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A Phase I Study of SAHA in Combination With Bortezomib in Relapsed and Refractory Multiple Myeloma

Phase 1
18 Years
Not Enrolling
Refractory Multiple Myeloma, Stage I Multiple Myeloma, Stage II Multiple Myeloma, Stage III Multiple Myeloma

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Trial Information

A Phase I Study of SAHA in Combination With Bortezomib in Relapsed and Refractory Multiple Myeloma


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.


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

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

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.

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

Type of Study:


Study Design:

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

Outcome Measure:

Maximum tolerated dose (MTD) of SAHA in combination with bortezomib determined by dose-limiting toxicities

Outcome Time Frame:

21 days

Safety Issue:


Principal Investigator

Ashraf Badros

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Maryland Greenebaum Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

November 2005

Completion Date:

Related Keywords:

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



University of Maryland Greenebaum Cancer Center Baltimore, Maryland  21201