Ixabepilone and Hydroxychloroquine in Treating Patients With Metastatic Breast Cancer

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 Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: hydroxychloroquine; Drug: ixabepilone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Hamilton, New Jersey, United States, 08690
      • Cancer Institute of New Jersey At Hamilton
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ixabepilone and hydroxychloroquine	Drug: hydroxychloroquine; Dose escalation from 200 mg po qd to 200 mg po bid.; Drug: ixabepilone; Starting dose of 40 mg/m2 and can dose reduce to 32 mg/m2.

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: University of Medicine and Dentistry of New Jersey
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Vassil Karantza-Wadsworth, MD, Rutgers Cancer Institute of New Jersey

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: October 2, 2008
• First Submitted That Met QC Criteria: October 2, 2008
• First Posted (Estimated): October 3, 2008

Study Record Updates

• Last Update Posted (Actual): August 9, 2023
• Last Update Submitted That Met QC Criteria: July 31, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: stage IV breast cancer; recurrent breast cancer; male breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: CDR0000615000; P30CA072720 (U.S. NIH Grant/Contract); CINJ-040804 (Other Identifier: CINJ); 0220080205 (Other Identifier: Rutgers University IRB)