Temozolomide and VNP40101M in Treating Patients With Relapsed or Refractory Leukemias

Vion Pharmaceuticals

Status and phase: Completed; Phase 1

Conditions: Leukemia

Treatments: Drug: laromustine; Drug: temozolomide

Study type: Interventional

Funder types: Industry

Identifiers

NCT00098436

CDR0000405825 (Registry Identifier)

VION-CLI-036

CWRU-050419

Details and patient eligibility

About

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.

Full description

OBJECTIVES:

• Determine the maximum tolerated dose of temozolomide and VNP40101M in patients with relapsed or refractory leukemias.
• Determine the toxic effects of this regimen in these patients.

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.

Enrollment: 25 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following:

  • Acute myeloid leukemia
  • Acute lymphoblastic leukemia
  • Chronic myelogenous leukemia in blast crisis

• Relapsed or refractory disease

• No known standard therapy that is anticipated to result in a durable remission exists

• CNS leukemia allowed

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT or AST ≤ 3 times ULN
• Chronic hepatitis allowed

Renal

• Creatinine ≤ 2.0 mg/dL

Cardiovascular

• No active heart disease, including any of the following:

  • Myocardial infarction within the past 3 months
  • Symptomatic coronary artery disease
  • Arrhythmias not controlled by medication
  • Uncontrolled congestive heart failure

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study participation
• No uncontrolled active infection

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Concurrent hydroxyurea allowed within the first 10 days of study drug administration for control of elevated blast levels or platelet counts

  • Maximum hydroxyurea dose 5 g daily

• No persistent chronic toxic effects from prior chemotherapy > grade 1

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• Recovered from all prior therapy
• At least 2 weeks since prior myelosuppressive cytotoxic agents (in the absence of rapidly progressive disease)
• No more than 2 leukapheresis procedures within the first 10 days of study drug administration for control of elevated blast levels or platelet counts
• No concurrent disulfiram
• No other concurrent anticancer drugs
• No other concurrent standard or investigational treatment for leukemia