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
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Acute Myelogenous Leukemia
- Sponsor
- Threshold Pharmaceuticals
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- To determine the maximum tolerated dose of TH-302
- Status
- Completed
- Last Updated
- 10 years ago
Overview
Brief Summary
The primary objective of this study is 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 (CML), high risk myelodysplastic syndromes, advanced myelofibrosis or relapsed/refractory chronic lymphocytic leukemia (CLL).
Detailed Description
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.
Investigators
Eligibility Criteria
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 \[inv16, t(8;21)\].
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
Outcomes
Primary Outcomes
To determine the maximum tolerated dose of TH-302
Time Frame: 2 years
To determine the dose-limiting toxicity of TH-302
Time Frame: 2 years
TO determine the number of participants with Adverse Events as a measure of safety and tolerability
Time Frame: 2 years
Secondary Outcomes
- To determine the efficacy of TH-302 via specific response criteria(2 years)