Study to Evaluate Ibudilast and TMZ Combo Treatment in Recurrent GBM

This is a multi-center open-label, dose escalation study to evaluate the safety, tolerability
and efficacy of MN-166 (ibudilast) and Temozolomide combination treatment in patients with
recurrent glioblastomas. To be eligible, subjects are histologically confirmed GBM
(glioblastoma), WHO Grade IV, must have a Karnofsky Performance Status (KPS) ≥ 70 or Eastern
Cooperative Oncology Group (ECOG) performance status of 0-2.

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 (ibudilast) when given in
combination with TMZ, and determine the dose of MN-166 (ibudilast) to be used in Part 2 of
the study. A total of 15-18 adult subjects are planned to be enrolled in Part 1.

Part 2 will evaluate the efficacy of MN-166 (ibudilast) and temozolomide combination
treatment in patients with recurrent GBM as measured by the proportion of patients 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 and approximately 32
subjects are planned to be enrolled in Part 2.

Inclusion Criteria:

1. Age 18 or above

2. Ability and willingness to signed informed consent form

3. Histologically confirmed GBM (glioblastoma), WHO Grade IV

4. Patients must have a Karnofsky Performance Status (KPS) ≥ 70 or Eastern Cooperative
Oncology Group (ECOG) performance status of 0-2 (see Appendix 7)

5. 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.

6. 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) (Appendix 6)

7. 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 pre-treatment MRI and the start of study, a new baseline MRI
or CT is required.

8. Patients who tolerated prior TMZ therapy; (No grade 3 or greater hematologic toxicity
or grade 3 or greater nausea and vomiting despite maximal medical therapy and
completed at least 80% of prior TMZ administered concomitantly with radiation therapy
= at least 34 of 42 days of treatment).

9. A period Patient has a period of at least 3 months should have lapsed stability since
the patient has he or she received last TMZ and radiotherapy treatment.

10. Patients who suffered clinically significant toxic effects on prior therapy must have
recovered to grade 0 or 1 or pre-treatment baseline value (including but not limited
to exceptions of alopecia, laboratory values listed per inclusion criteria, and
lymphopenia which is common after therapy with TMZ).

11. Patients having undergone recent resection or open biopsy or stereotactic biopsy of
recurrent or progressive tumor will be eligible as long as the following conditions
apply:

1. They have recovered from the effects of surgery.

2. To best assess the extent of residual disease post-operatively, an MRI or CT scan
should ideally have been performed no later than 96 hours following surgery, or
at least 28 days post-operatively, but scans performed outside of this window are
considered acceptable if no alternative is available. In either case, the
baseline/screening MRI must be performed within 14 days prior to registration. If
the patient is taking corticosteroids, the 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 screening MRI or CT scan and the start of
treatment, a new baseline MRI or CT is required.

12. Confirmation of availability of sufficient tissue from a prior surgery for correlative
studies (ten formalin fixed paraffin embedded [FFPE] slides).

Exclusion Criteria:

1. History of Grade 2 (CTCAE v4.0) or greater intracranial or intratumoral hemorrhage
confirmed by either MRI or CT scan;

2. Any significant laboratory abnormality which, in the opinion of the Investigator, may
put the patient at risk and with the following laboratory abnormalities at screening:

- Inadequate Bone Marrow function WBCs < 3,000 mm3 Lymphocytes < 500 mm3Neutrophils
< 1500 mm3 Platelets < 100,000 mm3

- Inadequate Liver function ALT, AST, T.bil > 2x UNL

- Inadequate Renal function Serum Creatinine > 1.5 mg/dL or calculated Creatinine
Clearance > 50 mL/min;

3. Current use of anticoagulant treatment with coumadin (low-molecular-weight heparin and
factor Xa inhibitors are permitted);

4. Any systemic illness or unstable medical condition that might pose additional risk,
including: cardiac, unstable metabolic or endocrine disturbances, renal or liver
disease;

5. Patients with a history of a different malignancy except the following circumstances:

a) 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:

• Cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin;

6. Active drug or alcohol dependence or any other factors that, in the opinion of the
site investigators would interfere with adherence to study requirements;

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;

8. Pregnant or breastfeeding;

1. Women of childbearing potential must agree to use a medically approved
contraceptive method during the treatment period and for 3 months following the
last dose of ibudilast and TMZ. Men must agree to use a reliable method of birth
control and to not donate sperm during the study and for at least 3 months
following the last dose of ibudilast and TMZ. Contraceptive methods may include
an intrauterine device (IUD) or barrier method. If condoms are used as a barrier
method, a spermicidal agent should be added as a double barrier protection;

2. Women of childbearing potential must have a negative serum pregnancy test within
7 days prior to first dose of ibudilast and TMZ;

3. Women are considered post-menopausal and not of childbearing potential if they
have had 12 months of natural (spontaneous) amenorrhea with an appropriate
clinical profile (e.g., age appropriate, history of vasomotor symptoms) or six
months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol
< 20 pg/mL or have had surgical bilateral oophorectomy (with or without
hysterectomy) at least six weeks prior to screening. In the case of oophorectomy
alone, only when the reproductive status of the woman has been confirmed by
follow up hormone level assessment is she considered not of childbearing
potential;

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®);

10. ECG finding of resting pulse < 50 bpm, SA or AV block, QTc prolongation > 450 ms for
males and > 470 ms for females at screening.