EDO-S101 for MGMT Unmethylated Glioblastoma (nGBM)

Study Groups and Drug Administration:

If you are found to be eligible to take part in this study, you will be assigned to 1 of 2
groups based on when you join the study:

- If you are in Group 1, you will receive EDO-S101 on Day 1 of each 21-day Cycle.

- If you are in Group 2, you will receive EDO-S101 on Days 1 and 15 of each 28-day Cycle.
Participants in this group will also receive radiation therapy per standard of care.

Additionally, you will be assigned to a dose level of EDO-S101 based on when you joined this
study. Up to 6 dose levels of EDO-S101 will be tested. Up to 6 participants will be enrolled
at each dose level. The first set of participants will receive the lowest dose level. Each
new set will receive a higher dose than the set before it, if no intolerable side effects
were seen. This will continue until the highest tolerable dose of EDO-S101 is found.

Each time you receive EDO-S101, it will be given by vein over about 60 minutes.

You will be given standard corticosteroids to help decrease the risk of side effects. You may
ask the study staff for information about how the drug is given and its risks.

Length of Study:

You may receive EDO-S101 for up to 12 cycles. You will no longer be able to receive the study
drug if the disease gets worse, if intolerable side effects occur, or if you are unable to
follow study directions.

Study Visits for Group 1:

On Day 1 of each cycle:

- You will have a physical exam, including a neurological exam.

- Blood (about 2 teaspoons) will be drawn for routine tests. If you can become pregnant,
this sample will also be used for a pregnancy test.

On Day 1 of Cycles 1 and 2:

°You will have an EKG 3 times before and 1 time at 30 and 60 minutes during the infusion.

In addition to these tests, on Day 1 of odd-numbered cycles beginning with Cycle 3 (Cycles 3,
5, 7 and so on):

- Urine will be collected for routine tests.

- You will have an MRI.

On Days 8 Cycle 1:

- You will have a physical exam, including a neurological exam.

- Blood (about 1 teaspoon) will be drawn for routine tests.

On Days 15 of Cycle 1, blood (about 1 teaspoon) will be drawn for routine tests.

Study Visits for Group 2:

On Days 1 and 15 of each cycle:

- You will have a physical exam, including a neurological exam.

- Blood (about 2 teaspoons) will be drawn for routine tests. This sample will also be used
for a pregnancy test, if you can become pregnant (Day 1 only).

On Days 1 and 15 of Cycles 1 and 2:

°You will have an EKG 3 times before and 1 time at 30 and 60 minutes during the infusion.

In addition to these tests, on Day 1 of Cycle 3 and every odd-numbered cycles beginning with
Cycle 3 (Cycles 3, 5, 7 and so on):

- Urine will be collected for routine tests.

- You will have an MRI.

On Days 8 and 22 of Cycle 1, blood (about 1 teaspoon) will be drawn for routine tests.

At any time during the study, extra tests may be performed if the doctor thinks they are
needed. The study doctor will tell you more about any extra tests that may be needed.

Follow-Up:

Within 30 days after your last dose of study drug, and then every 3 months after that, the
study staff will call you to learn how you are doing. The call should take about 5-10
minutes.

If the disease gets worse and you have surgery as part of your standard care, tumor tissue
that is removed during this procedure will be collected for biomarker testing, including
genetic biomarkers.

If you stop taking the study drug and the disease has not gotten worse, you will have the
following as often as the doctor thinks is needed:

You will have a physical exam. Blood (about 2 teaspoons) will be drawn for routine tests. You
will have an MRI.

The study doctor will discuss with you how often these tests may be performed. If the disease
gets worse or the study ends, you will no longer have these tests for the study.

Inclusion Criteria:

1. Be willing and able to provide written informed consent for the trial.

2. Be >/= 18 years of age on day of signing informed consent.

3. Have histologically confirmed World Health Organization Grade IV glioma (GB or
gliosarcoma).

4. Patients must have preliminary GBM MGMT status (tumor must be MGMT promoter
unmethylated) determined prior to study entry. If initial MGMT status is determined to
be "unmethylated", by an outside institution the patient may be enrolled and begin
treatment. However, MGMT status must be retested following enrollment by central
laboratory CLIA certified testing at MD Anderson, if tissue is available. Confirmed
IDH wildtype. The presence of an IDH mutation will be an exclusionary criteria for
trial enrollment.

5. Have a performance status of >/= 60 on the Karnofsky Performance Scale (KPS).

6. If patient is on steroids, patient must be on a stable or decreasing dose of steroids
for at least 5 days at the time of baseline brain MRI.

7. Demonstrate adequate organ function. All screening labs should be performed within 14
days (+3 working days) of treatment initiation. Absolute neutrophil count (ANC) >/=
1,500 /mcL; Platelets >/= 100,000 /mcL; Hemoglobin >/= 9 g/dL or >/= 5.6 mmol/L; Serum
creatinine OR Measured or calculated creatinine clearance (GFR can also be used in
place of creatinine or CrCl) /= 60 mL/min
for subject with creatinine levels > 1.5 X institutional ULN; Serum total bilirubin

1.5 ULN; AST (SGOT) and ALT (SGPT) or Prothrombin Time (PT), Activated Partial Thromboplastin Time (aPTT)
8. Female subjects of childbearing potential should have a negative serum pregnancy test
within 72 hours of starting first dose of study drug.

9. Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the
duration of the study. Subjects of childbearing potential are those who have not been
surgically sterilized or have not been free from menses for > 1 year.

10. Male subjects should agree to use an adequate method of contraception during the
course of the study.

11. Patients must have completed standard radiation therapy with concurrent TMZ and must
not have evidence of progressive disease on post treatment imaging. Progression can
only be defined using diagnostic imaging if there is new enhancement outside of the
radiation field (beyond the high-dose region or 80% isodose line) or if there is
unequivocal evidence of viable tumor on histopathologic sampling (e.g., solid tumor
areas [i.e, > 70% tumor cell nuclei in areas], high or progressive increase in MIB-1
proliferation index compared with prior biopsy, or evidence for histologic progression
or increased anaplasia in tumor). Note: Given the difficulty of differentiating true
progression from pseudoprogression, clinical decline alone, in the absence of
radiographic or histologic confirmation of progression, will not be sufficient for
definition of progressive disease in the first 12 weeks after completion of concurrent
chemoradiotherapy. (For Stage 1: Post-chemoradiation group only)

12. Patients must have undergone surgery of their GBM, and must not have had any further
treatment following surgery. A minimal interval of 7 days between the day of surgery
and the day of inclusion should be respected; a maximal interval of 31 days between
the day of surgery and the day of inclusion should be respected; the patient should
have fully clinically recovered from the surgery. (For Stage 2: Radiation with
concurrent and adjuvant EDO-S101 only)

13. Patients must undergo surgery and must not have further treatment. (For MTD Expansion
cohort only)

Exclusion Criteria:

1. Has received prior interstitial brachytherapy, implanted chemotherapy, or therapeutics
delivered by local injection or convection enhanced delivery. Prior treatment with
Gliadel® wafers will be excluded. Concomitant use of the Optune device will also be
excluded.

2. Is currently participating or has participated in any other investigational or
therapeutic trial before or after chemoradiation.

3. Any serious medical condition that interferes with adherence to study procedures.

4. Has had prior chemotherapy, targeted small molecule therapy, within 2 weeks prior to
study Day 1 or who has not recovered (i.e., events due to a previously administered agent. Note: Subjects with neuropathy are an exception to this criterion and may qualify for the study. Note: If
subject received major surgery, they must have recovered adequately from the toxicity
and/or complications from the intervention prior to starting therapy. ( For Stage 1:
Post-chemoradiation group only)

5. Patients with a history of a second malignancy diagnosed within three (3) years of
study enrollment or have a known additional malignancy that is progressing or requires
active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell
carcinoma of the skin, or in situ cervical cancer that has undergone potentially
curative therapy.

6. New York Heart Association (NYHA) stage III/IV congestive heart failure, arrhythmias
not adequately controlled.

7. Patients with prolonged QTc interval defined as male >450 msec and female > 470 msec.

8. Patients who are on treatment with drugs known to prolong the QT/QTc interval.

9. Has known gliomatous meningitis, extracranial disease, or multifocal disease. Subject
has multifocal GBM, defined as discrete sites of contrast enhancing disease without
contiguous T2/FLAIR abnormality that require distinct radiotherapy ports. Satellite
lesions that are associated with a contiguous area of T2/FLAIR abnormality as the main
lesion(s) and that are encompassed within the same radiotherapy port as the main
lesion(s) are permitted.

10. Has an active infection requiring systemic therapy.

11. Has an ongoing or previous history of spontaneous intratumoral hemorrhage.

12. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.

13. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

14. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit.

15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
Testing not required.

16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected). (Testing not required for Stage 2 and MTD Expansion
cohort)

17. Has received a live vaccine within 30 days prior to the first dose of trial treatment.

18. Contraindication for undergoing MRIs

19. Use of any drug with HDAC inhibiting activity.

20. Use of valproate in any of its indications (epilepsy, mood disorder). Valproate, due
to its HDAC inhibiting activity is contraindicated. For those patients on valproate,
valproate will need to be discontinued and switched to a different anti-epileptic
agent or psychotropic agent. A washout period of 4 days from valproate acid will be
allowed prior to enrolling into the trial.

21. Has had any prior chemotherapy, targeted small molecule therapy. (For Stage 2:
Radiation with concurrent and adjuvant EDO-S101 and MTD Expansion cohort only)