A Phase I Study Of Cloretazine™ (VNP40101M) And Temozolomide In Patients With Hematologic Malignancies
A Phase I Study Of Cloretazine™ (VNP40101M) And Temozolomide In Patients With Hematologic Malignancies
RATIONALE: Drugs used in chemotherapy, such as temozolomide and VNP40101M, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Temozolomide may also help VNP40101M kill more cancer cells by making cancer cells more sensitive to the drug. Giving temozolomide together with VNP40101M may kill more cancer cells.
PURPOSE: This phase I trial is studying the side effects and best dose of temozolomide and VNP40101M in treating patients with relapsed or refractory leukemias.
OBJECTIVES:
OUTLINE: This is an open-label, dose-escalation, multicenter study.
Patients receive oral temozolomide twice daily on days 1-3 (for 5 doses) followed by VNP401010M IV over 15-60 minutes on day 3 (course 1). Patients achieving a complete or partial response or having ≥ 50% reduction in bone marrow blasts may receive a second course of therapy no earlier than day 43. Courses may be repeated approximately every 6 weeks at the discretion of the sponsor and in the absence of disease progression or unacceptable toxicity.
Cohorts of 6 patients receive escalating doses of temozolomide until a dose that depletes leukemic blast AGT in at least 4 of 6 patients is determined. Once this dose is determined, cohorts of 3-6 patients receive escalating doses of VNP401010M until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 10 patients are treated at the MTD.
PROJECTED ACCRUAL: Approximately 25 patients will be accrued for this study.
DISEASE CHARACTERISTICS:
Diagnosis of 1 of the following:
Relapsed or refractory disease
No known standard therapy that is anticipated to result in a durable remission exists
CNS leukemia allowed
PATIENT CHARACTERISTICS:
Age
Performance status
Life expectancy
Hematopoietic
Hepatic
Renal
Cardiovascular
No active heart disease, including any of the following:
Other
PRIOR CONCURRENT THERAPY:
Biologic therapy
Chemotherapy
Concurrent hydroxyurea allowed within the first 10 days of study drug administration for control of elevated blast levels or platelet counts
No persistent chronic toxic effects from prior chemotherapy > grade 1
Endocrine therapy
Radiotherapy
Surgery
Other