Phase I/IB Trial of Eribulin and Everolimus in Patients With Triple Negative Metastatic Breast Cancer
Overview
- Phase
- Phase 1
- Intervention
- everolimus
- Conditions
- Estrogen Receptor Negative
- Sponsor
- City of Hope Medical Center
- Enrollment
- 27
- Locations
- 3
- Primary Endpoint
- Number of Participants Experiencing a Dose Limiting Toxicity (DLT) (Phase I) and the Recommended Phase IB Dose (RP2D)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Treatment (everolimus, eribulin mesylate)
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.
Intervention: everolimus
Treatment (everolimus, eribulin mesylate)
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.
Intervention: eribulin mesylate
Treatment (everolimus, eribulin mesylate)
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.
Intervention: pharmacological study
Treatment (everolimus, eribulin mesylate)
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.
Intervention: laboratory biomarker analysis
Outcomes
Primary Outcomes
Number of Participants Experiencing a Dose Limiting Toxicity (DLT) (Phase I) and the Recommended Phase IB Dose (RP2D)
Time Frame: First cycle on treatment, up to 21 days
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.
Number of Subjects With Disease Progression Using the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (Phase IB)
Time Frame: Up to 2 years
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.
Secondary Outcomes
- Median Overall Survival (Phase IB)(From start of treatment to death due to any cause, assessed up to 2 years)
- Number of Participants With Grade 3 or Higher Toxicities (Phase IB)(On treatment, 21 days per cycle up to 2 years)
- Best Response Using the RECIST (Phase IB)(Up to 2 years)
- Median Progression Free Survival (Phase IB)(Form the date treatment begins until the first date on which recurrence, progression, or death due to any cause, assessed up to 2 years)