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

NCT ID: NCT00002878

Last Updated: 2023-06-15

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Study Classification: INTERVENTIONAL
• Study Start Date: 1997-06-30

Brief 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.

Detailed 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.

Conditions

Multiple Myeloma and Plasma Cell Neoplasm

Study Design

• Allocation Method: RANDOMIZED
• Primary Study Purpose: TREATMENT

Interventions

dexamethasone

Intervention Type: DRUG

doxorubicin hydrochloride

Intervention Type: DRUG

valspodar

Intervention Type: DRUG

vincristine sulfate

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

SWOG Cancer Research Network

NETWORK

Sponsor Role: collaborator

Cancer and Leukemia Group B

NETWORK

Sponsor Role: collaborator

NCIC Clinical Trials Group

NETWORK

Sponsor Role: collaborator

European Organisation for Research and Treatment of Cancer - EORTC

NETWORK

Sponsor Role: collaborator

Eastern Cooperative Oncology Group

NETWORK

Sponsor Role: lead

Principal Investigators

William R. Friedenberg, MD

Role: STUDY_CHAIR

Guthrie Cancer Center at Guthrie Clinic Sayre

Karl H. Hanson, MD

Role: STUDY_CHAIR

Saint Luke's Cancer Institute at Saint Luke's Hospital

Richard A. Larson, MD

Role: STUDY_CHAIR

University of Chicago

Chaim Shustik, MD

Role: STUDY_CHAIR

Royal Victoria Hospital - Montreal

Pieter Sonneveld, MD, PhD

Role: STUDY_CHAIR

University Medical Center Rotterdam at Erasmus Medical Center

Locations

University of California San Diego Cancer Center

La Jolla, California, United States

UCSF Cancer Center and Cancer Research Institute

San Francisco, California, United States

CCOP - Christiana Care Health Services

Wilmington, Delaware, United States

Walter Reed Army Medical Center

Washington D.C., District of Columbia, United States

CCOP - Mount Sinai Medical Center

Miami Beach, Florida, United States

University of Chicago Cancer Research Center

Chicago, Illinois, United States

Holden Comprehensive Cancer Center at The University of Iowa

Iowa City, Iowa, United States

Marlene & Stewart Greenebaum Cancer Center, University of Maryland

Baltimore, Maryland, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

University of Massachusetts Memorial Medical Center

Worcester, Massachusetts, United States

University of Minnesota Cancer Center

Minneapolis, Minnesota, United States

Ellis Fischel Cancer Center - Columbia

Columbia, Missouri, United States

Barnes-Jewish Hospital

St Louis, Missouri, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

CCOP - Southern Nevada Cancer Research Foundation

Las Vegas, Nevada, United States

Norris Cotton Cancer Center

Lebanon, New Hampshire, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

CCOP - North Shore University Hospital

Manhasset, New York, United States

Schneider Children's Hospital at North Shore

Manhasset, New York, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

New York Presbyterian Hospital - Cornell Campus

New York, New York, United States

Mount Sinai Medical Center, NY

New York, New York, United States

State University of New York - Upstate Medical University

Syracuse, New York, United States

CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.

Syracuse, New York, United States

Lineberger Comprehensive Cancer Center, UNC

Chapel Hill, North Carolina, United States

Duke Comprehensive Cancer Center

Durham, North Carolina, 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

Rhode Island Hospital

Providence, Rhode Island, United States

University of Tennessee, Memphis Cancer Center

Memphis, Tennessee, United States

Vermont Cancer Center

Burlington, Vermont, United States

MBCCOP - Massey Cancer Center

Richmond, Virginia, United States

CancerCare Manitoba

Winnipeg, Manitoba, Canada

Moncton Hospital

Moncton, New Brunswick, Canada

Cancer Care Ontario-London Regional Cancer Centre

London, Ontario, 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

Centre Hospitalier de l'Universite de Montreal

Montreal, Quebec, Canada

McGill University

Montreal, Quebec, Canada

Countries

United States; Canada

References

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 refractory multiple myeloma (E1A95): a trial of the Eastern Cooperative Oncology Group. Cancer. 2006 Feb 15;106(4):830-8. doi: 10.1002/cncr.21666.

Reference Type: RESULT

PMID: 16419071 (View on PubMed)

Other Identifiers

E-1A95

Identifier Type: -

Identifier Source: secondary_id

CAN-NCIC-MY8

Identifier Type: -

Identifier Source: secondary_id

CLB-E1A95

Identifier Type: -

Identifier Source: secondary_id

EORTC-E1A95/06971

Identifier Type: -

Identifier Source: secondary_id

SWOG-E1A95

Identifier Type: -

Identifier Source: secondary_id

CAN-NCIC-J1A95

Identifier Type: -

Identifier Source: secondary_id

CLB-9596

Identifier Type: -

Identifier Source: secondary_id

SWOG-S1A95

Identifier Type: -

Identifier Source: secondary_id

CDR0000065178

Identifier Type: -

Identifier Source: org_study_id