Clinical trial NCT00088855: Bortezomib and Pegylated Liposomal Doxorubicin Hydrochloride in Treating Patients With Previously Untreated Symptomatic Multiple Myeloma
Official title: Phase II Study of Bortezomib (PS-341) and Pegylated Liposomal Doxorubicin as Initial Therapy for Adult Patients With Symptomatic Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: DS Stage I Plasma Cell Myeloma
DS Stage II Plasma Cell Myeloma
DS Stage III Plasma Cell Myeloma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2004-08-05
Enrollment: 55
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed description: PRIMARY OBJECTIVE:

I. 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.

II. To evaluate the toxicity of the bortezomib/pegylated liposomal doxorubicin regimen in patients with previously untreated, symptomatic multiple myeloma.

SECONDARY OBJECTIVES:

I. 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.

II. 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.

III. 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.

IV. 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.

V. 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.

Eligibility criteria: 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

Primary outcomes:
measure: CR+nCR rate
timeFrame: After 18 weeks (6 courses of treatment)
Secondary outcomes:
measure: CR+nCR+PR rate
timeFrame: After 18 weeks (6 courses of treatment)
measure: Maximal response rate
timeFrame: After 18 weeks (6 courses of treatment)
measure: Incidence of adverse events, graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
timeFrame: Up to 5 years
measure: Progression-free survival
timeFrame: From on-study date to the date of progression or death, whichever comes first, assessed up to 5 years
measure: Overall survival
timeFrame: From on-study date to the date of death, assessed up to 5 years
measure: Changes in IL-6 and MIP-1
timeFrame: Baseline to up to day 2 of course 1
Other outcomes:
Locations:
city: Mountain View
country: United States
facility: Palo Alto Medical Foundation-Camino Division
state: California
city: Newark
country: United States
facility: Christiana Care Health System-Christiana Hospital
state: Delaware
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Holy Cross Hospital
state: Florida
city: Jupiter
country: United States
facility: Jupiter Medical Center
state: Florida
city: Miami Beach
country: United States
facility: Mount Sinai Medical Center
state: Florida
city: Orlando
country: United States
facility: AdventHealth Orlando
state: Florida
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Prairie Village
country: United States
facility: Kansas City NCI Community Oncology Research Program
state: Kansas
city: Bethesda
country: United States
facility: Walter Reed National Military Medical Center
state: Maryland
city: Minneapolis
country: United States
facility: Minneapolis VA Medical Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Missouri Baptist Medical Center
state: Missouri
city: Saint Louis
country: United States
facility: Center for Cancer Care and Research
state: Missouri
city: Rochester
country: United States
facility: Frisbie Hospital
state: New Hampshire
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Kinston
country: United States
facility: Lenoir Memorial Hospital
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Greenville
country: United States
facility: Greenville Health System Cancer Institute-Eastside
state: South Carolina
city: Berlin
country: United States
facility: Central Vermont Medical Center/National Life Cancer Treatment
state: Vermont
city: Burlington
country: United States
facility: University of Vermont and State Agricultural College
state: Vermont
city: Danville
country: United States
facility: Danville Regional Medical Center
state: Virginia
Study officials:
affiliation: Alliance for Clinical Trials in Oncology
name: Robert Z Orlowski
role: PRINCIPAL_INVESTIGATOR
References: