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

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.

Study Type: Interventional

Study Design: Treatment, Open Label

Study Primary Completion Date: August 2011

OBJECTIVES:

Primary - To determine the recommended phase II dose of ixabepilone and hydroxychloroquine in patients with metastatic breast cancer. (Phase I) - 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.

Intervention(s) in this Clinical Trial

• Drug: hydroxychloroquine
• Drug: ixabepilone

Primary Measures

• Recommended phase II dose of ixabepilone and hydroxychloroquine
  • Safety Issue?: No
• Tumor response rate assessed using RECIST criteria
  • Safety Issue?: No

Secondary Measures

• Duration of response
  • Safety Issue?: No
• Time to progressive disease
  • Safety Issue?: No
• Survival time
  • Safety Issue?: Yes
• Toxicity
  • Safety Issue?: Yes
• Pharmacodynamic markers for autophagy detection
  • Safety Issue?: No
• Effects of hydroxychloroquine on autophagy
  • Safety Issue?: No
• Correlation of estrogen receptor, progesterone receptor and/or HER2 status with treatment response
  • Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Cancer Institute of New Jersey

Overall Clinical Trial Officials and Contacts

Vassil Karantza-Wadsworth, MD Principal Investigator Cancer Institute of New Jersey  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00765765

Study ID Number: CDR0000615000

ClinicalTrials.gov Identifier: NCT00765765

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database