Vorinostat and Bortezomib in Treating Patients With Relapsed or Refractory Multiple Myeloma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00310024
First received: March 29, 2006
Last updated: February 6, 2013
Last verified: February 2013
  Purpose

This phase I trial is studying the side effects and best dose of vorinostat when given together with bortezomib in treating patients with relapsed or refractory multiple myeloma. Vorinostat and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving vorinostat together with bortezomib may kill more cancer cells


Condition Intervention Phase
Refractory Multiple Myeloma
Stage I Multiple Myeloma
Stage II Multiple Myeloma
Stage III Multiple Myeloma
Drug: bortezomib
Drug: vorinostat
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1

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

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) of SAHA in combination with bortezomib determined by dose-limiting toxicities [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Inhibition of histone deacetylation [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
  • Response [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
    The estimates and the corresponding 90% confidence intervals will be calculated.

  • Survival (disease specific and overall) [ Time Frame: Up to 1 month ] [ Designated as safety issue: No ]
    Will be estimated using the Kaplan-Meir method.


Enrollment: 40
Study Start Date: November 2005
Primary Completion Date: February 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (vorinostat, bortezomib)

Patients receive bortezomib IV on days 1, 4, 8, and 11 followed by oral SAHA twice daily on days 4-11. Beginning in course 3, some patients may receive low-dose oral dexamethasone on days 4-8. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional cohort of 10 patients receive treatment at the MTD.

Patients undergo blood collection and tumor biopsies periodically during study for pharmacologic and biomarker correlative studies.

Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Drug: vorinostat
Given orally
Other Names:
  • L-001079038
  • SAHA
  • suberoylanilide hydroxamic acid
  • Zolinza
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) of vorinostat (SAHA) when given together with bortezomib in patients with relapsed or refractory multiple myeloma (MM).

II. Determine the toxicity of this regimen in these patients.

SECONDARY OBJECTIVES:

I. Determine whether giving SAHA together with bortezomib inhibits histone deacetylation in normal cells (buccal mucosal cells and/or peripheral blood monocytes) as well as in MM cells.

II. Evaluate the effect of dexamethasone when given together with SAHA and bortezomib.

III. Explore molecular mechanisms involved in apoptosis in MM mediated by SAHA and bortezomib.

IV. Correlate change of histone acetylation with clinical outcome in patients treated with this regimen.

OUTLINE: This is a multicenter, dose escalation study of vorinostat (SAHA).

Patients receive bortezomib IV on days 1, 4, 8, and 11 followed by oral SAHA twice daily on days 4-11. Beginning in course 3, some patients may receive low-dose oral dexamethasone on days 4-8. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of SAHA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. An additional cohort of 10 patients receive treatment at the MTD.

Patients undergo blood collection and tumor biopsies periodically during study for pharmacologic and biomarker correlative studies.

After completion of study treatment, patients are followed at least once a month.

  Eligibility

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

Inclusion Criteria:

  • Histologically and clinically confirmed multiple myeloma

    • Relapsed or refractory disease after prior chemotherapy or transplantation*
  • Measurable disease, defined by quantitative immunoglobulin levels in serum and/or urine and bone marrow plasmacytosis

    • Non-secretory disease allowed provided MRI or positron emission tomography or CT scan can accurately measure at least one plasmacytoma lesion
  • No known CNS involvement
  • Life expectancy > 3 months
  • ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%
  • Absolute neutrophil count ≥ 1,000/mm³ (unless myelosuppression is secondary to bone marrow plasmacytosis [> 80% involvement])
  • Platelet count ≥ 50,000/mm³ (unless myelosuppression is secondary to bone marrow plasmacytosis [> 80% involvement])
  • Bilirubin ≤ 2 times upper limit of normal (ULN)
  • AST and ALT ≤ 2 times ULN
  • Creatinine < 2 mg/dL OR creatinine clearance > 40 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Able to swallow pills
  • Patients with a history of seizures are eligible provided seizures are under adequate control with non-enzyme inducing anticonvulsant medication
  • No history of allergic reactions attributed to study agents
  • No sensory or motor neuropathy ≥ grade II
  • No uncontrolled current illness including, but not limited to, the following:

    • Ongoing or active infection
    • Symptomatic congestive heart failure
    • Unstable angina pectoris
    • Cardiac arrhythmia
    • Psychiatric illness or social situation that would limit study compliance
  • No grade 3 QT prolongation (i.e., > 500 msec) at baseline
  • See Disease Characteristics
  • Prior bortezomib allowed
  • At least 2 weeks since prior therapy for multiple myeloma
  • Concurrent growth factors (filgrastim [G-CSF] and epoetin alfa) to sustain peripheral blood counts (during the first course of therapy only) allowed
  • Concurrent steroid therapy (≤ 20 mg of prednisone) for patients requiring chronic use for disorders other than myeloma allowed
  • No concurrent combination antiretroviral therapy for HIV-positive patients
  • No other concurrent investigational or commercial agents or therapies for this malignancy
  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: NCT00310024

Locations
United States, Maryland
University of Maryland Greenebaum Cancer Center
Baltimore, Maryland, United States, 21201-1595
Sponsors and Collaborators
Investigators
Principal Investigator: Ashraf Badros University of Maryland Greenebaum Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00310024     History of Changes
Other Study ID Numbers: NCI-2012-02693, GCC 0514, N01CM62204, CDR0000466109
Study First Received: March 29, 2006
Last Updated: February 6, 2013
Health Authority: United States: Food and Drug Administration

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
Vorinostat
Bortezomib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 01, 2014