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Bevacizumab, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Stage II or III Multiple Myeloma

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00410605
First Posted: December 13, 2006
Last Update Posted: September 1, 2017
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.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
  Purpose
This phase II trial is studying how well giving bevacizumab together with lenalidomide and dexamethasone works in treating patients with relapsed or refractory stage II or stage III multiple myeloma. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Bevacizumab and lenalidomide may stop the growth of multiple myeloma by blocking blood flow to the cancer. Dexamethasone may stimulate the immune system in different ways and stop cancer cells from growing. Giving bevacizumab together with lenalidomide and dexamethasone may kill more cancer cells.

Condition Intervention Phase
Multiple Myeloma in Relapse Stage II Multiple Myeloma Stage III Multiple Myeloma Biological: bevacizumab Drug: lenalidomide Drug: dexamethasone Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of Bevacizumab Combined With Lenalidomide and Dexamethasone (BEV/REV/DEX) in Relapsed or Refractory Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Confirmed Anti-tumor Response Rate (Complete Response and Partial Response) to the Combination of Bevacizumab and Lenalidomide [ Time Frame: Up to 5 years ]
    Patient response to the treatment were determined by the definitions for complete response, partial response, marginal response, stable disease, and progressive disease outlined by IMBTR/ABMTR (Blade criteria). Responses were analyzed by descriptive statistics and summarized in tabular format (frequency tables). Furthermore, two-sided 95% confidence intervals for the proportions of subjects with a confirmed anti-tumor response were computed using the method proposed by Chang, which takes into account the multiplicity problem associated with the two-stage testing procedure. The objective response rate was estimated by using Whitehead's bias-adjustment approach.

  • Progression Free Survival (Time to Progression) [ Time Frame: up to five years ]
    Patient response to the treatment were determined by the definitions for complete response, partial response, marginal response, stable disease, and progressive disease outlined by IMBTR/ABMTR (Blade criteria). Progression free survival was summarized using point estimates of the median time to progression and associated 95% confidence intervals. The data was presented graphically using Kaplan-Meier plots. Exploratory analysis, including multivariate Cox regression with demographic variables and markers of myeloma activity as covariates was performed.


Secondary Outcome Measures:
  • Toxicity and Tolerability of the Bevacizumab and Lenalidomide Combination [ Time Frame: Up to 5 years ]
    Adverse events/toxicities were collected during regular clinical visits. Confidence intervals for the estimate of the true number of patients suffereing from grade 3 or 4 toxicities per common terminology criteria were calculated using the Wilson interval. Ninety-five percent confidence intervals for the proportions of patients with complications (grade 3 or higher toxicities) were constructed.

  • Effect of Bev/Rev on Markers of Myeloma Activity in Myeloma Cells and Stromal Cells at Baseline [ Time Frame: Baseline ]
    A Wilconxon signed-rank test conducted to determine if biomarker levels differed between baseline levels and those after three full cycles of treatment for all patients.

  • Local Cytokine Milieu Using Tissue Micro Arrays of Bone Marrow Biopsy Specimens [ Time Frame: Up to 5 years ]
  • Effect of Bev/Rev on Markers of Myeloma Activity in Myeloma Cells and Stromal Cells at 3 Months Post-baseline [ Time Frame: Up to Course 4 Day 1 (3 Months Post-baseline) ]
    A Wilconxon signed-rank test conducted to determine if biomarker levels differed between baseline levels and those after three full cycles of treatment for all patients.


Enrollment: 39
Study Start Date: November 2006
Study Completion Date: June 2014
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I
Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Biological: bevacizumab
Given IV
Other Names:
  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
Drug: lenalidomide
Given orally
Other Names:
  • CC-5013
  • IMiD-1
  • Revlimid
Drug: dexamethasone
Given orally
Other Names:
  • Aeroseb-Dex
  • Decaderm
  • Decadron
  • DM
  • DXM

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the overall response rate (complete response and partial response) in patients with relapsed or refractory stage II or III multiple myeloma treated with bevacizumab, lenalidomide, and dexamethasone.

SECONDARY OBJECTIVES:

I. Determine time to progression in these patients. II. Determine the toxicity and tolerability of this regimen. III. Determine the effect of bevacizumab and lenalidomide on markers of myeloma activity in myeloma cells and stromal cells, including interleukin-6, macrophage inflammatory protein-1α, vascular endothelial growth factor, and STAT3.

IV. Assess local cytokine milieu using tissue microarrays of bone marrow biopsy specimens.

OUTLINE: This is a multicenter, open-label study.

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and before courses 2 and 4. Blood samples are examined for vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) polymorphisms by pyrosequencing and VEGF, VEGFR1, VEGFR2, interleukin-6, and macrophage inflammatory protein 1 by immunoenzyme techniques. Relationships between plasma cell myeloma and stroma and the effect of study treatment on these relationships are examined in tissue sections of bone marrow before and after treatment utilizing microvessel density measurements, VEGF staining, and STAT3 staining (by immunohistochemistry and fluorescent in situ hybridization [FISH]).

After completion of study treatment, patients are followed periodically for at least 5 years.

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


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

Inclusion Criteria:

  • Histologically or cytologically confirmed symptomatic multiple myeloma:

    • Stage II or III disease
    • Relapsed or refractory disease after >= 2 courses of prior chemotherapy
  • Measurable levels of monoclonal protein (M protein) > 1.0 g/dL by serum protein electrophoresis OR > 200 mg of monoclonal light chain by 24-hour urine protein electrophoresis
  • Measurable bone disease, defined as >= 1 unidimensionally measurable lesion (longest diameter to be recorded) >= 20 mm with conventional techniques OR >= 10 mm with spiral CT scan (for patients with lytic bone disease)
  • No known brain metastases
  • ECOG performance status (PS) 0-2 OR Karnofsky PS 70-100%

    • Patients with PS of 3 are eligible if it is due to pain that is likely to improve with treatment
  • Life expectancy > 6 months
  • No known HIV positivity
  • No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
  • No active infections requiring oral or intravenous antibiotics within the past week
  • No proteinuria (i.e., albuminuria) > 1,000 mg/24 hours unless related to the diagnosis of multiple myeloma

    • Patients with light chain (i.e., "Bence-Jones") proteinuria are still eligible if the non-light chain component of protein is < 1,000 mg/24 hours
  • No serious nonhealing wound or ulcer
  • No blood pressure > 150/90 mm Hg (even with medication)
  • No significant traumatic injury within the past 28 days
  • No clinically significant peripheral vascular disease
  • No evidence of bleeding diathesis or coagulopathy
  • No unstable angina or myocardial infarction within the past 6 months
  • No stroke within the past 6 months
  • No New York Heart Association class III or IV heart failure
  • No secondary malignancy within the past 2 years except squamous cell or basal cell carcinoma of the skin or carcinoma in situ of the cervix
  • Hemoglobin > 9 g/dL (may be supported by transfusion or growth factors)
  • WBC >= 2,000/mm^3
  • Absolute neutrophil count >= 1,000/mm^3
  • Platelet count >= 75,000/mm^3
  • Bilirubin =< 2.5 mg/dL
  • At least 4 weeks since prior chemotherapy or radiotherapy and recovered
  • More than 7 days since prior minor surgical procedures, fine-needle aspirations, or core biopsies:

More than 24 hours since prior bone marrow biopsy or central veinous access placement

  • More than 28 days since prior major surgical procedure or open biopsy
  • At least 4 weeks since prior and no concurrent participation in another experimental drug study
  • Prior autologous peripheral blood stem cell transplantation allowed
  • No prior lenalidomide
  • Concurrent full-dose anticoagulants allowed provided all of the following criteria are met:

    • No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)
    • No thrombocytopenia requiring transfusion
    • Platelet count > 75,000/mm3
    • INR 2-3 and stable
  • No concurrent major surgery
  • No concurrent sargramostim (GM-CSF)
  • No other concurrent investigational agents
  • No other concurrent anticancer agents or therapies
  • AST and ALT =< 5 times upper limit of normal
  • Creatinine < 2.5 mg/dL
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use 2 methods of effective contraception 4 weeks before, during, and 4 weeks after completion of study treatment
  • No history of allergic reactions attributed to compounds of similar chemical or biological composition to lenalidomide and/or bevacizumab or other agents used in the study
  Contacts and Locations
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): NCT00410605


Locations
United States, Pennsylvania
University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, United States, 15232
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Natalie Callander University of Wisconsin, Madison
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00410605     History of Changes
Obsolete Identifiers: NCT00406328
Other Study ID Numbers: NCI-2009-00150
NCI-2009-00150 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
H-2006-0269 ( Other Identifier: UW Health Sciences IRB )
CDR0000521546
HO06401 ( Other Identifier: University of Wisconsin Hospital and Clinics )
7313 ( Other Identifier: CTEP )
U01CA062491 ( U.S. NIH Grant/Contract )
P30CA014520 ( U.S. NIH Grant/Contract )
First Submitted: December 11, 2006
First Posted: December 13, 2006
Results First Submitted: June 13, 2016
Results First Posted: September 1, 2017
Last Update Posted: September 1, 2017
Last Verified: August 2017

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
Dexamethasone acetate
Dexamethasone
Lenalidomide
Bevacizumab
Thalidomide
BB 1101
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids