Combination Chemotherapy With or Without PSC 833 in Treating Patients With Relapsed or Refractory Multiple Myeloma

Multiple Myeloma and Plasma Cell Neoplasm Clinical Trial

Official title:

A PHASE III STUDY OF PSC-833 IN COMBINATION WITH VINCRISTINE, DOXORUBICIN AND DEXAMETHASONE (PSC-833/VAD) VERSUS VAD ALONE IN PATIENTS WITH RELAPSING OR REFRACTORY MULTIPLE MYELOMA

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00002878
• Other study ID #: CDR0000065178
• Secondary ID: E-1A95CAN-NCIC-M
• Status: Completed
• Phase: Phase 3
• Start date: June 30, 1997

Study information

• Verified date: June 2023
• Source: Eastern Cooperative Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Some tumors become resistant to chemotherapy drugs. Combining PSC 833 with chemotherapy may reduce resistance to the drug, and allow more tumor cells to be killed. It is not yet known whether combination chemotherapy plus PSC 833 is more effective than combination chemotherapy alone in treating patients with relapsed or refractory multiple myeloma.

PURPOSE: Randomized phase III trial to compare the effectiveness of combination chemotherapy with or without PSC 833 in treating patients with relapsed or refractory multiple myeloma.

Description:

OBJECTIVES:

• Compare the overall survival and objective response rate of patients with relapsed or refractory multiple myeloma treated with vincristine, doxorubicin, and dexamethasone (VAD) with or without PSC 833.

• Compare event free survival and subjective response in patients treated with these regimens.

• Correlate treatment outcome with p-glycoprotein expression.

• Determine whether prognostic factors previously determined to be useful in untreated patients (i.e., plasma cell labeling index and multidrug resistance determined from bone marrow aspirates, serum beta 2-microglobulin and interleukin-6 receptor levels) correlate with objective and subjective response and event-free and overall survival in patients treated with these regimens.

• Compare the toxicity of VAD with or without PSC 833.

OUTLINE: This is a randomized, multicenter study. Patients are stratified by response to prior treatment, prior doxorubicin and/or vincristine, prior autologous peripheral blood stem cell transplantation, and center.

Patients are randomized to 1 of 2 treatment arms:

• Arm I: The first group receives vincristine, doxorubicin, and dexamethasone (VAD). Patients receive higher dose vincristine IV over 96 hours and higher dose doxorubicin IV over 96 hours on days 1-4 and oral dexamethasone daily on days 1-4 and 15-18.

• Arm II: The second group receives VAD plus oral PSC 833. Patients receive oral PSC 833 every 6 hours beginning on day 1 and continuing for 20 doses. Patients receive lower dose vincristine IV over 96 hours and lower dose doxorubicin IV over 96 hours on days 2-5 and oral dexamethasone daily on days 2-5 and 16-19.

Treatment in both arms repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. After completion of 2 courses, patients are reevaluated, and those with stable or responding disease continue treatment for 2 courses beyond maximum response. Doxorubicin is discontinued in patients who receive a maximum lifetime dose but still have stable or responding disease.

Patients are followed every 2 months for survival.

PROJECTED ACCRUAL: A total of 360 patients will be accrued for this study over approximately 20 months.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 0
• Est. primary completion date: April 2003
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

DISEASE CHARACTERISTICS:

• Multiple myeloma of any stage confirmed by:

• Bone marrow plasmacytosis with at least 10% plasma cells, sheets of plasma cells, or biopsy proven plasmacytosis

• Myeloma (M) protein in serum and/or urine

• Measurable disease by at least one of the following:

• Serum M-component at least 1.0 g/dL by electrophoresis

• Baseline measurement by nephelometry also, if used to follow response

• Urine M-protein excretion greater than 200 mg/24 hours by electrophoresis

• The following are not considered measurable but are followed for response:

• Lytic bone lesions

• Bone marrow plasmacytosis

• Anemia

• Serum beta 2-microglobulin

• Objective evidence of progression by at least one of the following:

• Increased serum M-protein (by electrophoresis unless M-spike less than 1.5 g/dL)

• At least 50% above lowest remission level or by at least 2 g/dL

• To more than 1.0 g/dL if sole protein indication of relapse

• Nephelometry may be used instead of electrophoresis

• Increased urine M-protein

• To 50% above lowest level OR by 2 g/24 hours

• To greater than 200 mg/24 hours

• Definite new lytic bone lesions or at least a 50% increase in size of existing lesions (discussion with ECOG Study Chairman required if sole indication of progression)

• Increase in serum or urine M-protein by 25% to under 50% (as above) plus one of the following:

• Serum calcium greater than 12 mg/dL without other cause

• Hemoglobin decreased by more than 2.0 g/dL not attributed to chemotherapy, interferon therapy, or a myelodysplastic syndrome

• Less than 11 g/dL in men

• Less than 10 g/dL in women

• At least a 50% increase in bone marrow plasmacytosis

• Failure of prior cytotoxic therapy defined by one of the following:

• Never responded

• Relapsed within 2 months of last treatment

• Relapsed 2-12 months after last treatment following initial response

• Adequate prior chemotherapy required, e.g.:

• At least 2 courses of combination chemotherapy (e.g., VBMCP, VBAP, MP)

• Prior vincristine, doxorubicin, and dexamethasone (VAD) allowed

• No demonstrated resistance to VAD

• At least 3 months since prior VAD

• Cumulative doxorubicin dose no more than 250 mg/m2

• Prior autologous peripheral blood stem cell transplant allowed if performed prior to development of drug resistance

• No prior allogeneic transplant

• No smoldering myeloma, localized plasmacytoma, or monoclonal gammopathy of undetermined significance (MGUS)

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• ECOG 0-3

Life expectancy:

• At least 2 months

Hematopoietic:

• Absolute neutrophil count at least 1,000/mm^3

• Platelet count at least 50,000/mm^3

Hepatic:

• Bilirubin less than 1.5 times upper limit of normal (ULN)

• AST less than 1.5 times ULN

• No chronic or active hepatitis or cirrhosis

Renal:

• Creatinine less than 3.0 mg/dL

Cardiovascular:

• Ejection fraction at least 50%

• No history of congestive heart failure

• No overt angina despite medication

• No myocardial infarction within 2 months

• No poorly controlled hypertension (i.e., pressure 200/110 or higher despite medication)

• No arrhythmia requiring therapy (i.e., sustained atrial or ventricular arrhythmia or multifocal premature ventricular contraction)

• Digoxin to control ventricular rate of atrial fibrillation that has been chronic for more than 1 month allowed

Neurologic:

• No peripheral neuropathy with weakness

• No cerebellar disease with ataxia

Gastrointestinal:

• Adequate gastrointestinal function to allow absorption of PSC 833

• No active peptic ulcer

Other:

• No hypersensitivity to PSC 833 or cyclosporine

• No active infection

• HIV negative

• No uncontrolled diabetes mellitus

• No second malignancy within the past 5 years except curatively treated nonmelanomatous skin cancer, carcinoma in situ of the cervix, or other localized cancer treated with surgery alone

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No other serious medical problem unless sufficiently stabilized

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Prior biologic therapy (e.g., interferon) allowed

Chemotherapy:

• See Disease Characteristics

• At least 3 weeks since other prior chemotherapy (including plicamycin)

Endocrine therapy:

• At least 2 weeks since high dose steroids (at least 100 mg/m2/day of prednisone or at least 40 mg/day of dexamethasone (including steroids for hypercalcemia)

Radiotherapy:

• At least 2 weeks since prior radiotherapy except limited radiotherapy to a single bone lesion

Surgery:

• At least 4 weeks since prior major surgery

Other:

• No concurrent anticoagulants

• No concurrent drugs known to modulate cyclosporine blood concentrations

Related Conditions & MeSH terms

• Multiple Myeloma
• Multiple Myeloma and Plasma Cell Neoplasm
• Neoplasms, Plasma Cell
• Plasmacytoma

Intervention

Drug:
• dexamethasone

• doxorubicin hydrochloride

• valspodar

• vincristine sulfate

Locations

Country	Name	City	State
Canada	Cancer Care Ontario-London Regional Cancer Centre	London	Ontario
Canada	Moncton Hospital	Moncton	New Brunswick
Canada	Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec
Canada	McGill University	Montreal	Quebec
Canada	Hotel Dieu Health Sciences Hospital - Niagara	St. Catharines	Ontario
Canada	Toronto General Hospital	Toronto	Ontario
Canada	Cancer Care Ontario - Windsor Regional Cancer Centre	Windsor	Ontario
Canada	CancerCare Manitoba	Winnipeg	Manitoba
United States	Marlene & Stewart Greenebaum Cancer Center, University of Maryland	Baltimore	Maryland
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Vermont Cancer Center	Burlington	Vermont
United States	Lineberger Comprehensive Cancer Center, UNC	Chapel Hill	North Carolina
United States	University of Chicago Cancer Research Center	Chicago	Illinois
United States	Ellis Fischel Cancer Center - Columbia	Columbia	Missouri
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	Holden Comprehensive Cancer Center at The University of Iowa	Iowa City	Iowa
United States	University of California San Diego Cancer Center	La Jolla	California
United States	CCOP - Southern Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	Norris Cotton Cancer Center	Lebanon	New Hampshire
United States	CCOP - North Shore University Hospital	Manhasset	New York
United States	Schneider Children's Hospital at North Shore	Manhasset	New York
United States	University of Tennessee, Memphis Cancer Center	Memphis	Tennessee
United States	CCOP - Mount Sinai Medical Center	Miami Beach	Florida
United States	University of Minnesota Cancer Center	Minneapolis	Minnesota
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	Mount Sinai Medical Center, NY	New York	New York
United States	New York Presbyterian Hospital - Cornell Campus	New York	New York
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Rhode Island Hospital	Providence	Rhode Island
United States	MBCCOP - Massey Cancer Center	Richmond	Virginia
United States	Barnes-Jewish Hospital	Saint Louis	Missouri
United States	UCSF Cancer Center and Cancer Research Institute	San Francisco	California
United States	CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.	Syracuse	New York
United States	State University of New York - Upstate Medical University	Syracuse	New York
United States	Walter Reed Army Medical Center	Washington	District of Columbia
United States	CCOP - Christiana Care Health Services	Wilmington	Delaware
United States	CCOP - Southeast Cancer Control Consortium	Winston-Salem	North Carolina
United States	Comprehensive Cancer Center at Wake Forest University	Winston-Salem	North Carolina
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts

Sponsors (6)

Lead Sponsor	Collaborator
Eastern Cooperative Oncology Group	Cancer and Leukemia Group B, European Organisation for Research and Treatment of Cancer - EORTC, National Cancer Institute (NCI), NCIC Clinical Trials Group, SWOG Cancer Research Network

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

Friedenberg WR, Rue M, Blood EA, Dalton WS, Shustik C, Larson RA, Sonneveld P, Greipp PR. Phase III study of PSC-833 (valspodar) in combination with vincristine, doxorubicin, and dexamethasone (valspodar/VAD) versus VAD alone in patients with recurring or — View Citation