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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

Phase 1/Phase 2
18 Years
Open (Enrolling)
Multiple Myeloma and Plasma Cell Neoplasm

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Trial Information

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


- Determine the objective tumor response rate (confirmed complete response and confirmed
partial response) of brostallicin in patients with recurrent or refractory multiple

- 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.

Inclusion Criteria


- 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

- 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 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

- 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



- 18 and over

Performance status

- ECOG 0-2

Life expectancy

- At least 12 weeks


- 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


- Bilirubin no greater than 1.5 times upper limit of normal (ULN)

- SGOT no greater than 2.5 times ULN

- Alkaline phosphatase no greater than 2.5 times ULN


- Creatinine no greater than 3.0 times ULN

- Calcium no greater than 12 mg/dL


- 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


Biologic therapy

- See Chemotherapy

- No concurrent anticancer biological response modifiers

- No concurrent immunotherapy

- No concurrent sargramostim (GM-CSF)


- 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)


- 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


- More than 14 days since prior surgery

- No plans for surgery within the next 6 months


- 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

Type of Study:


Study Design:

Masking: Open Label, Primary Purpose: Treatment

Principal Investigator

Hillard M. Lazarus, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Case Comprehensive Cancer Center


United States: Federal Government

Study ID:




Start Date:

December 2002

Completion Date:

Related Keywords:

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



Ireland Cancer Center Cleveland, Ohio  44106-5065