Hydroxychloroquine in Metastatic Estrogen Receptor-Positive Breast Cancer Progressing on Hormonal Therapy

Study Overview
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Brief Summary
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To determine the safety and tolerability of orally administered hydroxychloroquine with hormonal therapy. To assess the response rate of hydroxychloroquine in combination with hormonal therapy.

Detailed Description
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To determine the number of patients with adverse effects To assess the clinical response to the combination

Official Title
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Phase Ib/II Study of Hydroxychloroquine in Metastatic ER-Positive Breast Cancer Progressing on Hormonal Therapy

Conditions
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Estrogen Receptor Positive Breast Cancer

Intervention / Treatment
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* Drug: hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ 18 years of age with histologically confirmed, metastatic ER + breast cancer with clinical progression of disease (including radiographically stable disease with at least 50% increment of an elevated tumor marker by two measurements at least 2 weeks apart (this particular tumor marker will be used for disease status assessment in the study) on current hormonal therapy with PFS for at least 3 months. Karnofsky Performance Status (KPS) ≥70% and a life expectancy >3 months. Participants must have at least one target visceral lesion that allows for evaluation of tumor response or in the case of bone-only metastases, patients need to have a positive imaging study such as bone scan, magnetic resonance imaging (MRI) or positron emission tomography-computed tomography (PET-CT) or CT, and an elevated tumor marker at least twice as high as upper limit. Absolute neutrophil count > 1500 mm3, platelet count ≥ 80×109 L, hemoglobin ≥ 8.5 g/dL Creatinine clearance ≥ 30 mL/min, total bilirubin ≤ 2 mg/dL, AST/ALT ≤ 3 times the upper limit of normal range No remaining grade 2 or higher toxicity from prior cancer therapies unless judged to be clinically insignificant by the Principal Investigator At least two (2) weeks from prior major surgery Willingness to provide permission to biopsy one of the lesions if applicable before the study (All the patients are encouraged to have post-therapy biopsy upon progression of disease, but it is optional) as well as blood samples for pertinent laboratory studies Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically sterile) must be willing to use an acceptable non-hormonal contraceptive method (abstinence, or double barrier method) for the duration of the study and for 30 days following the last dose of study drug, and must have a negative urine or serum pregnancy test within 2 weeks prior to beginning treatment on this trial - Exclusion Criteria: On combination hormonal therapy with everolimus or any other investigational agent Patients have symptomatic untreated brain metastasis or leptomeningeal metastases or treated but still symptomatic requiring the use of steroid 18Jul2014 Protocol v3: ABC 01 Anti-Autophagy for Met Breast Cancer Page 4 of 16 Lymphangitic carcinomatosis involving ≥ 50% of the lungs; evidence of metastases involving more than one third of the liver on sonogram or computed tomography Lactating females Uncontrolled cardiac disease, congestive heart failure, angina or hypertension Myocardial infarction or unstable angina within 2 months of treatment Known human immunodeficiency virus (HIV) infection or chronic active Hepatitis B or C (patients are NOT required to be tested for the presence of such viruses prior to therapy on this protocol) Active clinically serious infection > CTCAE (version 4.03) Grade 2 Serious non-healing wound, ulcer, or bone fracture Concurrent psychiatric illness/social situations that would limit safety and compliance with study requirements Inability to complete informed consent process and adhere to the protocol treatment plan and follow-up requirements Currently receiving any other investigational therapeutic agents Patients with known glucose-6-phosphate dehydrogenase deficiency, porphyria, cirrhosis or any other conditions with potential significant known risks Patients with history of retinal damage

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: hydroxychloroquine plus hormonal therapy<br>Add hydroxychloroquine to the current hormonal therapy | Drug: hydroxychloroquine<br>* administration of hydroxychloroquine in combination with the current hormonal therapy<br>* Other names: Plaquenil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events as a Measure of the safety profile of orally administered hydroxychloroquine with hormonal therapy | Assess the dose-limiting side effects such as neutropenia, anemia, or thormbocytopenia, or non-hematologic side effects nausea, vomiting, diarrhea, or vision problems at the study dose | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The recommended phase 2 clinical dose (RP2D) of orally administered hydroxychloroquine with hormonal therapy | orally administered hydroxychloroquine with hormonal therapy | 18 months | 
| The pharmacodynamic (PD) profile of hydroxychloroquine with hormonal therapy | microtubule-associated protein 1 light chain 3 b (LC3b) level in the biopsy, WBCs in pre- and post-treatment samples | 18 months | 
| The anti-tumor activity of hydroxychloroquine with hormonal therapy with clinical benefit rate (CBR). Clinical benefits are defined as complete remission (CR), partial remission (PR) and stable disease (SD) | The anti-tumor activity of hydroxychloroquine with hormonal therapy with clinical benefit rate (CBR). Clinical benefits are defined as complete remission (CR), partial remission (PR) and stable disease (SD) | 18 months | 
| The disease-free survival (DFS) when adding hydroxychloroquine to hormonal therapy | The disease-free survival (DFS) when adding hydroxychloroquine to hormonal therapy | 18 months |