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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Threshold Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT01149915
First received: June 1, 2010
Last updated: December 10, 2013
Last verified: December 2013
  Purpose

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).


Condition Intervention Phase
Acute Myelogenous Leukemia
Acute Lymphoblastic Leukemia
Chronic Myelogenous Leukemia
High-risk Myelodysplastic Syndrome
Chronic Lymphocytic Leukemia
Advanced Myelofibrosis
Drug: TH-302
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Threshold Pharmaceuticals:

Primary Outcome Measures:
  • To determine the maximum tolerated dose of TH-302 [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • To determine the dose-limiting toxicity of TH-302 [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
  • TO determine the number of participants with Adverse Events as a measure of safety and tolerability [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To determine the efficacy of TH-302 via specific response criteria [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 40
Study Start Date: June 2010
Study Completion Date: August 2013
Primary Completion Date: August 2013 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: TH-302
    TH-302 will be administered as a 30-minute intravenous infusion daily for 5 days every 21 days. Patients who successfully complete a 3-week treatment cycle without evidence of significant treatment-related toxicity or clinically significant progressive disease will continue to receive treatment for up to six cycles.
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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)].
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01149915

Locations
United States, Texas
University of Texas M.D. Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Threshold Pharmaceuticals
Investigators
Principal Investigator: Marina Konopleva, MD, PhD M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: Threshold Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01149915     History of Changes
Other Study ID Numbers: TH-CR-407
Study First Received: June 1, 2010
Last Updated: December 10, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Threshold Pharmaceuticals:
Advanced Leukemias
Relapsed/Refractory Leukemias
AML
ALL
CML
MDS
CLL
MF

Additional relevant MeSH terms:
Primary Myelofibrosis
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Myelodysplastic Syndromes
Preleukemia
Anoxia
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Precancerous Conditions
Signs and Symptoms, Respiratory
Signs and Symptoms

ClinicalTrials.gov processed this record on August 21, 2014