Clinical Trials /

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

NCT02120469

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Eribulin Mesylate and Everolimus in Treating Patients With Triple-Negative Metastatic Breast Cancer
  • Official Title: Phase I/IB Trial of Eribulin and Everolimus in Patients With Triple Negative Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: 14036
  • SECONDARY ID: NCI-2014-00844
  • SECONDARY ID: 14036
  • NCT ID: NCT02120469

Conditions

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

Interventions

DrugSynonymsArms
everolimus42-O-(2-hydroxy)ethyl rapamycin, Afinitor, RAD001Treatment (everolimus, eribulin mesylate)
eribulin mesylateB1939, E7389, ER-086526, halichrondrin B analogTreatment (everolimus, eribulin mesylate)

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (everolimus, eribulin mesylate)ExperimentalPatients 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.
  • everolimus
  • eribulin mesylate

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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity (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 (Phase I)
Time Frame:21 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence of adverse events, graded according to the NCI CTCAE v4.0 (Phase IB)
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Response rate using the RECIST (Phase IB)
Time Frame:Up to 2 years
Safety Issue:
Description:Rates and associated 95% confidence limits will be estimated.
Measure:Overall survival (Phase IB)
Time Frame:Up to 2 years
Safety Issue:
Description:Kaplan Meier methods will be used to estimate the median and 95% confidence limits.
Measure:PK parameters of everolimus in blood samples (Phase Ib)
Time Frame:Baseline, 1, 2, 4, 6, and 24 hours on day 1 of course 1 and 2
Safety Issue:
Description: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.
Measure:PK parameters of eribulin mesylate in plasma samples (Phase Ib)
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
Safety Issue:
Description:Compartmental analyses will be performed for eribulin mesylate 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.
Measure:Progression free survival (Phase Ib)
Time Frame:Up to 2 years
Safety Issue:
Description:Kaplan Meier methods will be used to estimate the median and 95% confidence limits.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:City of Hope Medical Center

Last Updated

May 24, 2021