Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

Study of Combination Therapy With VELCADE, Doxil, and Dexamethasone (VDd) in Multiple Myeloma

This study has been completed.
Sponsor:
Information provided by:
University of Michigan Cancer Center
ClinicalTrials.gov Identifier:
NCT00135187
First received: August 23, 2005
Last updated: February 5, 2012
Last verified: February 2012
  Purpose

Patients are being asked to take part in this research study because they have multiple myeloma which has relapsed after (come back), or is refractory to (unaffected by), initial therapy.

For patients who have relapsed or are refractory to therapy, there is no agreed upon standard treatment. Treatment options include chemotherapy and, for some patients, bone marrow transplants. None of the available treatments are curative and investigators are continually looking for more effective treatments. This study involves treatment with a new combination of standard drugs: VELCADE, Doxil, and Dexamethasone. Preliminary results from a study using a combination of VELCADE with Doxil showed high response rates (disease reduction). Two other studies showed that an addition of Dexamethasone to VELCADE in patients not responding to VELCADE alone improved response rate. The proposed combination of all three drugs may improve efficacy and response.

VELCADE is approved by the Food and Drug Administration (FDA) for use in multiple myeloma. Doxil is not approved for use in multiple myeloma but is an approved drug for use in patients with some other cancers. Several published clinical trials provide evidence that Doxil is an active agent in multiple myeloma and it is used in treatment combinations for multiple myeloma in general practice. Dexamethasone is approved for use in multiple myeloma. The combination of all three drugs is experimental (not FDA approved).

The goals of this study are to determine if this new combination therapy with VELCADE, Doxil and Dexamethasone is an effective treatment, and also to determine the side effects that occur when this combination treatment is given.


Condition Intervention
Multiple Myeloma
Drug: VELCADE
Drug: Doxil
Drug: Dexamethasone

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of Combination Therapy With VELCADE, Doxil, and Dexamethasone (VDd) in Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by University of Michigan Cancer Center:

Primary Outcome Measures:
  • Estimate an overall response rate to combination therapy with VELCADE, Doxil, and Dexamethasone, defined as at least partial response (PR), i.e. > 50% reduction in serum monoclonal protein and/or >90% reduction in Bence-Jones protein by EBMT criteria. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    Multiple myeloma remains a non-curable disease. Combination therapies such as VAD have been effective, with partial response rates in ~40-60% range and tolerable toxicity. The purpose of this study is to see if this combination is more effective


Secondary Outcome Measures:
  • Estimate a rate of complete response (CR), very good partial response (VGPR, >90% reduction in serum monoclonal protein), minimal response (MR, >25% and <50% reduction in monoclonal) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Estimate the duration of response, progression-free survival, overall survival [ Time Frame: 24 months ] [ Designated as safety issue: No ]

Enrollment: 30
Study Start Date: July 2004
Study Completion Date: December 2007
Primary Completion Date: August 2006 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: VELCADE

    VELCADE will be used biweekly at 1.3 mg/m2 during week 1 and 2 on (days

    1, 4, 8, and 11) followed by a 1-week break.

    Drug: Doxil
    Doxil will be administered at 30 mg/m2 IV on day 4
    Drug: Dexamethasone
    Dexamethasone at 40 mg during the first cycle and 20 mg during cycles 2-6 po or IV daily on days of VELCADE and day after VELCADE (i.e. days 1, 2, 4, 5, 8, 9, 11, 12). The patient will be treated for six 3-week cycles followed by three 5-week maintenance cycles.
Detailed Description:

Multiple myeloma remains a non-curable disease. Combination therapies such as VAD have been effective, with partial response rates in ~40-60% range and tolerable toxicity. A recent study showed that substituting Doxil for Doxorubicin in a regimen similar to VAD (DVd) resulted in an improved toxicity profile and similar efficacy. The most active agents in VAD (and presumably in DVd) are Doxorubicin (or Doxil) and Dexamethasone, while Vincristine adds little, if at all to the efficacy of these regimen(s). One of the new active agents in multiple myeloma is VELCADE (bortezomib, formerly known as VELCADE). This molecule has a novel mechanism of action by specifically inhibiting the proteasome. A recently reported Phase II trial showed that VELCADE as a single agent induced at least minimal responses (i.e. > 25% reduction in monoclonal protein) in 35% of patients and at least a stabilization of the disease in 59% of patients with relapsed/refractory multiple myeloma using strict SWOG criteria. An additional 18% responded when Dexamethasone was added to VELCADE. Pre-clinical observations showed that the addition of VELCADE to other chemotherapeutic agents, such as doxorubicin, enhances cytotoxicity of multiple myeloma cells. Preliminary results from Phase I study of combination of VELCADE with Doxil showed 60% response rate (i.e. > partial response) with acceptable toxicity. In this study we propose to combine three active agents, i.e. Doxil, Dexamethasone (two most active agents from DVd), and VELCADE. The ultimate goal is to show that this combination of drugs is more efficacious than VAD or VELCADE with either Dexamethasone or Doxil and without additional toxicity.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Each patient must meet all of the following inclusion criteria to be enrolled in the study:

  • An Institutional Review Board (IRB)-approved signed informed consent
  • Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements
  • Age greater than or equal to 18 years
  • Female patient is either postmenopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e. hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study
  • Male patient agrees to use an acceptable method of contraception for the duration of the study
  • Expected survival greater than or equal to 3 months
  • Pre-study Karnofsky performance status > 60%
  • Histologic confirmation of multiple myeloma
  • Patient was previously diagnosed with stage II or III multiple myeloma based on standard criteria and currently requires second or higher line therapy because of progression of disease (PD), defined as a 25% increase in M-protein; development of new or worsening of existing lytic lesions or soft tissue plasmacytomas; or hypercalcemia (> 11.5 mg/dl); or relapse from complete response (CR) or because of refractory disease, defined as less than minimal response (MR) after 2 cycles of the most recent treatment, including first line of therapy.
  • Patients with measurable disease defined as: serum monoclonal protein greater than 1 g/dl for IgG type and greater than 0.5 g/dl for IgA type, and, where applicable, greater than 0.2 g/24 hour urine light chain excretion.
  • Patients with oligosecretory or nonsecretory myeloma will be eligible if measurable disease can be established, such as measurable soft tissue plasmacytoma greater than 2 cm, by either physical examination and/or applicable radiographs (i.e. magnetic resonance imaging [MRI], computed tomography [CT]-scan) and/or bone marrow involvement greater than 20%.
  • Patients refractory or relapsing after treatment with any one or two of the agents used in this protocol will be allowed.
  • Prior radiation therapy will be allowed but radiation therapy must be completed 2 weeks prior to registration.
  • Left ventricular ejection fraction (LVEF) > 50% by multiple-gated acquisition (MUGA) or echocardiogram (ECHO)
  • Patients previously on investigational drugs if no long-term toxicity is expected, and the patients have been off the drugs for one or more weeks
  • Patient has received less than 250 mg/m2 cumulative dose of doxorubicin or equivalent.
  • Patient has the following laboratory values at and within 14 days before Baseline (Day 1 of Cycle 1, before study drug administration):

    • Platelet count > 50 x 10^9/L without transfusion support within 7 days before the laboratory test (> 30 x 10^9/L if significant bone marrow [BM] involvement is present);
    • Hemoglobin > 7.5 x 10^9/L, without transfusion support within 7 days before the laboratory test;
    • Absolute neutrophil count (ANC) > 1.0 x 10^9/L, without the use of colony stimulating factors;
    • Corrected serum calcium < 14 mg/dl (3.5 mmol/L);
    • Aspartate transaminase (AST): < 2.5 x upper limit of normal (ULN);
    • Alanine transaminase (ALT): < 2.5 x ULN;
    • Alkaline phosphatase: <1.5 x the ULN;
    • Total bilirubin: < 1.5 x the ULN; and
    • Calculated or measured creatinine clearance: > 20 mL/minute.

Exclusion Criteria:

Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

  • Patient had major surgery within 3 weeks before enrollment.
  • Patient had a myocardial infarction within 6 months of enrollment or clinical evidence of congestive heart failure.
  • Patient is known to be human immunodeficiency virus (HIV)-positive (patients assessed to be at risk should be tested).
  • Patient is known to be hepatitis B surface antigen-positive or has known active hepatitis C infection (patients assessed by the investigator to be at risk should be tested)
  • Patient has >= Grade 2 peripheral neuropathy within 14 days before enrollment.
  • Patient has hypersensitivity to bortezomib, boron or mannitol, or other study drugs.
  • Serious nonmalignant disease, including uncontrolled diabetes mellitus (DM) or hypertension (HTN), or infection which, in the opinion of the investigator and/or the sponsor, would compromise other protocol objectives
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00135187

Locations
United States, Michigan
University of Michigan Cancer Center
Ann Arbor, Michigan, United States, 48109
Sponsors and Collaborators
University of Michigan Cancer Center
Investigators
Principal Investigator: Andrzej J Jakubowiak, MD, PhD University of Michigan Cancer Center
  More Information

No publications provided

Responsible Party: Andrzej J. Jakubowiak, MD, PhD, University of Michigan Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT00135187     History of Changes
Obsolete Identifiers: NCT00670085
Other Study ID Numbers: UMCC 2004.003, Legacy 2004-419
Study First Received: August 23, 2005
Last Updated: February 5, 2012
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Blood Protein Disorders
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Paraproteinemias
Vascular Diseases
BB 1101
Bortezomib
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Anti-Inflammatory Agents
Antiemetics
Antineoplastic Agents
Antineoplastic Agents, Hormonal
Autonomic Agents
Central Nervous System Agents
Enzyme Inhibitors
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on November 27, 2014