Cancer Stem Cell High-Throughput Drug Screening Study

This protocol describes a prospective single-center Phase 0/1 open-label study to evaluate
the safety and efficacy of a high-throughput drug sensitivity assay to predict targeted
therapies for patients who have GBM that has recurred or progressed following prior
radiation therapy and TMZ. The underlying hypothesis is that treatment of patients with up
to 3 lead candidates identified from individualized CSC/ HTS assays will safely (1) delay
disease progression, and (2) increase survival. There is an abundance of literature strongly
supporting the importance of a regimen for targeting CSCs and preventing tumor recurrence,
as an additional strategy to improve the overall prognosis of cancer patients.

Inclusion Criteria:

Determined at pre-screening:

- A histological diagnosis of GBM [WHO grade IV].

- Subjects ≥18 years of age

- Signed informed consent for tumor collection prior to initiation of any
study-specific procedure. The patient or the patient's legal authorized
representative must be able to provide written informed consent (ICF) and understand
the potential risks and benefits from study enrollment and treatment

- Patients must have a life expectancy of >12 weeks

Determined at or around surgery, and prior to performing HTS:

- Patients must have a surgically accessible tumor with the intent for a gross or near
total resection of the tumor mass (GBM, WHO grade IV)

- Collection of sufficient tumor material for processing CSCs

Determined at or around tumor recurrence, and after completion of HTS:

• Disease progression following radiation and TMZ therapy (as defined by RANO criteria
(45); Appendix 3). Unlimited relapses are allowed, provided the functional status and
other eligibility criteria for enrollment are met

Determined at baseline:

- Signed informed consent for CSC/HTS based therapy prior to initiation of any
study-specific procedure or treatment. The patient or the patient's legal authorized
representative must be able to provide written informed consent (ICF) and understand
the potential risks and benefits from study enrollment and treatment

- Patients must have a KPS rating of ≥70 (see Appendix 4: Karnofsky Performance Scale)

- Patients must have recovered from the toxic effects of prior therapy to < Grade 2
toxicity per NCI CTCAE version 4 (Appendix 6) prior to Day 1 of Cycle 1. The minimum
duration required between prior therapy and initiation of study drug treatment is as
follows:

- At least 12 weeks from completion of radiation therapy except if there is
unequivocal evidence for tumor recurrence (such as histological confirmation) in
which case at least 4 weeks from completion of radiation will suffice

- 4 weeks from prior cytotoxic chemotherapy

- 4 weeks from prior experimental drug

- 6 weeks from nitrosoureas

- 3 weeks from procarbazine

- 1 week for non-cytotoxic agents.

- Subjects must have adequate renal, hepatic and bone marrow function based on
screening laboratory assessments. Baseline hematologic studies and chemistry and
coagulation profiles must meet the following criteria:

- Hemoglobin (Hgb)> 8 g/dL

- Absolute Neutrophil Count (ANC) > 1,000/mm3

- Platelet count > 100,000/mm3

- Creatinine < 2 mg/dL

- Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) and Alanine
Aminotransferase (ALT) < 3x upper limit of normal (ULN)

- Patients of childbearing potential must agree to use an adequate method of
contraception for the duration of the study, and for 90 days following
discontinuation of study drugs

- Females of childbearing potential must have a negative pregnancy test

- Patients must be negative for HIV, Hepatitis B and C

- Patients are cooperative and able to complete all the assessment procedures.

Exclusion Criteria:

- Any condition, including the presence of clinically significant laboratory
abnormalities, which places the subject at unacceptable risk if they were to
participate in the study or confounds the ability to interpret data from the study

- Active infection, (including known Acquired Immunodeficiency Syndrome (AIDS) and
Hepatitis C) within 3 days prior to the study enrollment

- Diseases or conditions that obscure toxicity or dangerously alter drug metabolism

- Serious intercurrent medical illness (e.g., symptomatic congestive heart failure)

- Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from providing informed consent unless they have a legal
authorized representative that can consent on their behalf

- Inadequately controlled hypertension (defined as systolic blood pressure >140 mmHg
and/or diastolic blood pressure >90 mmHg)

- Prior history of hypertensive crisis or hypertensive encephalopathy

- New York Heart Association (NYHA) Grade II or greater congestive heart failure

- History of myocardial infarction or unstable angina within 6 months

- History of stroke or transient ischemic attack within 6 months

- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months

- History of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1
month.

- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation).

- Grade 2 or higher peripheral neuropathy per NCI CTCAE version 4

- History of abdominal fistula or gastrointestinal (GI) perforation within 6 months.

- Serious, non-healing wound, active ulcer, or untreated bone fracture

- Allergies to reagents used in this study

- Women of child bearing age not willing to use a reliable form of contraception

- Pregnancy (positive pregnancy test) or lactation

- Patient is positive for HIV, Hepatitis B or C

- Concurrent use of enzyme-inducing anti-epileptic drugs (EIAEDs) Patients must
discontinue an EIAED at least two weeks prior to starting study drug

- Concurrent use of herbal medications

- Patient is simultaneously participating in another clinical trial during the Phase 1
(treatment phase) of this study. Patients may enroll/consent in the Phase 0 portion
of this study for tissue collection and HTS while being treated with standard of care
or clinical trial for newly diagnosed GBM prior to recurrence. Inability or unwilling
to comply with protocol or study procedures.