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Phase II Trial of Bevacizumab Combined With Lenalidomide and Dexamethasone (BEV/REV/DEX) in Relapsed or Refractory Multiple Myeloma

Phase 2
18 Years
Open (Enrolling)
Refractory Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

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Trial Information

Phase II Trial of Bevacizumab Combined With Lenalidomide and Dexamethasone (BEV/REV/DEX) in Relapsed or Refractory Multiple Myeloma


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.


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

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

- 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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Confirmed anti-tumor response rate (complete response and partial response) to the combination of bevacizumab and lenalidomide

Outcome Description:

Responses will be 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 will be 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 will be estimated by using Whitehead's bias-adjustment approach.

Outcome Time Frame:

Up to 5 years

Safety Issue:


Principal Investigator

Natalie Callander

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Wisconsin Hospital and Clinics


United States: Food and Drug Administration

Study ID:




Start Date:

November 2006

Completion Date:

Related Keywords:

  • Refractory Multiple Myeloma
  • Stage II Multiple Myeloma
  • Stage III Multiple Myeloma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell



University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania  15213
University of Wisconsin Hospital and Clinics Madison, Wisconsin  53792-0001