Iododoxorubicin in Treating Patients With Primary Systemic Amyloidosis

Study Overview
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Brief Summary
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Iododoxorubicin may dissolve protein deposits and be an effective treatment for primary systemic amyloidosis. Phase I trial to determine the effectiveness of iododoxorubicin in treating patients who have primary systemic amyloidosis

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of iododoxorubicin in patients with primary systemic amyloidosis. SECONDARY OBJECTIVES: I. Determine the safety, especially cardiac safety, of this drug in these patients. II. Determine the survival rate of patients treated with this drug. III. Determine, preliminarily, the clinical efficacy of this drug in these patients. IV. Determine the pharmacokinetics of this drug in these patients. OUTLINE: This is a dose-escalation study. Patients receive iododoxorubicin IV over 15 minutes on days 1, 8, 15, and 22. Treatment repeats every 12 weeks for a total of 4 courses or a cumulative dose of 400 mg/m^2 in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of iododoxorubicin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Patients are followed at 3 months.

Official Title
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Phase I Trial of 4'-IODO-4'-Deoxydoxorubicin in Primary Amyloidosis (AL)

Conditions
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Primary Systemic Amyloidosis

Intervention / Treatment
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* Drug: 4'-iodo-4'-deoxydoxorubicin
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histochemically confirmed amyloidosis by polarizing microscopy of greenbirefringent material in Congo red-stained tissue specimens At least one of the following: Demonstrable M-protein in serum or urine Clonal population of plasma cells in bone marrow Immunohistochemical stain with anti-light chain antisera of amyloid fibrils Symptomatic organ involvement, including liver involvement, mild cardiac involvement, renal involvement, grade 1 or 2 peripheral neuropathy, or soft tissue involvement (including tongue) No purpura or carpal tunnel syndrome as sole manifestation of disease No clinically overt multiple myeloma defined as monoclonal bone marrow platelet concentration greater than 20% and at least one of the following: Bone lesions Anemia Hypercalcemia Performance status - ECOG 0-3 (3 allowed only if related to muscular infiltration by amyloid or peripheral neuropathy) Platelet count at least 100,000/mm^3 Absolute neutrophil count at least 1,500/mm^3 Total bilirubin no greater than 2.0 mg/dL Direct bilirubin no greater than 1.0 mg/dL Alkaline phosphatase no greater than 4 times upper limit of normal (ULN) AST or ALT no greater than 3 times ULN Creatinine clearance at least 40 mL/min Ejection fraction at least 50% by echocardiogram No New York Heart Association class III or IV heart disease No enzyme-documented myocardial infarction within the past 3 years No chronic atrial fibrillation No grade 2 or 3 atrioventricular block (Mobitz type I allowed) No sustained (greater than 30 seconds) ventricular tachycardia, more than 1 episode of non-sustained ventricular tachycardia (3 consecutive ventricular beats), or frequent (more than 20 in 24 hours) ventricular pairs by 24-hour ambulatory electrocardiographic monitoring No intraventricular septum greater than 16 mm by echocardiogram Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No uncontrolled infection No other active malignancy except nonmelanoma skin cancer or cervical cancer No psychiatric illness or social situation that would preclude study No severe diarrhea (greater than grade 3) that is not controllable with medication or that requires total parenteral nutrition More than 4 weeks since prior interferon alfa No concurrent immunotherapy More than 4 weeks since prior melphalan or other alkylating agents No prior anthracycline exposure greater than 120 mg/m^2 Recovered from prior chemotherapy No other concurrent chemotherapy More than 4 weeks since prior high-dose dexamethasone No concurrent radiotherapy No concurrent investigational ancillary therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (iododoxorubicin)<br>Patients receive iododoxorubicin IV over 15 minutes on days 1, 8, 15, and 22. Treatment repeats every 12 weeks for a total of 4 courses or a cumulative dose of 400 mg/m^2 in the absence of disease progression or unacceptable toxicity. | Drug: 4'-iodo-4'-deoxydoxorubicin<br>* Given IV<br>* Other names: iododoxorubicin;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of IDOX defined as the highest safely-tolerated dose where =< 1 patient experiences DLT with the next higher dose having at least 2 patients who experience DLT | The number and severity of toxicity incidents will indicate the level of tolerance of IDOX in the treatment of primary amyloidosis. Non-hematologic toxicities will be evaluated via the ordinal CTC standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir and percent change from baseline values) as well as categorization via CTC standard toxicity grading. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Laboratory correlates | Descriptive statistics and simple scatterplots will form the basis of presentation of these data. Correlations between these laboratory values and other outcome measures will be carried out by standard parametric and non-parametric correlation procedures (Pearson's and Spearman's coefficients). Prerequisite normality testing of these data will be carried out via standard Shapiro and Wilk (25) testing. | Up to 3 months post treatment |