Months |  | Up to 6 months | 
| Phase 2 Primary Outcome: Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related To Treatment |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent glioblastoma, recurrent GBM