Study of Melphalan and Topotecan (MT) Followed by Autologous Stem Cell Rescue in Patients With Multiple Myeloma.

Study Overview
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Brief Summary
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The purpose of this research study is to determine the safest dose of topotecan when given in a high dose before a stem cell transplant; topotecan will be given with melphalan.

Detailed Description
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The stem cells being transplanted are cells found in the bone marrow and blood that are responsible for making red blood cells, white blood cells, and platelets. The stem cells are collected by a process called leukapheresis and will be frozen for later use. After receiving the chemotherapy drugs, the stem cells will be thawed and given like a blood transfusion. This is called autologous stem cell transplant or rescue. The study doctors will be measuring how well the disease responds to the drugs as well as any side effects to the drugs. During the course of this study, blood and bone marrow samples will be obtained to measure levels of the chemotherapy drugs as well as levels of certain enzymes (proteins). The staff of the Blood and Marrow Transplant program will continue to collect information about the participant's disease and its treatment for the rest of their life.

Official Title
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A Study of Intensive-Dose Melphalan and Topotecan (MT) Followed by Autologous Stem Cell Rescue in Patients With Multiple Myeloma.

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: melphalan
* Drug: topotecan (TPT)
* Procedure: Autologous Stem Cell Rescue


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Multiple Myeloma Criteria = Newly diagnosed with drug sensitive disease (>50% tumor response to standard chemotherapy) and poor prognostic indicators, such as Salmon-Durie stage III, serum b-2-microglobulin >3.0 mg/L, high proliferative fraction or hypodiploidy. Relapsed patients after a response to standard chemotherapy. Patients with primary refractory disease. Patients with non-secretory multiple myeloma are eligible for enrollment on this study. They will be followed for toxicity, survival and molecular endpoint analyses, but will not be followed for response. Patients with plasma cell leukemia, either occurring de novo or arising from existing multiple myeloma, are ineligible for this study. Patients greater than or equal to 18 years of age are eligible. Patients must have histologically confirmed diagnosis by a pathologic review at the H. Lee Moffitt Cancer Center and Research Institute. Patients must have undergone a complete psychosocial evaluation and been considered capable of compliance. Patients willing and able to receive palifermin (young cohort only) Exclusion Criteria: Patients with a diffusing lung capacity oxygenation (DLCO) less than 50% (adjusted) of normal or with symptomatic obstructive or restrictive disease are ineligible. Patients with a serum creatinine of greater than 2.0 mg/dL OR a creatinine clearance of less than 40 ml/minute. Creatinine clearance can be measured or calculated. Patients with renal dysfunction secondary to multiple myeloma may be enrolled at the discretion of the principal investigator. However, patients on hemodialysis or peritoneal dialysis are ineligible. Patients with a total bilirubin greater than 2.0 mg/dL and serum glutamate oxaloacetate transaminase (SGOT) or serum glutamate pyruvate transaminase (SGPT) greater than two and a half times normal (unless due to primary malignancy), or a history of severe hepatic dysfunction are ineligible. Patients who have evidence of severe cardiac dysfunction are ineligible. A gated blood pool (MUGA) scan must show an ejection fraction of at least 50%. Patients must be free of major heart disease. Patients are ineligible if they have received a total dose of doxorubicin of greater than 450 mg/m2 (or daunorubicin equivalent) unless the left ventricular ejection fraction by MUGA scan is at least 50%. Patients must not be taking nitroglycerin preparations for angina pectoris or antiarrhythmic drugs for major ventricular dysrhythmias. Patients with essential hypertension controlled with medications are eligible for study. Any patient with congenital or acquired heart disease or cardiac arrhythmias will have a cardiology consult and evaluation. Patients with active infections are ineligible. Patients who are HIV antibody positive are ineligible. Patients with active leptomeningeal involvement are ineligible. Patients with a history of previous cerebrospinal fluid (CSF) tumor involvement without symptoms or signs are eligible provided the CSF is now free of disease on lumbar puncture and MRI of the brain shows no tumor involvement. Patients with severe symptomatic central nervous system (CNS) disease of any etiology are ineligible. Patients with uncontrolled insulin-dependent diabetes mellitus or uncompensated major thyroid or adrenal dysfunction are ineligible. Patients with an Eastern Cooperative Oncology Group (ECOG) performance status of > or = 2 are ineligible. Patients with ECOG performance status 2 to 3 secondary to bone pain may be enrolled at the discretion of the institutional investigator. Patients with ECOG performance status 2 to 3 secondary to a potentially reversible disease-related problem may be enrolled at the discretion of the institutional investigator. Patients who are pregnant or lactating are ineligible. Patients with any previous malignancy other than non-melanoma skin cancer are ineligible, unless the patient is without evidence of disease > or = 5 years after the treatment for the cancer was completed. Patients previously treated with topotecan or any other topoisomerase I inhibitor.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Age Group A - Melphalan and Topotecan plus Stem Cell Rescue<br>Participants 18 - 60 years of age. Intensive-Dose Melphalan and Topotecan (MT) followed by Stem Cell transplant. | Drug: melphalan<br>* (Days -4,-3,-2) 50 mg/m^2/day IV over 30 minutes (total dose 150 mg/m^2)<br>* Other names: Alkeran®;Drug: topotecan (TPT)<br>* Phase I Dose Escalation: Level 1 - 20 mg/m^2; Level 2 - 30 mg/m^2; Level 4 - 54 mg/m^2; Level 5 - 72 mg/m^2; Level 6 - 96 mg/m^2; Level 7 - 127.8 mg/m^2; Level 8 - 170.1 mg/m^2 Phase II: Treatment at maximum tolerated dose (MTD)<br>* Other names: Hycamtin®;Procedure: Autologous Stem Cell Rescue<br>* Day 0<br>* Other names: Stem Cell Transplant;|
| Active Comparator: Age Group B - Melphalan and Topotecan plus Stem Cell Rescue<br>Participants 61 years of age or older. Intensive-Dose Melphalan and Topotecan (MT) followed by Stem Cell transplant. | Drug: melphalan<br>* (Days -4,-3,-2) 50 mg/m^2/day IV over 30 minutes (total dose 150 mg/m^2)<br>* Other names: Alkeran®;Drug: topotecan (TPT)<br>* Phase I Dose Escalation: Level 1 - 20 mg/m^2; Level 2 - 30 mg/m^2; Level 4 - 54 mg/m^2; Level 5 - 72 mg/m^2; Level 6 - 96 mg/m^2; Level 7 - 127.8 mg/m^2; Level 8 - 170.1 mg/m^2 Phase II: Treatment at maximum tolerated dose (MTD)<br>* Other names: Hycamtin®;Procedure: Autologous Stem Cell Rescue<br>* Day 0<br>* Other names: Stem Cell Transplant;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I - Maximum Tolerated Dose (MTD) Level | MTD of topotecan in multiple myeloma patients receiving autologous transplant when give with melphalan 150 mg/m^2 for three days. Two parallel dose escalations were used, one each for young (18-60 years of age) and elderly patients (> 61 years of age). Elderly patients began a dose level once it had been found to be safe for the young cohort. The purpose of this approach was to expand the access of this trial to elderly patients while ensuring safety. Phase I Dose Escalation: Level 1 - 20 mg/m^2; Level 2 - 30 mg/m^2; Level 4 - 54 mg/m^2; Level 5 - 72 mg/m^2; Level 6 - 96 mg/m^2; Level 7 - 127.8 mg/m^2; Level 8 - 170.1 mg/m^2 | Phase I - 5 years, 2 months | 
| Phase II Participants - Overall Response Rate | Re-evaluation of participants who had responsive disease prior to transplant. All changes in monoclonal protein and immunoglobulins will be referenced to those levels obtained immediately prior to cyclophosphamide priming chemotherapy. Complete Response (CR): A CR will be defined as the disappearance of the monoclonal protein by immunofixation studies of serum and urine (100x concentrate) and less than or equal to 5% plasma cells in a bone marrow aspirate. Partial Response (PR): 50% - 74% decrease in the measurable monoclonal protein (M-component from an SPEP and/or UPEP with immunofixation). | Phase II - Phase start at 62 months up to 120 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase II Event Free Survival (EFS) | Time to treatment failure, which is defined as the time from day 0 to the time of progressive disease. Progressive disease is defined by unequivocal objective evidence and constitutes any of the following: 1). an increase in the total amount of monoclonal protein (M-component from Serum Protein Electrophoresis (SPEP) and/or Urine Protein Electrophoresis (UPEP) with immunofixation) by more than 100% from the lowest level of serum myeloma protein seen after high-dose chemotherapy by serum protein electrophoresis; 2). an increase in the total amount of monoclonal protein above the remission level of the myeloma peak (i.e., an increase of >25% above the lowest level in a 24 hour urine or serum protein; 3). the reappearance of the M-protein if the patient had entered a CR: 4). definite increase in the size (> 1 cm) or number of lytic bone lesions. Compression fractures do not constitute a relapse. | Phase II - Phase start at 62 months up to 120 months | 
| Phase II Overall Survival (OS) | Time from start of treatment until death from any cause. | Phase II - Phase start at 62 months up to 120 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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melphalan, topotecan, topoisomerase, bone marrow transplant, drug sequence