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
The goal of this clinical research study is to find the highest tolerable dose of TH-302 that can be given to patients with leukemia. The safety of this drug will also be studied.
Disease Group: Leukemia,Myeloproliferative Diseases
Treatment Agent: Oral Hypoxyprobe-1,TH-302
Treatment Location: Only at MDACC
Sponsor: Threshold Pharmaceuticals, Inc.
Primary objectives: 1. To determine the maximum tolerated dose, dose limiting toxicity, safety and tolerability of TH-302 in patients with acute leukemias, advanced phase chronic myelogenous leukemia (Arm A), high risk myelodysplastic syndromes (Arm A), advanced myelofibrosis (Arm A) or relapsed/refractory chronic lymphocytic leukemia (Arm A). Secondary objectives: 1. To determine the clinical activity of TH-302 2. To evaluate the pharmacokinetics (PK) of TH-302 and Br-IPM. The exploratory objectives are: To determine the extent of hypoxia in the bone marrow of patients with advanced leukemias To explore the association of bone marrow hypoxia and the efficacy and safety of TH-302 To compare the safety and efficacy of TH-302 administered as a 30-60 minute infusion with TH-302 administered as a continuous infusion
IRB Review and Approval Date: 06/18/2010
Recruitment Status: Not Accepting
Projected Accrual: N/A
1) At least 18 years of age.
2) 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.
3) Relapsed/refractory leukemias for which no standard therapy options are anticipated to result in a durable remission: Acute myelogenous leukemia (AML), or 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 tyrosine-kinase inhibitor therapy; Chronic lymphocytic leukemia (CLL) relapsed or refractory to standard therapy (Arm A only); Chronic myelogenous leukemia (CML) in accelerated or blast phase failing tyrosine kinase-containing therapy (Arm A only); High-risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) with >5% marrow blasts, relapsed or refractory to standard therapy (Arm A only);
4) Continued from #3 above: Advanced myelofibrosis (MF) resistant or refractory to standard therapy; or untreated with one of following: hemoglobin < 10 g/dL, platelet count < 100 x 109/L, WBC < 4 or > 30 x 109/L, or splenomegaly >/=10 cm below costal margin (Arm A only).
5) Age >/= 60 years with AML not candidates for or have refused standard chemotherapy, excluding subjects with acute promyelcytic leukemia (APL) or with favorable cytogenetic abnormalities [inv16, t(8;21)].
6) ECOG performance status of less than or equal to 3.
7) Adequate organ function as indicated by the following laboratory assessments performed within 14 days prior to the first dose of study drug: 1) Total bilirubin </= 1.5 times upper limit of normal (x ULN) (</= 3 x ULN if due to leukemic involvement or Gilbert’s syndrome); 2) Aspartate aminotransferase or alanine aminotransferase </= 2.5 x ULN (</= 5.0 x ULN if due to leukemic involvement); 3) Serum creatinine </= 1.5 x ULN.
8) All women of childbearing potential must have a negative urine or 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.
1) New York Heart Association (NYHA) Class III or IV, cardiac disease,
myocardial infarction within 6 months prior to Day 1, or unstable arrhythmia.
2) Uncontrolled seizure disorder.
3) Severe chronic obstructive pulmonary disease with hypoxemia or in the opinion of the investigator any physiological state leading to hypoxemia.
4) Major surgery, other than diagnostic surgery, within 4 weeks prior to Day 1, without complete recovery.
5) Active uncontrolled infections.
6) Systemic chemotherapy (with the exception of hydroxyurea and/or steroids) within 14 days (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.
7) Known active infection with HIV, hepatitis B, or hepatitis C.
8) Patients who have exhibited allergic reactions to a structural compound similar to TH-302 or its excipients.
9) Females who are pregnant or breast-feeding.
10) Unwillingness or inability to comply with the study protocol for any reason.
11) 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
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