Ixabepilone and Hydroxychloroquine in Treating Patients With Metastatic Breast Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as ixabepilone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Hydroxychloroquine may help ixabepilone work better by making tumor cells more sensitive to the drug. PURPOSE: This phase I/II trial is studying the side effects and best dose of ixabepilone given together with hydroxychloroquine and to see how well they work in treating patients with metastatic breast cancer.

Detailed Description
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OBJECTIVES: The primary objective of this study is to assess the antitumor activity, measured by tumor response rate, in patients who receive this regimen as a third-line treatment. (Phase II) Secondary To measure the duration of response for responding patients. To measure the time to progressive disease. To measure survival time. To characterize the quantitative and qualitative toxicities of this regimen in these patients. To develop pharmacodynamic markers for autophagy detection in patient specimens. To characterize the effects of hydroxychloroquine on autophagy in patients in vivo. To investigate whether the estrogen receptor, progesterone receptor, and/or HER2 status of breast tumors correlates with treatment response. OUTLINE: This is a multicenter, phase I dose-escalation study of ixabepilone followed by a phase II study. During the first course, patients receive ixabepilone IV over 3 hours on day 1 and oral hydroxychloroquine twice daily on days 3-21. On all subsequent courses, patients receive ixabepilone IV over 3 hours on day 1 and oral hydroxychloroquine twice daily on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed every 6 months.

Official Title
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Phase I/II Study of Ixabepilone in Combination With the Autophagy Inhibitor Hydroxychloroquine for the Treatment of Patients With Metastatic Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: hydroxychloroquine
* Drug: ixabepilone


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed breast cancer Histologic or cytologic elements can be established on metastatic tumor aspirate or biopsy Metastatic disease Measurable disease according to RECIST criteria Must have received 2 prior chemotherapy regimens for metastatic breast cancer Anthracycline-resistant (or treated with minimum cumulative doxorubicin dose of 240 mg/m^2 or epirubicin dose of 360 mg/m^2) and taxane-resistant disease Anthracycline resistance is defined as progression while on therapy or within 6 months in the adjuvant/neoadjuvant setting or 3 months in the metastatic setting Taxane resistance is defined as progression while on therapy or within 12 months in the adjuvant/neoadjuvant setting or 4 months in the metastatic setting Hormone receptor status known No known CNS metastases or previously treated and now stable CNS metastases PATIENT CHARACTERISTICS: Menopausal status not specified ECOG performance status 0-2 ANC ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 9 g/dL Total bilirubin ≤ upper limit of normal (ULN) If patient has Gilbert's disease, then patient must have isolated hyperbilirubinemia (e.g., no other liver function test abnormality), with maximum bilirubin ≤ 2 times ULN AST and ALT ≤ 2.5 times ULN, independently of liver metastases Alkaline phosphatase ≤ 2.5 times ULN Creatinine ≤ 1.5 times ULN OR calculated creatinine clearance ≥ 60 mL/min Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No other active malignancy History of basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix within the past 3 years allowed provided patient has been treated with curative intent History of prior malignancy allowed provided patient has been treated with curative intent and has been disease free > 3 years None of the following conditions within the past 6 months: Myocardial infarction Stroke Symptomatic peripheral vascular disease No unstable angina or NYHA class II-IV congestive heart failure No history of psoriasis or porphyria No history of hypersensitivity to 4-aminoquinoline compound No retinal or visual field changes from prior 4-aminoquinoline-compound use No history of G6PD deficiency No GI pathology that would interfere with drug bioavailability No motor or sensory neuropathy ≥ grade 2 (NCI CTCAE) at study entry No serious uncontrolled medical disorder or active infection at study entry No rheumatoid arthritis or systemic lupus erythematosus requiring active treatment No history of HIV No history of any condition (social or medical) that, in the opinion of the investigator, might interfere with the patient's ability to comply with the protocol or pose additional or unacceptable risk to the patient PRIOR CONCURRENT THERAPY: See Disease Characteristics Prior radiation to tumor sites allowed provided: Radiation was completed ≥ 3 weeks prior to study treatment All radiation-related toxicities have resolved to ≤ grade 1 No more than 3 prior chemotherapy regimens in the metastatic setting No prior ixabepilone or another epothilone No concurrent highly active antiretroviral therapy No other concurrent hydroxychloroquine for treatment or prophylaxis of malaria No other concurrent anticancer investigational or commercial agents or therapies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Ixabepilone and hydroxychloroquine<br> | Drug: hydroxychloroquine<br>* Dose escalation from 200 mg po qd to 200 mg po bid.<br>Drug: ixabepilone<br>* Starting dose of 40 mg/m2 and can dose reduce to 32 mg/m2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response Rate | Overall Complete Response and Partial Response will be considered tumor response. Ixabepilone as a single agent (40 mg/m2 as an intravenous infusion every 3 weeks) was evaluated in a previous (Phase II) study in women with metastatic breast cancer and that the objective tumor response rate was 11.5%. In another(Phase III) study, Ixabepilone in combination with capecitabine resulted in an objective tumor response rate of 35%, compared to that of capecitabine alone (14%). Therefore, in the Phase II portion of the ixabepilone plus hydroxychloroquine combination treatment study, a tumor response rate of less than 15% will be deemed uninteresting. The target tumor response rate will be 35%. Due to uncertainty about the true response rate of ixabepilone plus hydroxychloroquine combination on this patient poupation, we also will consider a response rate of 30% to be encouraging. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response |  | 5 years | 
| Time to Progressive Disease |  | 5 years | 
| Survival Time |  | 5 years | 
| Pharmacodynamic Markers for Autophagy Detection |  | 2 years | 
| Effects of Hydroxychloroquine on Autophagy |  | 2 years | 
| Correlation of Estrogen Receptor, Progesterone Receptor and/or HER2 Status With Treatment Response |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage IV breast cancer, recurrent breast cancer, male breast cancer