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

Sponsor

Eastern Cooperative Oncology Group (Other)

Overall Status

Completed

CT.gov ID

NCT00002878

Collaborator

National Cancer Institute (NCI) (NIH), Southwest Oncology Group (Other), Cancer and Leukemia Group B (Other), NCIC Clinical Trials Group (Other), European Organisation for Research and Treatment of Cancer - EORTC (Other)

Locations

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Drug: dexamethasone Drug: doxorubicin hydrochloride Drug: valspodar Drug: vincristine sulfate	Phase 3

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.

Study Design

Study Type:

Interventional

Allocation:

Randomized

Primary Purpose:

Treatment

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

Study Start Date :

Mar 1, 1997

Actual Primary Completion Date :

Apr 1, 2003

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California San Diego Cancer Center	La Jolla	California	United States	92093-0658
2	UCSF Cancer Center and Cancer Research Institute	San Francisco	California	United States	94143-0128
3	CCOP - Christiana Care Health Services	Wilmington	Delaware	United States	19899
4	Walter Reed Army Medical Center	Washington	District of Columbia	United States	20307-5000
5	CCOP - Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
6	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637-1470
7	Holden Comprehensive Cancer Center at The University of Iowa	Iowa City	Iowa	United States	52242-1009
8	Marlene & Stewart Greenebaum Cancer Center, University of Maryland	Baltimore	Maryland	United States	21201
9	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
10	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts	United States	01655
11	University of Minnesota Cancer Center	Minneapolis	Minnesota	United States	55455
12	Ellis Fischel Cancer Center - Columbia	Columbia	Missouri	United States	65203
13	Barnes-Jewish Hospital	Saint Louis	Missouri	United States	63110
14	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-3330
15	CCOP - Southern Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
16	Norris Cotton Cancer Center	Lebanon	New Hampshire	United States	03756-0002
17	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
18	CCOP - North Shore University Hospital	Manhasset	New York	United States	11030
19	Schneider Children's Hospital at North Shore	Manhasset	New York	United States	11030
20	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10021
21	New York Presbyterian Hospital - Cornell Campus	New York	New York	United States	10021
22	Mount Sinai Medical Center, NY	New York	New York	United States	10029
23	State University of New York - Upstate Medical University	Syracuse	New York	United States	13210
24	CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.	Syracuse	New York	United States	13217
25	Lineberger Comprehensive Cancer Center, UNC	Chapel Hill	North Carolina	United States	27599-7295
26	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
27	CCOP - Southeast Cancer Control Consortium	Winston-Salem	North Carolina	United States	27104-4241
28	Comprehensive Cancer Center at Wake Forest University	Winston-Salem	North Carolina	United States	27157-1082
29	Rhode Island Hospital	Providence	Rhode Island	United States	02903
30	University of Tennessee, Memphis Cancer Center	Memphis	Tennessee	United States	38103
31	Vermont Cancer Center	Burlington	Vermont	United States	05401-3498
32	MBCCOP - Massey Cancer Center	Richmond	Virginia	United States	23298-0037
33	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R3E 0V9
34	Moncton Hospital	Moncton	New Brunswick	Canada	E1C 6ZB
35	Cancer Care Ontario-London Regional Cancer Centre	London	Ontario	Canada	N6A 4L6
36	Hotel Dieu Health Sciences Hospital - Niagara	St. Catharines	Ontario	Canada	L2R 5K3
37	Toronto General Hospital	Toronto	Ontario	Canada	M5G 2C4
38	Cancer Care Ontario - Windsor Regional Cancer Centre	Windsor	Ontario	Canada	N8W 2X3
39	Centre Hospitalier de l'Universite de Montreal	Montreal	Quebec	Canada	H2L-4M1
40	McGill University	Montreal	Quebec	Canada	H2W 1S6

Sponsors and Collaborators

Eastern Cooperative Oncology Group
National Cancer Institute (NCI)
Southwest Oncology Group
Cancer and Leukemia Group B
NCIC Clinical Trials Group
European Organisation for Research and Treatment of Cancer - EORTC

Investigators

Study Chair: William R. Friedenberg, MD, Guthrie Cancer Center at Guthrie Clinic Sayre
Study Chair: Karl H. Hanson, MD, Saint Luke's Cancer Institute at Saint Luke's Hospital
Study Chair: Richard A. Larson, MD, University of Chicago
Study Chair: Chaim Shustik, MD, Royal Victoria Hospital - Montreal
Study Chair: Pieter Sonneveld, MD, PhD, University Medical Center Rotterdam at Erasmus Medical Center