Study Combining Bortezomib With High Dose Melphalan to Treat Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to determine the tolerance and potential efficacy of combining dose intense melphalan with escalating doses of bortezomib in patients with multiple myeloma undergoing autologous stem cell transplantation.

Detailed Description
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Multiple myeloma is the second most common hematological malignancy that has affected approximately 40,000 Americans.Conventional chemotherapy has achieved limited control of this disease but studies have reported improved response rates for patients who are treated with dose-intense therapy and autologous hematopoietic stem cell transplantation. This Phase I/II study will investigate the potential of combination therapy of dose-intense melphalan with escalating doses of bortezomib.

Official Title
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A Phase I/II Study of Escalating Doses of Bortezomib in Conjunction With High Dose Melphalan as a Conditioning Regimen for Autologous Peripheral Blood Stem Cell Transplantation in Patients With Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Bortezomib 1 mg/m2
* Drug: Bortezomib 1.3 mg/m2
* Drug: Bortezomib 1.6 mg/m2
* Drug: Melphalan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A confirmed diagnosis of multiple myeloma Show progression of disease after a previous cycle of dose-intense melphalan, or less than 25% decrease in paraprotein measured at 8 weeks after a prior cycle of dose-intense melphalan May have received intervening therapies for disease progression after dose-intense melphalan and enrollment in this protocol Age:18yrs-76yrs at time of melphalan administration Gender: There is no gender restriction Availability of >2x10^6 autologous peripheral blood CD34+ cells/kg or a syngeneic donor meeting eligibility criteria for syngeneic donation Syngeneic transplantation is preferred For patients enrolled in the phase I part of this study, >1x10^6 autologous or syngeneic peripheral blood CD34+ cells/kg remaining in storage as backup in case of engraftment failure Recovery from complications of salvage therapy, if administered - Exclusion Criteria: Diagnosis other than multiple myeloma Chemotherapy or radiotherapy within 28 days of initiating treatment in this study Prior dose-intense therapy within 56 days of initiating treatment in this study Uncontrolled bacterial,viral,fungal or parasitic infections Uncontrolled CNS metastases Known amyloid deposition in heart Organ dysfunction LVEF<40% or cardiac failure not responsive to therapy FVC,FEV1,or DLCO<50% of predicted and/or receiving supplementary continuous oxygen Evidence of hepatic synthetic dysfunction, or total bilirubin>2x or AST>3x ULN Measured creatinine clearance <20ml/min Sensory peripheral neuropathy grade 4 Karnofsky score<70% unless a result of bone disease directly caused by myeloma Life expectancy limited by another co-morbid illness History of another malignancy in remission <2yrs (other than basal cell carcinoma) Pregnant (women)or unwilling to use acceptable birth control methods (men or women) for twelve months after treatment Documented hypersensitivity to melphalan or bortezomib or any components of the formulation Patients unable or unwilling to provide consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 76 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: Sequential Assignment
Interventional Model Description: 3 + 3 Dose Escalation
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Cohort - Bortezomib 1 mg/m2<br>Bortezomib at 1 mg/m2 on days -4 and -1 before transplantation with melphalan 200 mg/m2 given on day -2. | Drug: Bortezomib 1 mg/m2<br>* Bortezomib is administered by rapid I.V. push (over 3-5 seconds) via a central or peripheral vein into a flowing saline line Bortezomib will be administered any time on day -4 and 24 hrs after the start of the melphalan infusion on day -1 Dosing will be based on actual body weight Patient weight must be measured within seven days of the start of the treatment regimen<br>* Other names: Velcade;Drug: Melphalan<br>* Melphalan is administered by rapid intravenous infusion via a central or peripheral vein over one hour Melphalan will be dissolved with 10 ml of diluent to a concentration of 5 mg/mL which is then immediately diluted in 0.9% normal saline to a concentration NOT exceeding 0.45 mg/mL prior to administration The final dilution of melphalan is physically and chemically stable for 60 minutes and therefore will be administered within that time period Melphalan will be given as a single dose (not split over 2 or more days) Dosing will be based body surface area calculated using actual body weight<br>* Other names: Alkeran;|
| Experimental: Phase I Cohort - Bortezomib 1.3 mg/m2<br>Bortezomib at 1.3 mg/m2 on days -4 and -1 before transplantation with melphalan 200 mg/m2 given on day -2. | Drug: Bortezomib 1.3 mg/m2<br>* Bortezomib is administered by rapid I.V. push (over 3-5 seconds) via a central or peripheral vein into a flowing saline line Bortezomib will be administered any time on day -4 and 24 hrs after the start of the melphalan infusion on day -1 Dosing will be based on actual body weight Patient weight must be measured within seven days of the start of the treatment regimen<br>* Other names: Velcade;Drug: Melphalan<br>* Melphalan is administered by rapid intravenous infusion via a central or peripheral vein over one hour Melphalan will be dissolved with 10 ml of diluent to a concentration of 5 mg/mL which is then immediately diluted in 0.9% normal saline to a concentration NOT exceeding 0.45 mg/mL prior to administration The final dilution of melphalan is physically and chemically stable for 60 minutes and therefore will be administered within that time period Melphalan will be given as a single dose (not split over 2 or more days) Dosing will be based body surface area calculated using actual body weight<br>* Other names: Alkeran;|
| Experimental: Phase I Cohort - Bortezomib 1.6 mg/m2<br>Bortezomib at 1.6 mg/m2 on days -4 and -1 before transplantation with melphalan 200 mg/m2 given on day -2. | Drug: Bortezomib 1.6 mg/m2<br>* Bortezomib is administered by rapid I.V. push (over 3-5 seconds) via a central or peripheral vein into a flowing saline line Bortezomib will be administered any time on day -4 and 24 hrs after the start of the melphalan infusion on day -1 Dosing will be based on actual body weight Patient weight must be measured within seven days of the start of the treatment regimen<br>* Other names: Velcade;Drug: Melphalan<br>* Melphalan is administered by rapid intravenous infusion via a central or peripheral vein over one hour Melphalan will be dissolved with 10 ml of diluent to a concentration of 5 mg/mL which is then immediately diluted in 0.9% normal saline to a concentration NOT exceeding 0.45 mg/mL prior to administration The final dilution of melphalan is physically and chemically stable for 60 minutes and therefore will be administered within that time period Melphalan will be given as a single dose (not split over 2 or more days) Dosing will be based body surface area calculated using actual body weight<br>* Other names: Alkeran;|
| Experimental: Phase II Cohort<br>Bortezomib at 1.6 mg/m2 on days -4 and -1 before transplantation with melphalan 200 mg/m2 given on day -2. | Drug: Bortezomib 1.6 mg/m2<br>* Bortezomib is administered by rapid I.V. push (over 3-5 seconds) via a central or peripheral vein into a flowing saline line Bortezomib will be administered any time on day -4 and 24 hrs after the start of the melphalan infusion on day -1 Dosing will be based on actual body weight Patient weight must be measured within seven days of the start of the treatment regimen<br>* Other names: Velcade;Drug: Melphalan<br>* Melphalan is administered by rapid intravenous infusion via a central or peripheral vein over one hour Melphalan will be dissolved with 10 ml of diluent to a concentration of 5 mg/mL which is then immediately diluted in 0.9% normal saline to a concentration NOT exceeding 0.45 mg/mL prior to administration The final dilution of melphalan is physically and chemically stable for 60 minutes and therefore will be administered within that time period Melphalan will be given as a single dose (not split over 2 or more days) Dosing will be based body surface area calculated using actual body weight<br>* Other names: Alkeran;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximum Tolerated Dose of Bortezomib (MTD) | The Maximum Tolerated Dose of Bortezomib (MTD) Will be Defined as the Dose Level Prior to That Resulting in Two Out of Six Patients Experiencing a DLT | During dosing of Bortezomib on Day -4 to Day -1 of ASCT |