Eribulin Mesylate and Everolimus in Treating Patients With Triple-Negative Metastatic Breast Cancer

Study Overview
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Brief Summary
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This phase I/IB trial studies the side effects and best dose of eribulin mesylate and everolimus in treating patients with breast cancer that does not have estrogen receptors, progesterone receptors, or large amounts of human epidermal growth factor receptor 2 protein (triple-negative) and has spread to other places in the body (metastatic). Eribulin mesylate and everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the safety and tolerability of everolimus and eribulin (eribulin mesylate), and determine the recommended Phase IB dose (RP2D) of the drug combination in patients with resistant metastatic triple negative breast cancer (TNBC). (Phase I) II. To evaluate the event-free survival (EFS) rate for patients with resistant metastatic TNBC at the RP2D of everolimus and eribulin to determine if the drug combination is worthy of further study. (Phase IB) SECONDARY OBJECTIVES: I. To determine response rate in patients with resistant metastatic TNBC. (Phase IB) II. To determine overall survival (OS) in patients with resistant metastatic TNBC. (Phase IB) III. To determine toxicity in patients with resistant metastatic TNBC. (Phase IB) IV. To determine pharmacokinetics (PK) for everolimus and eribulin in patients with resistant metastatic TNBC. (Phase IB) V. To collect blood, skin punch biopsies, and tumor biopsies before and after treatment from all patients and perform proteomic analysis to determine the level of inhibition of the phosphatidylinositol 3 kinase (PI3K) pathway in tumor cells versus non-therapeutic targets. (Phase IB) OUTLINE: This is a dose-escalation study of everolimus. Patients receive everolimus orally (PO) once daily (QD) on days 1-21 and eribulin mesylate intravenously (IV) on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 21 days and then periodically.

Official Title
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Phase I/IB Trial of Eribulin and Everolimus in Patients With Triple Negative Metastatic Breast Cancer

Conditions
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Progesterone Receptor-negative, Stage IV Breast Cancer, Estrogen Receptor Negative, HER2/Neu Negative, Triple-negative Breast Carcinoma

Intervention / Treatment
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* Drug: everolimus
* Drug: eribulin mesylate
* Other: pharmacological study
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically-confirmed stage IV TNBC (patients who had metastatic disease within 6 months of lumpectomy or mastectomy for treatment of TNBC may be excused from repeat biopsy) Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion; newly obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on day 1; subjects for whom newly obtained samples cannot be provide (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the study principle investigator (PI) Patients must have had prior treatment with anthracyclines and/or taxanes (resistant) or platinum including adjuvant or neoadjuvant therapy Both measurable as well as non-measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, will be allowed Patients with chemotherapy for metastatic disease (patients with 0-3 prior lines of chemotherapy for metastatic breast cancer [MBC]) Life expectancy of >= 3 months Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2 Hemoglobin >= 9.0 g/dl Absolute neutrophil count (ANC) >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Creatinine =< 1.5 times the upper limit of normal (ULN) Total bilirubin less =< to 1 times ULN Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< to 2.5 times the ULN if no liver metastases; for patients with known liver metastases, AST and ALT must be =< to 5 times the ULN Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for up to 8 weeks after ending treatment; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately Ability to understand and the willingness to sign a written informed consent document Be willing to use dexamethasone mouthwash as directed Exclusion Criteria: Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events (AEs) due to agents administered > 3 weeks prior to entering the study Patients may not be receiving any other investigational agents Patients with symptomatic brain metastases are excluded from this clinical trial Uncontrolled current illness including, but not limited to, ongoing or active infection (> grade 2 based on the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version [v]4.0), symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, cardiac ventricular arrhythmias requiring anti-arrhythmic therapy, or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women Prior eribulin use Patients with human immunodeficiency virus (HIV), chronic hepatitis B, or chronic hepatitis C (known from the existing medical record) Concomitant use with strong or moderate cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4)/P-glycoprotein (PgP) inhibitors and CYP3A4/PgP inducers Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must use highly effective methods of contraception during the study and 8 weeks after ending treatment; highly effective contraception methods include combination of any two of the following: Use of oral, injected or implanted hormonal methods of contraception or Placement of an intrauterine device (IUD) or intrauterine system (IUS) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository Total abstinence Male/female sterilization Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment Noncompliant with oral medication and/or dexamethasone mouth wash

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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 (everolimus, eribulin mesylate)<br>Patients receive everolimus PO QD on days 1-21 and eribulin mesylate IV on days 1 and 8. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: everolimus<br>* Given PO<br>* Other names: RAD001;Drug: eribulin mesylate<br>* Given IV<br>* Other names: halichrondrin B analog;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: laboratory biomarker analysis<br>* Optional correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing a Dose Limiting Toxicity (DLT) (Phase I) and the Recommended Phase IB Dose (RP2D) | DLT defined as an adverse event (AE) or abnormal laboratory value as at least possibly related to the study medication and meets any of the criteria per NCI CTCAE v4.0. | First cycle on treatment, up to 21 days | 
| Number of Subjects With Disease Progression Using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Phase IB) | Progression determined using response evaluation criteria in solid tumors (RECIST) version 1.1 or showed clinical progression. RECIST criteria for progression includes: At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started (including the baseline scan if that is the smallest), and at least a 5mm increase or the appearance of new lesions. Rates and associated 95% confidence limits will be estimated. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Grade 3 or Higher Toxicities (Phase IB) | Will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Rates and associated 95% exact Clopper and Pearson binomial confidence limits will be estimated for grade 3 or higher toxicities attributed to eribulin mesylate or everolimus. | On treatment, 21 days per cycle up to 2 years | 
| Best Response Using the RECIST (Phase IB) | RECIST Criteria: Complete Response (CR): Disappearance of all target lesions. Lymph node CR is when the lymph node has decreased to less than 10mm in the short axis. Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started (including the baseline scan if that is the smallest), and at least a 5mm increase or the appearance of new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started. | Up to 2 years | 
| Median Overall Survival (Phase IB) | Kaplan Meier methods will be used to estimate the median and 95% confidence limits across all dose levels per protocol plan. | From start of treatment to death due to any cause, assessed up to 2 years | 
| Median Progression Free Survival (Phase IB) | Kaplan Meier methods will be used to estimate the median and 95% confidence limits over all dose levels per protocol plan. | Form the date treatment begins until the first date on which recurrence, progression, or death due to any cause, assessed up to 2 years |