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

This study has been completed.
Sponsor:
Collaborators:
Southwest Oncology Group
Cancer and Leukemia Group B
NCIC Clinical Trials Group
European Organisation for Research and Treatment of Cancer - EORTC
Information provided by:
Eastern Cooperative Oncology Group
ClinicalTrials.gov Identifier:
NCT00002878
First received: November 1, 1999
Last updated: August 28, 2013
Last verified: August 2013
  Purpose

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 Intervention Phase
Multiple Myeloma and Plasma Cell Neoplasm
Drug: dexamethasone
Drug: doxorubicin hydrochloride
Drug: valspodar
Drug: vincristine sulfate
Phase 3

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by Eastern Cooperative Oncology Group:

Study Start Date: March 1997
Primary Completion Date: April 2003 (Final data collection date for primary outcome measure)
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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00002878

  Show 40 Study Locations
Sponsors and Collaborators
Eastern Cooperative Oncology Group
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
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT00002878     History of Changes
Other Study ID Numbers: CDR0000065178, E-1A95, CAN-NCIC-MY8, CLB-E1A95, EORTC-E1A95/06971, SWOG-E1A95, CAN-NCIC-J1A95, CLB-9596, SWOG-S1A95
Study First Received: November 1, 1999
Last Updated: August 28, 2013
Health Authority: United States: Federal Government

Keywords provided by Eastern Cooperative Oncology Group:
refractory multiple myeloma

Additional relevant MeSH terms:
Neoplasms
Multiple Myeloma
Neoplasms, Plasma Cell
Plasmacytoma
Neoplasms by Histologic Type
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Liposomal doxorubicin
Doxorubicin
Vincristine
BB 1101
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Central Nervous System Agents

ClinicalTrials.gov processed this record on August 18, 2014