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A Phase 1 Dose Escalation Study of Bortezomib (Velcade®), Pegylated Liposomal Doxorubicin (Doxil®), and Vorinostat (Suberoylanilide Hydromaxic Acid, Saha, Zolinzatm) in Patients With Relapse/Refractory Multiple Myeloma

Phase 1
18 Years
Open (Enrolling)
Multiple Myeloma and Plasma Cell Neoplasm

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Trial Information

A Phase 1 Dose Escalation Study of Bortezomib (Velcade®), Pegylated Liposomal Doxorubicin (Doxil®), and Vorinostat (Suberoylanilide Hydromaxic Acid, Saha, Zolinzatm) in Patients With Relapse/Refractory Multiple Myeloma



- To determine the maximum tolerated dose of vorinostat when added to the standard
regimen of bortezomib and pegylated liposomal doxorubicin hydrochloride in patients
with relapsed or refractory multiple myeloma.

- To identify the dose-limiting toxicities of this regimen in these patients.


- To gain preliminary evidence of antitumor activity of this regimen in these patients.

- To assess the degree of proteasome inhibition achieved with this regimen in these

- To evaluate the accumulation of acetylated alpha-tubulin after treatment with

- To evaluate overall survival, time to progression, and progression-free survival of
patients treated with this regimen.

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

Patients receive oral vorinostat once daily on days 1,2; 4,5; 8, 9; 11, 12; bortezomib IV on
days 1, 4, 8, and 11, and pegylated liposomal doxorubicin hydrochloride IV on day 4. Courses
repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Blood samples are collected periodically for proteasome inhibition assays and acetylated
alpha-tubulin studies.

After completion of study treatment, patients are followed at 1 and 3 months.

Inclusion Criteria


- Diagnosis of multiple myeloma

- Relapsed or refractory disease


- ECOG performance status 0-2

- Life expectancy ≥ 3 months

- ANC ≥ 1.0 x 10^9/L (no granulocyte growth factor support, e.g., G-CSF or GM-CSF

- Platelet count ≥ 100 x 10^9/L (erythropoietin allowed, no platelet or RBC transfusion
within the past 2 weeks)

- Hemoglobin ≥ 8 g/dL (erythropoietin allowed, no platelet or RBC transfusion within
the past 2 weeks)

- Creatinine clearance ≥ 30 mL/min

- AST or ALT ≤ 2.5 times upper limit of normal (ULN)

- Total bilirubin ≤ 1.5 times ULN

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception during and for 3 months after
completion of study treatment

- LVEF ≥ 45% by MUGA or ECHO

- Symptomatic neuropathy < grade 2

- No known history of HIV

- No active or serious infection, medical or psychiatric illness that would preclude
study participation

- No active hepatitis B or C infection

- No other prior or concurrent malignancy except for adequately treated basal cell or
squamous cell carcinoma of the skin, in situ malignancy, low-risk prostate cancer
after curative therapy, or other cancer for which the patient has been disease-free
for ≥ 3 years

- No history of hypersensitivity reaction to bortezomib or any of its components
(boron, mannitol), vorinostat, doxorubicin hydrochloride, or any of the components of

- No serum potassium ≤ 3.0 or serum magnesium ≤ 1.6 that cannot be corrected with
supplementation are excluded

- Patients must have adequate cardiovascular function, defined by all of the following:

- No EKG evidence of active, clinically significant conduction system

- No EKG evidence of QTc prolongation > grade 2

- NOTE: Any EKG abnormality at screening has to be documented by the investigator as
not medically significant.


- No limit to number of prior treatment regimens

- At least 30 days since prior therapy and recovered

- At least 3 months since prior autologous stem cell transplantation and recovered

- Prior allogeneic stem cell or bone marrow transplantation allowed provided the
following criteria are met:

- More than 1 year since transplantation

- No longer receiving immunosuppressive therapy or treatment for graft-versus-host
disease (GVHD) prophylaxis

- No active GVHD

- No active, uncontrolled infections

- No major surgery within the past 3 weeks

- No prior anthracycline dose > 360 mg/m^2 for doxorubicin hydrochloride (including
pegylated liposomal doxorubicin hydrochloride [PLD]) or 720 mg/m^2 for epirubicin

- No prior or concurrent histone deacetylase inhibitor (e.g., valproic acid)

- No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF) during course 1

- No other concurrent investigational or anticancer agent

Type of Study:


Study Design:

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum tolerated dose of vorinostat

Outcome Time Frame:

4 years

Safety Issue:


Principal Investigator

Peter Voorhees, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UNC Lineberger Comprehensive Cancer Center


United States: Institutional Review Board

Study ID:

LCCC 0715



Start Date:

October 2008

Completion Date:

June 2014

Related Keywords:

  • Multiple Myeloma and Plasma Cell Neoplasm
  • refractory multiple myeloma
  • stage I multiple myeloma
  • stage II multiple myeloma
  • stage III multiple myeloma
  • Neoplasms
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma



Duke Comprehensive Cancer Center Durham, North Carolina  27710
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill Chapel Hill, North Carolina  27599-7570
Mount Sinai Medical Center New York, New York  10029
Wake Forest University Comprehensive Cancer Center Winston-Salem, North Carolina  27157-1096