Brostallicin in Treating Patients With Recurrent or Refractory Multiple Myeloma

A Phase I/II Study of the Safety and Efficacy of Brostallicin (PNU-166196A) in Adult Patients With Multiple Myeloma That Has Progressed on Prior Chemotherapy

RATIONALE: Drugs used in chemotherapy such as brostallicin use different ways to stop cancer cells from dividing so they stop growing or die.

PURPOSE: Phase I/II trial to study the effectiveness of brostallicin in treating patients who have recurrent or refractory multiple myeloma.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma and Plasma Cell Neoplasm
• Intervention / Treatment: Drug: brostallicin

Detailed Description

OBJECTIVES:

• Determine the objective tumor response rate (confirmed complete response and confirmed partial response) of brostallicin in patients with recurrent or refractory multiple myeloma.
• Determine the maximum tolerated dose of this drug in these patients.
• Determine the time to and duration of response, time to treatment failure, time to tumor progression, and survival in patients treated with this drug.
• Determine the safety and tolerability of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.
• Correlate baseline whole blood levels and activity of glutathione with clinical outcome in patients treated with this drug.

OUTLINE: This is an open-label, multicenter, dose-escalation study.

• Phase I: Patients receive brostallicin IV over 10-30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of brostallicin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Additional patients are accrued and treated at the MTD of brostallicin as in phase I.

Patients are followed every 2 months.

PROJECTED ACCRUAL: A total of 23-52 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106-5065
      • Ireland Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Confirmed diagnosis of multiple myeloma based on prior or current demonstration of the following criteria*:

  • Major criteria:

    • Plasmacytoma on tissue biopsy
    • Bone marrow plasmacytosis with at least 30% plasma cells
    • Monoclonal globulin spike on serum electrophoresis exceeding 3.5 g/dL for IgG peaks or 2.0 g/dL for IgA peaks; greater than 1,000 mg/24hr of kappa or gamma light chain excretion on urine electrophoresis in the absence of amyloidosis

  • Minor criteria:

    • Bone marrow plasmacytosis with 10% to 30% plasma cells
    • Monoclonal globulin spike present but less than levels in major criterion III above
    • Lytic bone lesions
    • Residual normal immunoglobulin M (IgM) no greater than 0.5 g/dL, IgA no greater than 0.1 g/dL, or IgG no greater than 0.6 g/dL NOTE: *Diagnosis of multiple myeloma requires a minimum of 1 major and 1 minor criterion (I and a together is not sufficient; must be I and b, I and c, I and d; II and b, II and c, II and d; III and a, III and c, III and d) or 3 minor criteria that must include a and b (a, b, and c; a, b, and d)

• Measurable disease defined by 1 of the following values:

  • Serum myeloma (M) protein (IgG or IgA) level greater than 1.0 g/dL
  • Urine M protein (light chain disease) at least 300 mg/24hr
  • Soft tissue plasmacytoma with bidimensional measurement at least 20 x 20 mm (10 x 10 mm if spiral CT scan is used)
• Must have progressed during or within 12 months of discontinuing prior myelosuppressive chemotherapy (e.g., vincristine, doxorubicin, and dexamethasone (VAD) or melphalan) OR not responded after 2 courses of prior myelosuppressive chemotherapy
• No indolent or smoldering myeloma or localized plasmacytoma
• No known brain or leptomeningeal disease unless such lesions were previously irradiated, are currently not being treated with corticosteroids, and are associated with no clinical symptoms

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Eastern Cooperative Oncology Group (ECOG) 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• Absolute neutrophil count at least 1,500/mm^3 (at least 1,000/mm^3 if neutropenia due to replacement of the normal bone marrow cells by myeloma cells)
• Platelet count at least 100,000/mm^3 (at least 50,000/mm^3 if thrombocytopenia due to replacement of the normal bone marrow cells by myeloma cells)
• Hemoglobin at least 8.0 g/dL (no transfusion allowed)
• No hyperviscosity syndrome

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• Serum glutamate oxaloacetate transaminase (SGOT) no greater than 2.5 times ULN
• Alkaline phosphatase no greater than 2.5 times ULN

Renal

• Creatinine no greater than 3.0 times ULN
• Calcium no greater than 12 mg/dL

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and sampling for study analysis
• HIV negative
• No other malignancy within the past 5 years except adequately treated nonmelanoma skin cancer or carcinoma in situ of the cervix
• No AIDS-related illness
• No active infectious process or other severe concurrent disease that would make the patient inappropriate for study entry
• No mental incapacity or psychiatric illness that would preclude giving informed consent or completing follow-up

PRIOR CONCURRENT THERAPY:

Biologic therapy

• See Chemotherapy
• No concurrent anticancer biological response modifiers
• No concurrent immunotherapy
• No concurrent sargramostim (GM-CSF)

Chemotherapy

• See Disease Characteristics
• More than 2 years since prior high-dose chemotherapy with autologous bone marrow transplantation or stem cell support
• More than 4 weeks since prior myelosuppressive chemotherapy
• No other concurrent anticancer chemotherapy

Endocrine therapy

• See Disease Characteristics
• No concurrent anticancer hormonal therapy

• No concurrent chronic steroids

  • Acute pulse dosing required for treatment of a concurrent medical condition is allowed, provided treatment duration is no greater than 2 weeks
• No concurrent corticosteroids (e.g., dexamethasone)

Radiotherapy

• More than 14 days since prior radiotherapy
• No prior radiotherapy to more than 25% of bone marrow
• No plans for radiotherapy within the next 6 months
• Concurrent palliative radiotherapy for skeletal pain allowed

Surgery

• More than 14 days since prior surgery
• No plans for surgery within the next 6 months

Other

• Acute toxic effects of prior therapy (except for alopecia and neurotoxicity) must have resolved to grade 0, 1, or the patient's baseline

  • Treatment-related neurotoxicity must have resolved to the patient's baseline, not to exceed grade 2
• Chronic bisphosphonates for bone pain allowed only for maintenance doses
• More than 2 weeks since prior nonmyelosuppressive antimyeloma therapy
• More than 2 weeks since prior macrolide antibiotics
• No other concurrent investigational agents
• No concurrent macrolide antibiotics
• No concurrent participation in another treatment clinical study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Brostallicin

Drug: brostallicin; Patients receive brostallicin IV over 10-30 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of brostallicin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Tumor Response Rate	• Determine the objective tumor response rate (confirmed complete response and confirmed partial response) of brostallicin in patients with recurrent or refractory multiple myeloma	1 year

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall Survival	1 year
Time to tumor progression	1 year
Duration of Response	1 year
Maximum Tolerated Dose of brostallicin	1 year
Time to response	1 year
Time to treatment failure	1 year

Collaborators and Investigators

• Sponsor: Case Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Hillard M. Lazarus, MD, Case Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: December 1, 2002
• Primary Completion (Actual): March 1, 2003
• Study Completion (Actual): April 1, 2004

Study Registration Dates

• First Submitted: May 6, 2003
• First Submitted That Met QC Criteria: May 6, 2003
• First Posted (Estimate): May 7, 2003

Study Record Updates

• Last Update Posted (Estimate): January 16, 2014
• Last Update Submitted That Met QC Criteria: January 14, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: stage III multiple myeloma; refractory multiple myeloma
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma
• Other Study ID Numbers: PHAR1A02; CWRU-PHAR-1A02; PHARMACIA-196-ONC-0100-006