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

May 5, 2015 updated by: Threshold Pharmaceuticals

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 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).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Drug: TH-302

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.

Study Type

Interventional

Enrollment (Anticipated)

Phase

Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

United States
- Texas
  - Houston, Texas, United States, 77030
    - University of Texas M.D. Anderson Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: TREATMENT
Allocation: NA
Interventional Model: SINGLE_GROUP
Masking: NONE

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the maximum tolerated dose of TH-302 Time Frame: 2 years	2 years
To determine the dose-limiting toxicity of TH-302 Time Frame: 2 years	2 years
TO determine the number of participants with Adverse Events as a measure of safety and tolerability Time Frame: 2 years	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
To determine the efficacy of TH-302 via specific response criteria Time Frame: 2 years	2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Threshold Pharmaceuticals

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2010

Primary Completion (ACTUAL)

August 1, 2013

Study Completion (ACTUAL)

August 1, 2013

Study Registration Dates

First Submitted