RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining chemotherapy with peripheral stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells. PURPOSE: Phase I/II trial to study the effectiveness of combination chemotherapy plus peripheral stem cell transplantation in treating patients who have multiple myeloma.

Condition	Treatment or Intervention	Phase
stage I multiple myeloma stage II multiple myeloma stage III multiple myeloma refractory plasma cell neoplasm	Procedure: chemotherapy  Procedure: biological response modifier therapy  Procedure: peripheral blood stem cell transplantation  Drug: bone marrow ablation with stem cell support  Drug: cyclophosphamide  Drug: etoposide phosphate  Drug: melphalan  Drug: topotecan	Phase I Phase II

Further Study Details: 

OBJECTIVES: I. Determine the toxicity and potential efficacy of intensive high dose chemotherapy consisting of melphalan, topotecan, and etoposide phosphate followed by autologous stem cell transplantation in patients with stage II or III multiple myeloma or stage I with evidence of progressive disease. II. Determine the maximum tolerated dose of topotecan in combination with melphalan and etoposide phosphate in this patient population. III. Determine response rates and time to treatment failure in these patients when treated with this regimen. IV. Determine the pharmacokinetic profiles of these drugs and investigate the pharmacodynamic relationships with respect to the efficacy and toxicity of this regimen in these patients. V. Determine whether the sequencing of this chemotherapy regimen is appropriate and optimal in these patients.

PROTOCOL OUTLINE: This is a dose escalation study of topotecan. Patients are primed with cyclophosphamide IV over 2 hours for 2 days. Peripheral blood stem cells (PBSC) are collected. Approximately 4 weeks after PBSC collection, patients receive melphalan IV over 30 minutes and topotecan IV over 30 minutes on days -7 to -5. Etoposide phosphate IV is administered over 4 hours on days -4 and -3. PBSC are reinfused on day 0. Cohorts of 4-12 patients receive escalating doses of topotecan until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 6 of 12 patients experience dose limiting toxicities. Patients are followed 2-3 times a week for approximately 1 month, then at 3, 6, and 12 months.

PROJECTED ACCRUAL: A total of 34-60 patients will be accrued for this study within 24-36 months.

Ages Eligible for Study:  15 Years   -   69 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically confirmed multiple myeloma; Newly diagnosed, drug sensitive (i.e., greater than 50% response to standard chemotherapy), and poor prognostic indicators (e.g., Salmon-Durie stage III, serum beta-2-microglobulin greater than 3.0 ug/L, high proliferative fraction, or hypodiploidy) OR Relapsed after a response to standard chemotherapy OR Primary refractory disease
• No active leptomeningeal involvement
• History of prior CSF tumor involvement without symptoms or signs allowed provided CSF is now free of disease on lumbar puncture and MRI of brain shows no tumor involvement
• No severe symptomatic CNS disease of any etiology

--Prior/Concurrent Therapy--

• Biologic therapy: Not specified
• Chemotherapy: No prior total dose of doxorubicin or daunorubicin greater than 450 mg/m2; No prior topotecan or any other topoisomerase I inhibitor, etoposide, etoposide phosphate, or teniposide
• Endocrine therapy: Not specified
• Radiotherapy: Not specified
• Surgery: Not specified
• Other: No concurrent nitroglycerin preparations for angina pectoris; No concurrent antiarrhythmic drugs for major ventricular dysrhythmias

--Patient Characteristics--

• Age: 15 to 69
• Performance status: ECOG 0-1 ECOG 3-4 secondary to bone pain or a potentially reversible disease related problem eligible at investigator's discretion
• Life expectancy: At least 12 weeks
• Hematopoietic: Not specified
• Hepatic: Bilirubin no greater than 2.0 mg/dL; SGOT/SGPT no greater than 2.5 times upper limit of normal; No history of severe hepatic dysfunction
• Renal: Creatinine no greater than 2.0 mg/dL OR Creatinine at least 40 mL/min; No hemodialysis or peritoneal dialysis
• Cardiovascular: No evidence of severe cardiac dysfunction; Ejection fraction at least 50% by MUGA scan; No major heart disease; Essential hypertension controlled with medications allowed
• Pulmonary: DLCO at least 50% of normal; No symptomatic obstructive or restrictive pulmonary disease
• Other: Not pregnant or nursing; Negative pregnancy test; Fertile patients must use effective contraception; No psychosocial disorder that would preclude study compliance; No active infections; No uncontrolled insulin dependent diabetes mellitus; No uncompensated major thyroid or adrenal dysfunction; No other prior malignancy except for nonmelanoma skin cancer; HIV negative

Florida
      H. Lee Moffitt Cancer Center and Research Institute, Tampa,  Florida,  33612-9497,  United States

Study chairs or principal investigators

Daniel M. Sullivan,  Study Chair,  H. Lee Moffitt Cancer Center and Research Institute   

Study ID Numbers:  CDR0000067746; MCC-11752; NCI-G00-1749; MCC-IRB-4983
Record last reviewed:  January 2004
Last Updated:  October 13, 2004
Record first received:  June 2, 2000
ClinicalTrials.gov Identifier:  NCT00005792
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08