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 fludarabine, carboplatin, and topotecan in treating patients who have relapsed or refractory acute leukemia or advanced myelodysplastic syndrome.

Condition	Treatment or Intervention	Phase
Leukemia	Drug: carboplatin  Drug: fludarabine  Drug: topotecan	Phase I

Further Study Details: 

OBJECTIVES: I. Determine the maximum tolerated dose of topotecan when administered with carboplatin and fludarabine in patients with refractory or relapsed acute leukemia or advanced myelodysplastic syndrome. II. Determine treatment related and dose limiting toxicities of this regimen in these patients. III. Determine the antileukemia activity of this regimen in these patients. IV. Correlate treatment related toxicities with steady state levels of topotecan in these patients.

PROTOCOL OUTLINE: This is a dose escalation study of topotecan. Patients receive carboplatin IV continuously and fludarabine IV over 30 minutes on days 1-5, then topotecan IV continuously on days 6-8. Patients with residual leukemia in the bone marrow at day 15 may receive a second induction course. Patients who achieve partial or complete remission after 1-2 induction courses receive 1 consolidation course of fludarabine, carboplatin, and topotecan beginning 4-8 weeks after recovery from induction therapy. Cohorts of 3-6 patients receive escalating doses of topotecan until the maximum tolerated dose (MTD) is determined. The first 3 patients do not receive any topotecan. The MTD is defined as the dose at which no more than 2 of 6 patients experience dose limiting toxicity. Patients are followed monthly for 6 months.

PROJECTED ACCRUAL: A total of 6-15 patients will be accrued for this study within 15-21 months.

Ages Eligible for Study:  12 Years and above

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Diagnosis of one of the following: Acute myelogenous leukemia (M0-M7); M3 must have received tretinoin as part of induction or salvage chemotherapy; No greater than 2 prior intensive induction regimens; Acute lymphocytic leukemia (L1 or L2) in first or second relapse; Circulating blasts in blood or greater than 5% blasts in bone marrow; No greater than 2 prior intensive induction regimens; Chronic myelogenous leukemia in myeloid or lymphoid blast crisis; Initial diagnosis OR No greater than 2 prior intensive induction regimens; Acute myelogenous leukemia secondary to prior myelodysplastic syndrome or prior cytotoxic therapy; No greater than 2 prior intensive induction regimens; Myelodysplastic syndrome (must be neutropenic (absolute neutrophil count less than 500/mm3) or platelet or red cell transfusion dependent) Refractory anemia with excess blasts (RAEB) OR RAEB in transformation OR Chronic myelomonocytic leukemia
• Relapse after greater than 3 months since prior autologous stem cell transplant allowed
• No relapse after allogeneic bone marrow transplant
• No active CNS leukemia

--Prior/Concurrent Therapy--

• Biologic therapy: See Disease Characteristics; At least 5 days since prior hematopoietic growth factors
• Chemotherapy: See Disease Characteristics; At least 24 hours since prior hydroxyurea; At least 2 weeks since other prior cytotoxic anticancer therapy; Prior carboplatin, fludarabine, or topotecan allowed
• Endocrine therapy: Concurrent corticosteroids allowed
• Radiotherapy: Not specified
• Surgery: Not specified

--Patient Characteristics--

• Age: 12 and over
• Performance status: ECOG 0-3
• Life expectancy: At least 4 weeks
• Hematopoietic: See Disease Characteristics
• Hepatic: Bilirubin no greater than 2.0 mg/dL; AST and ALT less than 3 times upper limit of normal
• Renal: Creatinine clearance at least 50 mL/min
• Cardiovascular: No symptomatic cardiac disease; No active ischemic heart disease; No poorly controlled congestive heart failure; No myocardial infarction within past 6 months; Cardiac ejection fraction at least 40%
• Pulmonary: No symptomatic pulmonary disease; No symptomatic restrictive or obstructive lung disease
• Other: Not pregnant or nursing; Fertile patients must use effective contraception; No active infections, unless receiving antibiotics and clinically stable; Fever caused by tumor allowed; HIV negative; No other active malignant disease; Curatively treated prior malignancies allowed; No severe neurologic disease

Ohio
      Ireland Cancer Center, Cleveland,  Ohio,  44106-5065,  United States

Study chairs or principal investigators

Brenda W. Cooper,  Study Chair,  Ireland Cancer Center   

Study ID Numbers:  CDR0000067699; CWRU-1998; NCI-G00-1732; CWRU-059812
Record last reviewed:  February 2004
Last Updated:  October 13, 2004
Record first received:  May 2, 2000
ClinicalTrials.gov Identifier:  NCT00005593
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08