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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2015 by City of Hope Medical Center
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT02120469
First received: April 18, 2014
Last updated: August 25, 2015
Last verified: August 2015
  Purpose

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.


Condition Intervention Phase
Estrogen Receptor Negative
HER2/Neu Negative
Progesterone Receptor-negative
Stage IV Breast Cancer
Triple-negative Breast Carcinoma
Breast Adenocarcinoma
Drug: everolimus
Drug: eribulin mesylate
Other: pharmacological study
Other: laboratory biomarker analysis
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/IB Trial of Eribulin and Everolimus in Patients With Triple Negative Metastatic Breast Cancer

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • Dose limiting toxicity (DLT) defined as an 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 (Phase I) [ Time Frame: 21 days ] [ Designated as safety issue: Yes ]
    Tables will be created to summarize all toxicities and side effects by dose, course, organ and severity. Rates and associated 95% confidence limits will be estimated for dose-limiting toxicities at the RP2D.

  • Event-free survival using the Response Evaluation Criteria in Solid Tumors (RECIST) (Phase IB) [ Time Frame: At 4 months ] [ Designated as safety issue: No ]
    Rates and associated 95% confidence limits will be estimated. Kaplan Meier methods will be used to estimate the median and 95% confidence limits. Descriptive statistics will be provided for the patient demographics.


Secondary Outcome Measures:
  • Incidence of adverse events, graded according to the NCI CTCAE v4.0 (Phase IB) [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
    Tables will be created to summarize all toxicities and side effects by dose, course, organ and severity. Rates and associated 95% confidence limits will be estimated.

  • Response rate using the RECIST (Phase IB) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Rates and associated 95% confidence limits will be estimated.

  • Overall survival (Phase IB) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Kaplan Meier methods will be used to estimate the median and 95% confidence limits. Descriptive statistics will be provided for the patient demographics.

  • PK parameters of everolimus in blood samples [ Time Frame: Baseline, 1, 2, 4, 6, and 24 hours on day 1 of course 1 and 2 ] [ Designated as safety issue: No ]
    Non-compartmental PK analyses of everolimus will be performed using statistical moment theory and according to the rule of linear trapezoids and statistical moment theory. Everolimus PK parameters (maximum concentration, trough concentration, area under the curve [AUC], oral clearance, and half-life) will be determined for each individual and a two-stage approach will be used to describe the study population PK. Descriptive statistics will be provided for the PK parameters.

  • PK parameters of eribulin mesylate in plasma samples [ Time Frame: Baseline, 5, 10, 15, and 30 minutes, 1, 2, 4, 6, 24, 48, 72, and 167 hours on day 1 of course 2 ] [ Designated as safety issue: No ]
    Compartmental analyses will be performed for eribulin data. Secondary pharmacokinetic parameters (e.g. CLsys, Volume of distribution [Vd], half-life [t1/2], and area under the curve [AUC 0->infinity) will be determined for each individual and a two-stage approach will be used to describe the study population pharmacokinetics. Population means and standard deviations will be compared to values obtained from patients treated on trials of single agent eribulin mesylate.

  • Progression free survival (Phase Ib) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Kaplan Meier methods will be used to estimate the median and 95% confidence limits.


Estimated Enrollment: 45
Study Start Date: October 2014
Estimated Primary Completion Date: February 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: everolimus
Given PO
Other Names:
  • 42-O-(2-hydroxy)ethyl rapamycin
  • Afinitor
  • RAD001
Drug: eribulin mesylate
Given IV
Other Names:
  • B1939
  • E7389
  • ER-086526
  • halichrondrin B analog
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies
Other: laboratory biomarker analysis
Optional correlative studies

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 periodically.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with histologically-confirmed stage IV adenocarcinoma TNBC
  • Patients must have had prior treatment with anthracyclines and/or taxanes (resistant) including adjuvant or neoadjuvant therapy
  • Patients with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10 mm with spiral computed tomography (CT) scan; for patients with bone only metastases, there must be at least one measurable predominant lytic bone lesion
  • Patients with chemotherapy for metastatic disease (patients with 0-4 prior lines of chemotherapy for metastatic breast cancer [MBC]); this includes prior everolimus therapy
  • 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
  • Total bilirubin less =< to 1 times upper limit of normal (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

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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02120469

Locations
United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Yuan Yuan, MD, PhD    800-826-4673    YYuan@coh.org   
Principal Investigator: Yuan Yuan         
South Pasadena Cancer Center Recruiting
South Pasadena, California, United States, 91030
Contact: Stephen Koehler, MD    626-396-2900      
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: Yuan Yuan, MD, PhD City of Hope Medical Center
  More Information

No publications provided

Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT02120469     History of Changes
Other Study ID Numbers: 14036, NCI-2014-00844, 14036
Study First Received: April 18, 2014
Last Updated: August 25, 2015
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Adenocarcinoma
Carcinoma
Skin Diseases
Everolimus
Sirolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on September 02, 2015