Vorinostat, Bortezomib, and Doxorubicin Hydrochloride Liposome in Treating Patients With Relapsed or Refractory Multiple Myeloma

Sponsor

UNC Lineberger Comprehensive Cancer Center (Other)

Overall Status

Terminated

CT.gov ID

NCT00744354

Collaborator

Merck Sharp & Dohme LLC (Industry), Millennium Pharmaceuticals, Inc. (Industry), Ortho Biotech, Inc. (Industry)

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Vorinostat and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Bortezomib may also stop the growth of multiple myeloma by blocking blood flow to the tumor. Drugs used in chemotherapy, such as doxorubicin hydrochloride liposome, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving doxorubicin hydrochloride liposome together with vorinostat and bortezomib may kill more cancer cells.

PURPOSE: This phase I trial is studying the side effects and best dose of vorinostat and to see how well it works when given together with bortezomib and doxorubicin hydrochloride liposome in treating patients with relapsed or refractory multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Drug: bortezomib Drug: pegylated liposomal doxorubicin hydrochloride Drug: vorinostat	Phase 1

Detailed Description

OBJECTIVES:

Primary

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.

Secondary

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

Study Design

Study Type:

Interventional

Actual Enrollment :

32 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Oct 1, 2008

Actual Primary Completion Date :

Dec 1, 2011

Actual Study Completion Date :

Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Non-Randomized Open Label Single Arm Phase 1 dose escalation trial of vorinostat in combination with bortezomib and pegylated liposomal doxorubicin hydrochloride.	Drug: bortezomib Intravenous Push 1.3 mg/m2 Days 1, 4, 8, and 11 Other Names: Velcade Drug: pegylated liposomal doxorubicin hydrochloride Intravenous infusion, 30mg/m2, Day 4, each cycle Other Names: Doxil Drug: vorinostat Oral, 300mg, Days 1, 2, 4, 5, 8, 9, 11, 12, every cycle. Other Names: Zolinza

Arm

Intervention/Treatment

Experimental: Non-Randomized Open Label Single Arm

Phase 1 dose escalation trial of vorinostat in combination with bortezomib and pegylated liposomal doxorubicin hydrochloride.

Drug: bortezomib

Intravenous Push 1.3 mg/m2 Days 1, 4, 8, and 11

Other Names:

Velcade

Drug: pegylated liposomal doxorubicin hydrochloride

Intravenous infusion, 30mg/m2, Day 4, each cycle

Other Names:

Doxil

Drug: vorinostat

Oral, 300mg, Days 1, 2, 4, 5, 8, 9, 11, 12, every cycle.

Other Names:

Zolinza

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of vorinostat [4 years]

Secondary Outcome Measures

Overall response rate [5 years]
Duration of response [5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Diagnosis of multiple myeloma
Relapsed or refractory disease

PATIENT CHARACTERISTICS:

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 allowed)
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 PLD
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 abnormalities
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.

PRIOR CONCURRENT THERAPY:

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 hydrochloride
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mount Sinai Medical Center	New York	New York	United States	10029
2	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295
3	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
4	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096