A Phase I Open-Label Study to Assess the Safety, Tolerability and Preliminary Efficacy of TH-302, a Hypoxia-Activated Prodrug, in Patients With Advanced Leukemias
- 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
- 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
- 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
- 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
- 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
- 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