Doxil® + Melphalan + Velcade (DMV) in Relapsed/Refractory Multiple Myeloma
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Purpose
The median overall survival (OS) of relapsed/refractory multiple myeloma (MM) is less than nine months. However, phase II data with the proteasome inhibitor bortezomib (Velcade®) has been heartening, with 35% overall response rates and median survival of 16 months. In-vitro data has shown that this agent dramatically increases the sensitivity to chemotherapeutic agents. Liposomal doxorubicin (Doxil), melphalan, and bortezomib all have different mechanisms of action and toxicity profiles. Clinical studies employing two drug combinations with these agents in patients with refractory MM have found favorable efficacy (nearly no progression of disease) and tolerance data. Thus, the investigators are initiating a phase I/II study to examine the safety and efficacy of combining all three agents into the regimen DMV (Doxil® + melphalan + Velcade).
| Condition | Intervention | Phase |
|---|---|---|
|
Multiple Myeloma |
Drug: Doxil, melphalan, bortezomib |
Phase 1 Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | Phase I/II Study of Liposomal Doxorubicin (Doxil®)/Melphalan/Bortezomib (Velcade®) in Relapsed/Refractory Multiple Myeloma |
- To evaluate the safety and tolerability of four dose levels of liposomal doxorubicin, melphalan, and bortezomib in patients with relapsed/refractory MM [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
- To identify a maximum tolerated dose (MTD) of liposomal doxorubicin, melphalan, and bortezomib in patients with relapsed/refractory MM [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
- To determine the efficacy of DMV using: the overall response rate, and the time to response, progression-free survival, and overall survival [ Time Frame: 5 years ] [ Designated as safety issue: No ]
- Tabulate all toxicities of DMV at the MTD by NCI criteria [ Time Frame: 5 years ] [ Designated as safety issue: No ]
| Enrollment: | 13 |
| Study Start Date: | June 2004 |
| Study Completion Date: | January 2010 |
| Primary Completion Date: | January 2010 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
| Experimental: Doxil® + Melphalan + Velcade (DMV) |
Drug: Doxil, melphalan, bortezomib
Doxil®: IV over 30-60 min, Day 1 q28d Melphalan: IV over 30 min, Day 1 q28d Velcade®: IV bolus, Day 1, 4, 8, 11 q28d Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2 Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2 Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2 Other Name: Doxil, melphalan, Velcade
|
Detailed Description:
Dose Level 1: Doxil 10 mg/m2, Melphalan 5 mg/m2, Velcade 0.7 mg/m2
Dose Level 2: Doxil 10 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2
Dose Level 3: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 0.7 mg/m2
Dose Level 4: Doxil 20 mg/m2, Melphalan 10 mg/m2, Velcade 1.0 mg/m2
Adjunctive therapy with a bisphosphonate, either pamidronate or zolendronic acid, will be given monthly.
Dose Escalation Schedule: Dose escalation will occur only after patients have completed at least two cycles at a given dose level.
- If 0/3 experience DLT (as defined in attachment Section 6.0), the next three patients will be escalated by one dose level.
If 1/3 experience DLT, 3 additional patients enrolled at this dose level.
- If 0, 1, or 2 of these additional patients experience DLT (i.e. total 3/6), the dose will be escalated.
- If 3/3 experience DLT (i.e. total 4/6) then the next lower dose will be considered the MTD..
If 2/3 experience DLT, 3 additional patients enrolled at this dose level.
- If 0 or 1 of these additional patients experience DLT (i.e. total 3/6), the dose will be escalated.
- If 2 or more/3 experience DLT (i.e. total more than 3/6) then the next lower dose level is MTD
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Disease Characteristics:
- Patient previously diagnosed with MM;
- Progressive disease. For non-secretory multiple myeloma, progressive disease is defined as bone marrow biopsy with > 25% increase in plasma cells or an absolute increase of at least 10% over prior known level. Alternatively, development of new or worsening of existing lytic bone lesions or soft tissue plasmacytomas, or hypercalcemia (serum calcium >11.5 mg/dL), or relapse from CR.
Patient Characteristics:
- 18 yrs or older
- Patient has given voluntary written informed consent.
- Unless post-menopausal or surgically sterilized, a female must be willing to use an acceptable method of birth control
- Male patient must agree to use an acceptable method for contraception for the duration of the study.
- ECOG Performance Status 0-2.
- Life expectancy is at least 3 months.
• ANC over 1,000/ul without the use of colony stimulating factors
- Platelets over 50,000/ul without transfusion support 7 days
- Bilirubin 2.0 mg/dl or less
- AST 4 times or less upper limit normal Prior Therapy for Multiple Myeloma: Patients must have had at least 2 prior therapeutic regimens
Exclusion Criteria:
- Pregnant or breast feeding
- History of allergic reaction to compounds containing boron or mannitol.
- Active uncontrolled viral (including HIV), bacterial, or fungal infection.
- Grade III or IV toxicity due to previous anti-neoplastic therapy
- More than Grade 2 motor or sensory neuropathy
- MI within 6 months of enrollment or New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled arrhythmias, or electrocardiographic evidence of acute ischemia.
- For any patients whose lifetime cumulative doxorubicin dose exceeds 400mg/m2, patients with LVEF less than 35% by MUGA.
- Concurrent administration of liposomal doxorubicin, melphalan, and bortezomib (single or two drug combinations of these are permissible)
- Less than 3 weeks since most recent chemotherapy or concurrent chemotherapy
- Use of corticosteroids (mroe than 10 mg prednisone/day or equivalent)
Contacts and Locations| United States, California | |
| UCSF | |
| San Francisco, California, United States, 94143 | |
| United States, New York | |
| St. Vincent's Comprehensive Cancer Center | |
| New York, New York, United States | |
| Principal Investigator: | Thomas Martin, MD | University of California, San Francisco |
More Information
No publications provided
| Responsible Party: | University of California, San Francisco |
| ClinicalTrials.gov Identifier: | NCT00985907 History of Changes |
| Other Study ID Numbers: | 2408 |
| Study First Received: | September 25, 2009 |
| Last Updated: | October 2, 2012 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by University of California, San Francisco:
|
myeloma DMV |
Additional relevant MeSH terms:
|
Multiple Myeloma Neoplasms, Plasma Cell Neoplasms by Histologic Type Neoplasms Hemostatic Disorders Vascular Diseases Cardiovascular Diseases Paraproteinemias Blood Protein Disorders Hematologic Diseases Hemorrhagic Disorders Lymphoproliferative Disorders Immunoproliferative Disorders Immune System Diseases Doxorubicin |
Bortezomib Melphalan Antibiotics, Antineoplastic Antineoplastic Agents Therapeutic Uses Pharmacologic Actions Myeloablative Agonists Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Protease Inhibitors Enzyme Inhibitors |
ClinicalTrials.gov processed this record on May 19, 2013