Study of Hypoxia-Activated Prodrug TH-302 to Treat Advanced Leukemias

Tumor hypoxia has been associated with resistance to chemotherapy and radiotherapy (Brown et
al, 2004; Boyle 2006). TH-302, a hypoxia activated prodrug (HAP), exploits the hypoxic nature
of tumors while having little or no effect on normal tissue. TH-302 belongs to a class of
alkylating agents called oxazaphosphorines which have major experimental and clinical
activity (Brock 1989). Since TH-302 is selectively targeted to the hypoxic microenvironment,
this agent may represent an improvement over other agents in this class. Preclinical data
support the hypothesis that TH-302 targets hypoxic regions of tumors and also is able to kill
other tumor cells in normoxic regions as a result of cytotoxin diffusion, leading to
significant effects on tumor growth. Preclinical data has shown that TH-302 has anti-tumor
activity in multiple myeloma cells in vivo and in vitro.

Additional preclinical data demonstrated the marked expansion of the hypoxic bone marrow
areas in diseased mice with ALL. These results suggest that this agent may be useful in
treating advanced leukemias. The drug is stable in plasma and liver, does not appear to be at
risk for drug-drug interactions, and has mild, reversible toxicities. In this dose-escalation
study, patients with advanced leukemias will receive infusions of TH-302 to determine the
maximum tolerated dose.

Inclusion Criteria:

- At least 18 years of age.

- Ability to understand the purposes and risks of the study and has signed a written
informed consent form approved by the investigator's IRB/Ethics Committee.

- Relapsed/refractory leukemias for which no standard therapy options are anticipated to
result in a durable remission.

- Acute myelogenous leukemia (AML) by WHO classification relapsed or refractory to
standard chemotherapy; unsuitable for standard chemotherapy or unwilling to undergo
standard chemotherapy.

- Acute lymphoblastic leukemia (ALL) relapsed or refractory to standard chemotherapy;
unsuitable for standard chemotherapy or unwilling to undergo standard chemotherapy.
Philadelphia chromosome (Ph) positive ALL eligible if failed prior tyrosinekinase
inhibitor therapy.

- Chronic myelogenous leukemia (CML) in accelerated or blast phase failing prior
tyrosine kinase-containing therapy

- High-risk myelodysplastic syndrome (MDS) [i.e. refractory anemia with excess blasts
(RAEB-1 or RAEB-2) by WHO classification] or chronic myelomonocytic leukemia (CMML)
with >5% marrow blasts, relapsed or refractory to standard therapy

- Chronic lymphocytic leukemia (CLL) relapsed or refractory to standard therapy, not
eligible for protocols of higher priority

- Advanced myelofibrosis (MF) resistant or refractory to standard therapy; or untreated
with one of following features (1) hemoglobin < 10 g/dL, (2) platelet count < 100 x
109/L, WBC < 4 or > 30 x 109/L, or splenomegaly ≥ 10 cm below left costal margin

- Age > 60 years with AML not candidates for or have refused standard chemotherapy,
excluding subjects with acute promyelocytic leukemia (APL) or with favorable
cytogenetic abnormalities [inv16, t(8;21)].

- ECOG performance status of less than or equal to 3

- Adequate organ function as indicated by the following laboratory assessments performed
within 14 days prior to the first dose of study drug:

- Total bilirubin ≤ 1.5 times upper limit of normal (x ULN) (≤ 3 x ULN if due to
leukemic involvement or Gilbert's syndrome).

- Aspartate aminotransferase or alanine aminotransferase ≤ 2.5 x ULN (≤ 5.0 x ULN if due
to leukemic involvement)

- Serum creatinine ≤ 1.5 x ULN.

- All women of childbearing potential must have a negative serum pregnancy test and
women and men subjects must agree to use effective means of contraception (surgical
sterilization or the use or barrier contraception with either a condom or diaphragm in
conjunction with spermicidal gel or an IUD) with their partner from entry into the
study through 6 months after the last dose

Exclusion Criteria:

- New York Heart Association (NYHA) Class III or IV, cardiac disease, myocardial
infarction within 6 months prior to Day 1, or unstable arrhythmia

- Seizure disorders requiring anticonvulsant therapy

- Severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the
investigator any physiological state leading to hypoxemia

- Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without
complete recovery

- Active uncontrolled infection

- Systemic chemotherapy (with the exception of hydroxyurea and/or steroids) within 14
days (or within 5 half-lives for an investigational agent) prior to first dose of
study drug, unless there is evidence of rapidly progressive disease. Concurrent
therapy for CNS prophylaxis or continuation of therapy for controlled CNS disease is
permitted.

- Known active infection with HIV, hepatitis B, or hepatitis C

- Patients who have exhibited allergic reactions to a similar structural compound,
biological agent, or formulation (containing solutol and/or propylene glycol)

- Females who are pregnant or breast-feeding

- Concomitant disease or condition that could interfere with the conduct of the study,
or that would, in the opinion of the investigator, pose an unacceptable risk to the
subject in this study

- Unwillingness or inability to comply with the study protocol for any reason