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Doxil® + Melphalan + Velcade (DMV) in Relapsed/Refractory Multiple Myeloma (DMV)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00985907
Recruitment Status : Terminated (Low Accrual)
First Posted : September 29, 2009
Results First Posted : June 17, 2020
Last Update Posted : June 17, 2020
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
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 or disease Intervention/treatment Phase
Multiple Myeloma Patient Participation Drug: Doxil, melphalan, bortezomib Phase 1 Phase 2

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 zoledronic 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.

  1. If 0/3 experience DLT (as defined in attachment Section 6.0), the next three patients will be escalated by one dose level.
  2. 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..
  3. 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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Study of Liposomal Doxorubicin (Doxil®)/Melphalan/Bortezomib (Velcade®) in Relapsed/Refractory Multiple Myeloma
Actual Study Start Date : October 28, 2004
Actual Primary Completion Date : October 7, 2008
Actual Study Completion Date : January 12, 2010


Arm Intervention/treatment
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




Primary Outcome Measures :
  1. Number of Participants With Dose Limiting Toxicities (DLT) (Phase 1) [ Time Frame: Up to 2 cycles of treatment, approximately 56 days ]
    Safety assessments will be evaluated as the proportion of patients experiencing the following: treatment-related grade 3 or higher toxicity (hematologic and nonhematologic) and treatment-related death.

  2. Maximum Tolerated Dose (MTD) (Phase 1) [ Time Frame: Up to 1 year ]
    The MTD will be considered the dose below where <= 3 patients experience a DLT and the dose that two cycles can be given without meeting toxicity criteria.


Secondary Outcome Measures :
  1. Number of All Treatment-related Toxicities at the MTD (Phase 1) [ Time Frame: 5 years ]
    NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3 will be used to determine all treatment related toxicities at the MTD. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis

  2. Overall Response Rate [ Time Frame: Up to 5 years ]
    At each cycle, participants will be assessed for treatment response: Complete Response (CR), Near CR(nCR), Partial Response (PR), Minimal Response (MR), Stable Disease (SD), or Progressive Disease (PD) on at least 2 measurements at minimum of a 4 week interval. The overall response rate will use the best response of CR, nCR, PR, MR, or SD. In order to qualify for responses, the following events may NOT have occurred - new/increased size of plasmacytomas or bone lesions, recurrence or persistence of hypercalcemia. Collapse of bony structure from previous disease will not constitute progression or failure to respond. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis

  3. Time to Response (Phase 2) [ Time Frame: 28 days ]
    Efficacy of DMV as determined by time to first observed response. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis

  4. Progression-free Survival (Phase 2) [ Time Frame: Up to 5 years ]
    Efficacy of DMV as determined by progression free survival. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis

  5. Overall Survival (Phase 2) [ Time Frame: Up to 5 years ]
    Overall survival is defined as the amount of time from start of study therapy until death, or study completion. Participants entered at the MTD Dose level from the phase I portion of the study will also be included in this analysis



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Disease Characteristics:

  1. Patient previously diagnosed with multiple myeloma; Durie-Salmon Stage I, II, or III based on standard criteria
  2. 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 complete response.

Patient Characteristics:

  1. 18 yrs or older
  2. Patient has given voluntary written informed consent.
  3. Unless post-menopausal or surgically sterilized, a female must be willing to use an acceptable method of birth control
  4. Male patient must agree to use an acceptable method for contraception for the duration of the study.
  5. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.
  6. Life expectancy is at least 3 months.
  7. • Absolute Neutrophil Count (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
    • aspartate aminotransferase (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
  • Myocardial infarction 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 left ventricular ejection fraction (LVEF) less than 35% by multigated acquisition (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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00985907


Locations
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United States, California
University of California, San Francisco
San Francisco, California, United States, 94143
United States, New York
St. Vincent's Comprehensive Cancer Center
New York, New York, United States, 10011
Sponsors and Collaborators
University of California, San Francisco
Investigators
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Principal Investigator: Thomas Martin, MD University of California, San Francisco
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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00985907    
Other Study ID Numbers: 04262
NCI-2011-01238 ( Registry Identifier: University of California, San Francisco )
First Posted: September 29, 2009    Key Record Dates
Results First Posted: June 17, 2020
Last Update Posted: June 17, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by University of California, San Francisco:
myeloma
DMV
Additional relevant MeSH terms:
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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
Bortezomib
Melphalan
Liposomal doxorubicin
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic