Study to Evaluate Ibudilast and TMZ Combo Treatment in Newly Diagnosed and Recurrent Glioblastoma

Part 1 is an open-label, single-arm, dose escalation study of MN-166 (ibudilast) and temozolomide (TMZ) combination treatment. Evaluate safety and tolerability of ibudilast (MN-166) and TMZ combination treatment for 1 cycle (28 days); determine dosage in dose-finding study. Part 2 will evaluate efficacy of fixed-dose MN-166 (ibudilast) and TMZ combination treatment for 6 cycles (\~6 months) until disease progression, unacceptable tolerability and/or toxicity or loss of life.

This is a single-center open-label, dose-escalation study to evaluate the safety, tolerability and efficacy of MN-166 (ibudilast) and Temozolomide combination treatment in patients with newly diagnosed or recurrent glioblastoma. To be eligible, subjects are histologically confirmed glioblastoma or gliosarcoma, or astrocytomas with molecular features of glioblastoma, WHO Grade 4. Recurrent glioblastoma patients must have a Karnofsky Performance Status (KPS) ≥70 or Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients having newly diagnosed glioblastoma, gliosarcoma, or astrocytomas with molecular features of glioblastoma must have a KPS ≥60 and ECOG score 0-1. This is divided into a dose-escalation phase (Part 1) followed by a fixed-dose phase (Part 2).

Part 1 will evaluate the safety and tolerability of MN-166 when given in combination with temozolomide, and determine the dose of MN-166 to be used in Part 2 of the study. Up to 18 adult subjects are planned to be enrolled in Part 1.

Part 2 will evaluate the efficacy of MN-166 and temozolomide combination treatment as measured by the proportion of subjects who are progression-free at 6 months. Other outcome measures include the evaluation of overall survival, response rate, and median six-month progression-free survival up to 2 years and up to 50 subjects are planned to be enrolled in Part 2.

Eligibility Criteria:
Major Inclusion Criteria for Recurrent GBM Patients:

1. Age 18 or older;
2. Histologically confirmed GBM (glioblastoma), WHO Grade 4;
3. Patients must have a Karnofsky Performance Status (KPS) ≥70 or Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (see Appendix 7);
4. Previously received standard front-line GBM treatment including maximal surgical resection followed by external beam radiation therapy and TMZ therapy. Prior use of NovoTTF (Optune) and Gliadel wafers is allowed;
5. Patients must be in first relapse;

   1. Relapse is defined as progression following initial therapy (i.e., radiation and/or chemotherapy). The intent therefore is that patients had no more than 1 prior therapy (i.e., initial treatment). If the patient had a surgical resection for relapsed disease and no anti-cancer therapy was instituted for up to 12 weeks, and the patient undergoes another surgical resection, this is considered to constitute one (1) relapse;
   2. Documented recurrence or progression by brain MRI imaging ≤14 days before study registration;
   3. Measurable disease by RANO criteria (≥ 10 mm x 10 mm).

Major Inclusion criteria for newly diagnosed patients:

1. Ages 18 or older;
2. Newly diagnosed glioblastoma or gliosarcoma (WHO Grade 4) confirmed by histology or astrocytomas with molecular features of gliobastoma;
3. Starting maintenance therapy with temozolomide (150 mg/m\^2 on Days 1-5 every 28 days) within 4 weeks prior to screening phase;
4. If patient is receiving corticosteroid, dose must be stable or decreasing for at least 5 days prior to the scan. If steroids are added or the steroid dose is increased between the date of the pretreatment MRI and the start of study, a new baseline MRI or CT scan is required;
5. Karnofsky Performance Status ≥60 at time of screening;
6. ECOG score of 0 or 1 at time of screening;
7. Life expectancy of at least 3 months.

Exclusion Criteria (applied to all patients):

1. History of Grade 2 (CTCAE v4.0) or greater intracranial or intratumoral hemorrhage confirmed by either MRI or CT scan;
2. Current use of anticoagulant treatment with coumadin (low-molecular-weight heparin and factor Xa inhibitors are permitted);
3. Any systemic illness or unstable medical condition that might pose additional risk, including: cardiac, unstable metabolic or endocrine disturbances, renal or liver disease;
4. Patients with a history of a different malignancy except the following circumstances:

   1. They have been disease-free for at least 2 years prior to starting study drug and are deemed by the investigator to be at low risk for recurrence of that malignancy. Patients with the following cancers are eligible if diagnosed and treated within the past 2 years: i. Cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin;

7) Patients who have not recovered to ≤ Grade 1 toxicity by NCI CTCAE v4.0 from the toxic effects of previous therapy with exception of lymphopenia, alopecia and fatigue; 9) For use of other investigational drug or other anti-tumor treatment, the following time periods must have elapsed from the projected start of scheduled study treatment:

1. 4 weeks or 5 half-lives (whichever is shorter) from any investigational agent;
2. 4 weeks from cytotoxic therapy (except 23 days for TMZ; 6 weeks from nitrosoureas);
3. 6 weeks from antibodies treatment (i.e., anti-VEGF antibody);
4. 4 weeks or 5 half-lives (whichever is shorter) from other anti-tumor therapies;
5. 2 days from NOVO-TTF (Optune®).