Combination Chemotherapy in Treating Patients With Recurrent or Refractory Leukemia

Phase I Trial of Sequential Topotecan(NSC 609699)and Etoposide for Patients With Relapsed, Refractory,or High Risk Acute Myeloid or Lymphoid Leukemia

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining more than one drug may kill more cancer cells.

PURPOSE: Phase I trial to study the effectiveness of topotecan and etoposide in treating patients who have recurrent or refractory leukemia.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: etoposide; Drug: topotecan hydrochloride

Detailed Description

OBJECTIVES: I. Determine the maximum tolerated dose of topotecan when combined with etoposide in patients with relapsed or refractory acute myelogenous leukemia, acute lymphoblastic leukemia, or blastic phase chronic myelogenous leukemia. II. Determine the toxicity of this regimen in these patients. III. Measure serum levels of topotecan at steady state and correlate them with any change in topoisomerase II content in leukemic blasts. IV. Assess whether it is feasible to correlate any upregulation of topoisomerase II expression with tumor response to etoposide in subsequent Phase II studies. V. Assess whether levels of pretreatment expression of topoisomerases I and II in leukemic cells are predictive of clinical response. VI. Assess whether it is feasible to develop a pharmacodynamic assay based on posttreatment apoptotic changes in leukemic blasts and whether this could be correlated with tumor response in subsequent phase II trials. VII. Determine the response in patients treated with this regimen.

OUTLINE: Induction: 2-Drug Combination Chemotherapy. Topotecan, TOPO, NSC-609699; Etoposide, VP-16, NSC-141540. Consolidation: 2-Drug Combination Chemotherapy. TOPO; VP-16.

PROJECTED ACCRUAL: 15-23 patients will be accrued in approximately 18 months.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106-5065
      • Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS: Acute myelogenous leukemia (M0-M7) and acute lymphoblastic leukemia (L1-L2) Refractory or in first or subsequent relapse Circulating blasts present OR Greater than 5% blasts in bone marrow Acute myelogenous leukemia secondary to myelodysplastic syndrome or cytotoxic therapy Untreated OR Maximum of 2 intensive induction regimens Chronic myelogenous leukemia in blastic or lymphoid crisis Untreated OR Maximum of 2 intensive induction regimens No CNS leukemia

PATIENT CHARACTERISTICS: Age: Over 18 Performance status: ECOG 0-3 Life expectancy: At least 4 weeks Hematopoietic: Not specified Hepatic: Bilirubin no greater than 2.0 mg/dL AST and ALT less than 3 times normal Alkaline phosphatase less than 3 times normal Renal: Creatinine no greater than 1.5 mg/dL OR Creatinine clearance greater than 60 mL/min Cardiovascular: No myocardial infarction within 6 months No active ischemic cardiac disease No poorly controlled congestive heart failure No other symptomatic cardiac disease Left ventricular ejection fraction at least 40% Pulmonary: No symptomatic restrictive or obstructive lung disease Other: No severe neurologic disease No active infection unless stable on antimicrobial therapy or fever is tumor related HIV negative Not pregnant or nursing Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: At least 2 weeks since prior cytotoxic therapy (except hydroxyurea and steroids) Biologic therapy: No prior bone marrow transplantation At least 3 days since prior hematopoietic growth factors Chemotherapy: No prior topotecan or camptothecin analogues Prior etoposide allowed Endocrine therapy: Not specified Radiotherapy: Not specified Surgery: Not specified

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Determine the maximum tolerated dose of topotecan when combined with etoposide in patients with relapsed or refractory acute myelogenous leukemia, acute lymphoblastic leukemia, or blastic phase chronic myelogenous leukemia.

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Brenda W. Cooper, MD, Ireland Cancer Center at University Hospitals Case Medical Center, Case Comprehensive Cancer Center

Publications and helpful links

General Publications

• Cooper BW, Lazarus HM, Creger R, et al.: A phase I and pharmacodynamic study of sequential topotecan and etoposide (TE) in adult patients with refractory/relapsed acute leukemia (RAL) (Meeting abstact.). [Abstract] Proceedings of the American Society of Clinical Oncology 15: A1549, 1996.

Study record dates

Study Major Dates

• Study Start: August 1, 1994
• Primary Completion (Actual): July 1, 2000
• Study Completion (Actual): January 1, 2001

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: July 28, 2004
• First Posted (Estimate): July 29, 2004

Study Record Updates

• Last Update Posted (Estimate): June 11, 2010
• Last Update Submitted That Met QC Criteria: June 9, 2010
• Last Verified: June 1, 2010

More Information

Terms related to this study

• Keywords: secondary acute myeloid leukemia; recurrent adult acute myeloid leukemia; adult acute erythroid leukemia (M6); adult acute megakaryoblastic leukemia (M7); adult acute minimally differentiated myeloid leukemia (M0); adult acute monoblastic leukemia (M5a); adult acute monocytic leukemia (M5b); adult acute myeloblastic leukemia with maturation (M2); adult acute myeloblastic leukemia without maturation (M1); adult acute myelomonocytic leukemia (M4); blastic phase chronic myelogenous leukemia; relapsing chronic myelogenous leukemia; recurrent adult acute lymphoblastic leukemia; L1 adult acute lymphoblastic leukemia; L2 adult acute lymphoblastic leukemia; adult acute promyelocytic leukemia (M3)
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Topoisomerase I Inhibitors; Etoposide; Topotecan
• Other Study ID Numbers: CWRU2994; P30CA043703 (U.S. NIH Grant/Contract); CWRU-ICC-2994 (Other Identifier: Case Comprehensive Cancer Center); NCI-T94-0078D