2-Methoxyestradiol in Treating Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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Phase I trial to study the effectiveness of 2-methoxyestradiol in treating patients who have advanced solid tumors. 2-methoxyestradiol may stop or slow the growth of solid tumors by stopping blood flow to the tumor

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the optimal biologic dose and/or maximum tolerated dose of 2-methoxyestradiol in patients with advanced solid tumors. II. Determine the qualitative and quantitative toxic effects of this drug in these patients. III. Determine the pharmacokinetics and metabolism of this drug in these patients. IV. Determine the biologic changes within the tumor of these patients when treated with this drug. V. Correlate the pharmacokinetics and toxicity of this drug in these patients. VI. Evaluate the biologic evidence of angiogenesis inhibition in patients receiving this drug. VII. Correlate genetic polymorphisms in cytochrome P450 and sulfotransferases isoforms with the pharmacokinetics of this drug. OUTLINE: This is a dose-escalation study. Patients receive oral 2-methoxyestradiol (2-ME) once daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of 2-ME until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Additional patients are treated at the MTD. Patients are followed for 3 months. PROJECTED ACCRUAL: A total of 42-60 patients will be accrued for this study within 19 months.

Official Title
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A Phase I and Pharmacologic Study of 2-Methoxyestradiol in Patients With Advanced Solid Tumors

Conditions
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Refractory Multiple Myeloma, Stage III Multiple Myeloma, Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: 2-methoxyestradiol
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed solid tumor that is clinically unresectable No known standard therapy that is potentially curative or definitely capable of extending life expectancy Patients with multiple myeloma may be enrolled to expansion cohort once the recommended phase II dose is established Tumor amenable to serial biopsy No bone metastases as only site of disease No CNS metastases Performance status - ECOG 0-2 At least 12 weeks Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hemoglobin at least 10.0 g/dL Bilirubin normal AST no greater than 2.5 times upper limit of normal (ULN) Creatinine no greater than 1.5 times ULN No New York Heart Association class III or IV heart disease Adequate oral intake No malabsorption syndrome No disease of terminal small bowel No dysphagia or other condition that would interfere with ability to swallow intact capsules No clinical contraindications (e.g., anticoagulant therapy) to biopsy No uncontrolled infection No seizure disorder Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception More than 4 weeks since prior biologic therapy More than 4 weeks since prior immunotherapy No concurrent immunotherapy More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered No concurrent chemotherapy No concurrent megestrol More than 4 weeks since prior radiotherapy No prior radiotherapy to more than 25% of bone marrow No concurrent radiotherapy No prior extensive resection of terminal small bowel No prior major resection of the stomach or proximal small bowel No other concurrent ancillary investigational 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 (2-methoxyestradiol)<br>Patients receive oral 2-methoxyestradiol (2-ME) once daily. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: 2-methoxyestradiol<br>* Given orally<br>* Other names: Panzem;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated dose (MTD) based on the incidence of dose-limiting toxicity (DLT) as assessed by Common Toxicity Criteria (CTC) version 2.0 | Presented primarily in a descriptive fashion. | 28 days | 
| Number of toxicity incidents as assessed by CTC version 2.0 | Frequency distributions and other descriptive measures will form the basis of the analysis of these variables. | Up to 3 months after completion of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biologic activity rate (BAR) | A rate will be calculated by dividing the number of patients with BA by the number of patients treated at the phase II recommended dose level. | At day 1 and at day 28 | 
| Angiogenesis inhibition via an ex vivo angiogenesis assay | The relationship between each marker and dose level will be explored descriptively. | At day 1 and at day 28 | 
| Number of responses | Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. | Up to 3 months after completion of treatment |