A Phase II Study of Bevacizumab and Bortezomib in Patients With Relapsed/Refractory Multiple Myeloma

This study has been completed.
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Hackensack University Medical Center
ClinicalTrials.gov Identifier:
NCT00464178
First received: April 19, 2007
Last updated: September 4, 2013
Last verified: September 2013
  Purpose

The purpose of this study is to determine whether the combination of bevacizumab and bortezomib have increased efficacy in the treatment of relapsed/ refractory multiple myeloma.


Condition Intervention Phase
Multiple Myeloma
Drug: Bortezomilb
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Study of Bevacizumab and Bortezomib in Patients With Relapsed Refractory Multiple Myeloma

Resource links provided by NLM:


Further study details as provided by Hackensack University Medical Center:

Primary Outcome Measures:
  • Time to Tumor Progression (TTP)TTP is calculated at the time from randomization to the first documentation of progressive disease based on the myeloma response determination criteria developed by Bladé et al (Appendix F). [ Time Frame: 18 months ] [ Designated as safety issue: No ]

    Study Schema: Open label administration of bevacizumab at 15 mg/kg as an IV infusion on Day 1 of a 3 week schedule. Bortezomilb will be administered at 1.3 mglm2 IVP on Days 1. 4, 8, and 11. Response will be assessed subsequent to each cycle. A total of 8 cycles would be planned. Patients would be removed subsequent to Cycle 2. if progression of disease is documented. Patients with responsive disease (CR, PR, or MR, and SD at physician discretion) at the end of Cycle 8 would be eligible to continue on the combination of Bevacizumab at 15 mg/kg q3week and Bortezomib 1.3 mglm 2 once weekly for 4 weeks (days

    1, 8, 15, 22) followed by a 13 day rest period (days 23 to 35). (Adjustments in the dosing schedule of bortezomib would be made for patients with adequate response as per Blade criteria and continue until disease progression or 18 months).



Secondary Outcome Measures:
  • Overall Survival (OS) - Overall survival is calculated at the time of the screening evaluation to death from any cause. [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
    The secondary objective of this study is to assess the safely and tolerability of the combination treatment of bevacizumnab and bortezomnib. Patients with responsive disease (CR, PR, or MR, and SD at physician discretion) at the end of Cycle 8 would be eligible to continue on the combination of Bevacizumab at 15 mg/kg q3week and Bortezomib 1.3 mglm 2 once weekly for 4 weeks (days 1, 8, 15, 22) followed by a 13 day rest period (days 23 to 35). (Adjustments in the dosing schedule of bortezomib would be made for patients with adequate response as per Blade criteria and continue until disease progression or 18 months).


Enrollment: 7
Study Start Date: April 2007
Study Completion Date: February 2009
Primary Completion Date: February 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bortezomilb and bevacizumab
Bortezomilb will be administered at 1.3 mglm2 IVP on Days 1. 4, 8, and 11. Response will be assessed subsequent to each cycle. A total of 8 cycles would beplanned. Patients would be removed subsequent to Cycle 2. if progression of disease is documented.
Drug: Bortezomilb
Bortezomilb will be administered at 1.3 mglm2 IVP on Days 1. 4, 8, and 11. Response will be assessed subsequent to each cycle. A total of 8 cycles would beplanned. Patients would be removed subsequent to Cycle 2. if progression of disease is documented.
Other Name: Bortezomilb will be administered

Detailed Description:

Rationale: With the identification of thalidomide as an active agent in Multiple Myeloma, the role of angiogenesis in its pathogenesis has become a subject of much investigation. Micro vessel density (neovascularization) is inversely related to prognosis in Multiple Myeloma. Response to thalidomide was felt to correlate with a decline in microvessel density (Singhal et al NEJM). While the mechanism of neovascularization is yet to be fully elucidated, a number of models have shown VEGF to play a central role.

Thalidomide has been shown to synergize with a number of agents used to treat MM, including bortezomib. (Wang et al ASH 2005) This would justify the use of other therapeutics with known antiangiogenic activity in conjunction with established antimyeloma therapies.

Bortezomib, which has the precedence of known synergy with Thalidomide and has an extremely well established optimal dose, schedule, response rate, event free survival, and overall survival would make it an excellent candidate for combination therapy with other established antiangiogenic compounds.

There have been several reports of the role of VEGF in multiple myeloma. It has been shown that multiple myeloma cells secreteVEGF, which further promotes production of IL-6 in BMSCs, as well as migration and proliferation of the tumor cells. Thus VEGF is both an autocrine growth factor and trigger of IL-6-mediated paracrine multiple myeloma cell growth. Recent reports have highlighted the major role of VEGF in multiple myeloma pathogenesis, demonstrating the VEGF also increases microvessel density in the bone marrow. VEGF also inhibits dendritic cells. Taken together, these preclinical reports make strong suggestion for the promise of VEGF targeted agents in multiple myeloma (Le Gouill et al 2004).

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Must have been previously diagnosed with multiple myeloma based on Durie-Salmon criteria and/or the diagnostic criteria developed by the International Myeloma Working Group (IMWG).The patient must currently require therapy for relapsed (progressive disease, defined as a 25% increase in M-protein, development of new or worsening of existing lesions or soft tissue plasmacytoma, or hypercalcemia, or relapse from CR. Or patient must have disease that is refractory to most recent therapy. Defined as less than a 50% reduction in serum paraprotein or 90% reduction in urine paraprotein.
  • Must have measurable disease, defined as follows: For secretory multiple myeloma, measurable levels of monoclonal protein: greater than or equal to 0.5g/dL on electrophoresis or greater than or equal to 200mg of monoclonal light chain on a 24 hour protein electrophoresis.
  • Must have had at least one prior line of therapy but no more than three prior lines of therapy.
  • Must understand and voluntarily sign an informed consent form.
  • Must be greater than/equal to 18 years of age at time of signing consent.
  • Must be able to adhere to study visit schedule and other protocol requirements.
  • Must have an ECOG performance status of 0,1or 2
  • Women of Child-bearing potential (WCBP) defined as a sexually mature woman who has not undergone a hysterectomy or who has not been naturally post-menopausal for at least 24 consecutive months must have a negative serum or urine pregnancy test within 7 days of starting study drug. In addition, sexually active WCBP must agree to use adequate contraceptive methods (oral, injectable, or implantable hormonal contraceptive method; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) while on study medication.
  • All WCBP and all sexually active male patients must agree to use adequate methods of birth control throughout the study.

Exclusion Criteria:

  • Inability to comply with study and/or follow-up procedures
  • Life expectancy of less than 12 weeks
  • Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)
  • Any prior history of hypertensive crisis or hypertensive encephalopathy
  • New York Heart Association (NYHA) Grade II or greater congestive heart failure or left ventricular ejection fraction (LVEF) < 40% (Note: baseline evaluation of LVEF should be performed for any patient who has received >450mg/m2 of any anthracycline during prior chemotherapy.
  • History of myocardial infarction or unstable angina within 6 months prior to study enrollment
  • History of stroke or transient ischemic attack within 6 months prior to study enrollment
  • Known CNS disease
  • Significant vascular disease (e.g., aortic aneurysm, aortic dissection)
  • Symptomatic peripheral vascular disease
  • Known hypersensitivity to any component of bevacizumab and/or bortezomib
  • Previously treated with Bortezomib and/or Bevacizumab.
  • Received nitrosoureas within 3 weeks or any other chemotherapy, including thalidomide or clarithromycin, or radiation therapy before enrollment.
  • Received corticosteroids (greater than 10mg/day prednisone or equivalent) within three weeks prior to enrollment.
  • Received immunotherapy or antibody therapy within 8 weeks prior to enrollment.
  • Received plasmapheresis within 4 weeks before enrollment.
  • Had major surgery within 4 weeks before enrollment. (kyphoplasty is not considered major surgery)
  • History of allergic reactions attributable to compounds containing boron or mannitol.
  • Grade 3 or greater peripheral neuropathy as defined by the NCI Common Toxicity Criteria (NCI CTC version 3.0) Grade 3: Sensory loss or paresthesia interfering with ADLs. Grade 4: Permanent sensory loss that interferes with function.
  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: NCT00464178

Locations
United States, New Jersey
The Cancer Center at Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
Sponsors and Collaborators
Hackensack University Medical Center
Genentech, Inc.
Investigators
Principal Investigator: David S Siegel, MD, PhD The Cancer Center at Hackensack University Medical Center
  More Information

No publications provided

Responsible Party: Hackensack University Medical Center
ClinicalTrials.gov Identifier: NCT00464178     History of Changes
Other Study ID Numbers: AV3502s, AVF3502s, 20070359
Study First Received: April 19, 2007
Last Updated: September 4, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Hackensack University Medical Center:
multiple myeloma
myeloma
relapsed myeloma
refractory myeloma
relapsed, refractory myeloma
relapsed, refractory multiple myeloma
refractory multiple myeloma
relapsed multiple myeloma
B lymphoid malignancies
Multiple Myeloma
Myeloma, Plasma-Cell
Myeloma Proteins
hnRNP A1
myeloma helix-destabilizing protein, mouse
IgC3kappa Jir protein, human
gamma 3 myeloma protein Jir, human
M-proteins (Myeloma)
M315 myeloma protein, mouse
myeloma protein M 315, mouse
McPC603 antibody
myeloma protein McPC603 antibody
multiple myeloma M-proteins
M protein, multiple myeloma
myeloma cell activator
myeloma immunoglobulins
myeloma immunoglobulin M603
myeloma immunoglobulin S15
myeloma protein A48, mouse
A48 myeloma protein, mouse
ABPC48 myeloma protein, mouse

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
Bevacizumab
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 19, 2014