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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


Phase 3
18 Years
N/A
Not Enrolling
Both
Multiple Myeloma and Plasma Cell Neoplasm

Thank you

Trial Information

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


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.

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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Primary Purpose: Treatment

Principal Investigator

William R. Friedenberg, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Guthrie Cancer Center at Guthrie Clinic Sayre

Authority:

United States: Federal Government

Study ID:

CDR0000065178

NCT ID:

NCT00002878

Start Date:

March 1997

Completion Date:

Related Keywords:

  • Multiple Myeloma and Plasma Cell Neoplasm
  • refractory multiple myeloma
  • Neoplasms
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Plasmacytoma

Name

Location

Roswell Park Cancer InstituteBuffalo, New York  14263
Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
Walter Reed Army Medical CenterWashington, District of Columbia  20307-5000
University of Chicago Cancer Research CenterChicago, Illinois  60637
University of Massachusetts Memorial Medical CenterWorcester, Massachusetts  01655
University of Minnesota Cancer CenterMinneapolis, Minnesota  55455
Lineberger Comprehensive Cancer Center, UNCChapel Hill, North Carolina  27599-7295
Duke Comprehensive Cancer CenterDurham, North Carolina  27710
Rhode Island HospitalProvidence, Rhode Island  02903
Vermont Cancer CenterBurlington, Vermont  05401-3498
CCOP - Southern Nevada Cancer Research FoundationLas Vegas, Nevada  89106
University of California San Diego Cancer CenterLa Jolla, California  92093-0658
UCSF Cancer Center and Cancer Research InstituteSan Francisco, California  94115-0128
CCOP - Christiana Care Health ServicesWilmington, Delaware  19899
CCOP - Mount Sinai Medical CenterMiami Beach, Florida  33140
Marlene & Stewart Greenebaum Cancer Center, University of MarylandBaltimore, Maryland  21201
Ellis Fischel Cancer Center - ColumbiaColumbia, Missouri  65203
Barnes-Jewish HospitalSaint Louis, Missouri  63110
Norris Cotton Cancer CenterLebanon, New Hampshire  03756
CCOP - North Shore University HospitalManhasset, New York  11030
State University of New York - Upstate Medical UniversitySyracuse, New York  13210
CCOP - Southeast Cancer Control ConsortiumWinston-Salem, North Carolina  27104-4241
University of Tennessee, Memphis Cancer CenterMemphis, Tennessee  38103
MBCCOP - Massey Cancer CenterRichmond, Virginia  23298-0037
Mount Sinai Medical Center, NYNew York, New York  10029
New York Presbyterian Hospital - Cornell CampusNew York, New York  10021
Holden Comprehensive Cancer Center at The University of IowaIowa City, Iowa  52242-1009
Comprehensive Cancer Center at Wake Forest UniversityWinston-Salem, North Carolina  27157-1082
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
CCOP - Syracuse Hematology-Oncology Associates of Central New York, P.C.Syracuse, New York  13217
University of Nebraska Medical CenterOmaha, Nebraska  68198-3330
Schneider Children's Hospital at North ShoreManhasset, New York  11030