Clinical trial NCT00060203: Brostallicin in Treating Patients With Recurrent or Refractory Multiple Myeloma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma and Plasma Cell Neoplasm
Keywords: stage III multiple myeloma
refractory multiple myeloma
Lead sponsor: Case Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-05-07
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Objective Tumor Response Rate
timeFrame: 1 year
Secondary outcomes:
measure: Maximum Tolerated Dose of brostallicin
timeFrame: 1 year
measure: Time to response
timeFrame: 1 year
measure: Duration of Response
timeFrame: 1 year
measure: Time to treatment failure
timeFrame: 1 year
measure: Time to tumor progression
timeFrame: 1 year
measure: Overall Survival
timeFrame: 1 year
Other outcomes:
Locations:
city: Cleveland
country: United States
facility: Ireland Cancer Center
state: Ohio
Study officials:
affiliation: Case Comprehensive Cancer Center
name: Hillard M. Lazarus, MD
role: STUDY_CHAIR
References: