Bortezomib and Pegylated Liposomal Doxorubicin Hydrochloride in Treating Patients With Previously Untreated Symptomatic Multiple Myeloma

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Completed

CT.gov ID

NCT00088855

Collaborator

(none)

Enrollment

Locations

Arm

42.8

Actual Duration (Months)

2.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial studies the side effects and how well bortezomib and pegylated liposomal doxorubicin hydrochloride work in treating patients multiple myeloma that are experiencing symptoms and have not received prior treatment. Bortezomib and pegylated liposomal doxorubicin hydrochloride may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
DS Stage I Plasma Cell Myeloma DS Stage II Plasma Cell Myeloma DS Stage III Plasma Cell Myeloma	Drug: Bortezomib Other: Laboratory Biomarker Analysis Drug: Pegylated Liposomal Doxorubicin Hydrochloride	Phase 2

Detailed Description

PRIMARY OBJECTIVE:

To evaluate the complete response (CR) + near-complete response (nCR) rate of the bortezomib/pegylated liposomal doxorubicin (pegylated liposomal doxorubicin hydrochloride) regimen in patients with previously untreated, symptomatic multiple myeloma.
To evaluate the toxicity of the bortezomib/pegylated liposomal doxorubicin regimen in patients with previously untreated, symptomatic multiple myeloma.

SECONDARY OBJECTIVES:

To evaluate the overall response rate, including patients with CR, nCR, and partial response (PR), of the bortezomib/pegylated liposomal doxorubicin regimen in patients with previously untreated, symptomatic multiple myeloma.
To evaluate the impact of therapy with the bortezomib/pegylated liposomal doxorubicin regimen on the ability to collect peripheral blood stem cells in those patients going on to subsequent autologous stem cell transplantation.
To evaluate the time to progression (TTP) in all patients receiving bortezomib/pegylated liposomal doxorubicin therapy, both those who go on to autologous stem cell transplantation and those who do not go on to transplantation.
To evaluate the value of early changes in levels of serum interleukin 6 (IL-6) and macrophage inflammatory protein 1 alpha (MIP-1α) as predictors of response to bortezomib/pegylated liposomal doxorubicin.
To correlate pre-treatment clinical and biological characteristics with response to therapy and toxicity.

OUTLINE:

Patients receive bortezomib intravenously (IV) over 3-5 seconds on days 1, 4, 8, and 11 and pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 4. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 weeks for 2 years and then every 6 months for 3 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

55 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase II Study of Bortezomib (PS-341) and Pegylated Liposomal Doxorubicin as Initial Therapy for Adult Patients With Symptomatic Multiple Myeloma

Actual Study Start Date :

Jun 15, 2004

Actual Primary Completion Date :

Oct 31, 2006

Actual Study Completion Date :

Jan 8, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (bortezomib and pegylated liposomal doxorubicin) Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 4. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.	Drug: Bortezomib Given IV Other Names: [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid LDP 341 MLN341 PS-341 PS341 Velcade Other: Laboratory Biomarker Analysis Correlative studies Drug: Pegylated Liposomal Doxorubicin Hydrochloride Given IV Other Names: ATI-0918 Caelyx DOX-SL Doxil Doxilen Doxorubicin HCl Liposomal Doxorubicin HCl Liposome doxorubicin hydrochloride liposome Duomeisu Evacet LipoDox Lipodox 50 Liposomal Adriamycin liposomal doxorubicin hydrochloride Liposomal-Encapsulated Doxorubicin Pegylated Doxorubicin HCl Liposome S-Liposomal Doxorubicin Stealth Liposomal Doxorubicin TLC D-99

Arm

Intervention/Treatment

Experimental: Treatment (bortezomib and pegylated liposomal doxorubicin)

Patients receive bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11 and pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 4. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Drug: Bortezomib

Given IV

Other Names:

[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid

LDP 341

MLN341

PS-341

PS341

Velcade

Other: Laboratory Biomarker Analysis

Correlative studies

Drug: Pegylated Liposomal Doxorubicin Hydrochloride

Given IV

Other Names:

ATI-0918

Caelyx

DOX-SL

Doxil

Doxilen

Doxorubicin HCl Liposomal

Doxorubicin HCl Liposome

doxorubicin hydrochloride liposome

Duomeisu

Evacet

LipoDox

Lipodox 50

Liposomal Adriamycin

liposomal doxorubicin hydrochloride

Liposomal-Encapsulated Doxorubicin

Pegylated Doxorubicin HCl Liposome

S-Liposomal Doxorubicin

Stealth Liposomal Doxorubicin

TLC D-99

Outcome Measures

Primary Outcome Measures

CR+nCR rate [After 18 weeks (6 courses of treatment)]
Will be estimated with an exact 90% confidence interval.

Secondary Outcome Measures

CR+nCR+PR rate [After 18 weeks (6 courses of treatment)]
Will be estimated with an exact 90% confidence interval.
Maximal response rate [After 18 weeks (6 courses of treatment)]
Incidence of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [Up to 5 years]
Toxicities will be tabulated by type and grade.
Progression-free survival [From on-study date to the date of progression or death, whichever comes first, assessed up to 5 years]
Will be estimated using the Kaplan-Meier method.
Overall survival [From on-study date to the date of death, assessed up to 5 years]
Will be estimated using the Kaplan-Meier method.
Changes in IL-6 and MIP-1 [Baseline to up to day 2 of course 1]
The association of response with pre-treatment characteristics such as cytogenetics and fluorescence in situ hybridization and with early changes in IL-6 and MIP-1 will be described by reporting response rates (and their confidence intervals) according to subgroup (e.g., response rates by age group; response rates by large/small change in IL-6 level).

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have a histologically confirmed diagnosis of symptomatic multiple myeloma with evaluable disease parameters
A diagnosis of symptomatic multiple myeloma requires:
A monoclonal serum and/or urine protein
Clonal bone marrow plasmacytosis, or a histologically confirmed plasmacytoma
Related organ or tissue impairment, consisting of:
Hypercalcemia (serum calcium > 0.25 mmol/l above the upper limit of normal, or > 2.75 mmol/l [i.e. > 11.5 mg/dl]) AND/OR
Renal insufficiency (serum creatinine > 173 mmol/l [i.e., > 2 mg/dL]); (please note that serum creatinine may not be >= 2.5 mg/dL) AND/OR
Anemia (hemoglobin 2 g/dl below the lower limit of normal, or hemoglobin < 10 g/dl) AND/OR
Bony lesions (lytic bony lesions, or osteoporosis with compression fractures) AND/OR
Other findings, such as symptomatic hyperviscosity, amyloidosis, or recurring bacterial infections (> 2 episodes in 12 months)
Patients may not have undergone any prior therapy, with the following exceptions:
Prior plasmapheresis with plasma exchange (PLEX) for a hyperviscosity syndrome is allowed, providing the patient has no current evidence of hyperviscosity and has not required PLEX for at least one week prior to initiation of therapy
Prior radiation therapy to areas of spinal cord compression by plasmacytomas, painful lesions due to bony involvement, or other myeloma-related indications, is allowed provided that radiation will have been completed 3 weeks before initiation of therapy
Prior surgical intervention, such as for bony fractures or other myeloma-related complications, is allowed provided that this will have been completed 3 weeks before the initiation of therapy, and patients have recovered from surgery
Prior therapy with corticosteroids for indications other than multiple myeloma is allowed, provided such therapy has been discontinued at least two weeks prior to study entry, and at least two weeks before their baseline disease evaluation
Prior supportive therapy with bisphosphonates or erythropoietin is allowed
Inclusion of females of childbearing potential requires a negative pregnancy test
Eastern Cooperative Oncology Group (ECOG) performance status =< 2
Patients may not have a prior history of a hypersensitivity reaction to pegylated liposomal doxorubicin or doxorubicin, bortezomib or other boronic acid-based compounds
Patients with a history of reactions to liposomal drug formulations other than pegylated liposomal doxorubicin will be evaluated individually, and if their reactions were felt to have been due to the liposomal component itself, as opposed to the encapsulated agent, they will be excluded at the discretion of the investigators
Patients who are known to be human immunodeficiency virus (HIV)-seropositive and are taking anti-retrovirals may not participate in this study; patients who are HIV-seropositive and not on anti-retroviral therapy, and who otherwise meet the organ function criteria, will be eligible for the study
Patients who are known to have active hepatitis A, B, or C viral infection may not participate in this study
No electrocardiogram (EKG) evidence of acute ischemia
No EKG evidence of medically significant conduction system abnormalities
No history of myocardial infarction within the last 6 months
Left ventricular ejection fraction (LVEF) must be >= 45% by either echocardiography or radionuclide-based multiple gated acquisition (radionuclide ventriculography [RNV] or multiple gate acquisition scan [MUGA])
No class 3 or class 4 New York Heart Association congestive heart failure
Creatinine < 2.5 mg/dL
Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) and aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 times the upper limit of the institutional normal value
Total bilirubin =< 1.2 times the upper limit of the institutional normal value
Absolute neutrophil count (ANC) >= 1,000/ul
Platelets >= 100,000/ul
Hemoglobin >= 8 g/dl (transfusion- and/or growth factor-dependent patients are not excluded if the above parameters can be achieved with such support)
For those patients receiving warfarin (Coumadin), unfractionated heparin, or low-molecular weight heparin therapy, the applicable coagulation parameter that is being monitored must be within the accepted therapeutic ranges for those indications

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Palo Alto Medical Foundation-Camino Division	Mountain View	California	United States	94040
2	Christiana Care Health System-Christiana Hospital	Newark	Delaware	United States	19718
3	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
4	MedStar Washington Hospital Center	Washington	District of Columbia	United States	20010
5	Holy Cross Hospital	Fort Lauderdale	Florida	United States	33308
6	Jupiter Medical Center	Jupiter	Florida	United States	33458
7	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
8	AdventHealth Orlando	Orlando	Florida	United States	32803
9	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
10	Kansas City NCI Community Oncology Research Program	Prairie Village	Kansas	United States	66208
11	Walter Reed National Military Medical Center	Bethesda	Maryland	United States	20889-5600
12	Minneapolis VA Medical Center	Minneapolis	Minnesota	United States	55417
13	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
14	Missouri Baptist Medical Center	Saint Louis	Missouri	United States	63131
15	Center for Cancer Care and Research	Saint Louis	Missouri	United States	63141
16	Frisbie Hospital	Rochester	New Hampshire	United States	03867
17	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
18	UNC Lineberger Comprehensive Cancer Center	Chapel Hill	North Carolina	United States	27599
19	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
20	Lenoir Memorial Hospital	Kinston	North Carolina	United States	28501
21	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
22	Greenville Health System Cancer Institute-Eastside	Greenville	South Carolina	United States	29615
23	Central Vermont Medical Center/National Life Cancer Treatment	Berlin	Vermont	United States	05602
24	University of Vermont and State Agricultural College	Burlington	Vermont	United States	05405
25	Danville Regional Medical Center	Danville	Virginia	United States	24541