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Entinostat, Lapatinib Ditosylate and Trastuzumab in Treating Patients With Locally Recurrent or Distant Relapsed Metastatic Breast Cancer Previously Treated With Trastuzumab Only

NCT01434303

Description:

This phase I trial studies the side effects and best dose of entinostat when given together with lapatinib ditosylate and trastuzumab in treating patients with breast cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes or has recurred (come back) at or near the same place as the original (primary) tumor, usually after a period of time during which the cancer could not be detected. Entinostat and lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. Giving entinostat together with lapatinib ditosylate and trastuzumab may kill more tumor cells.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Entinostat, Lapatinib Ditosylate and Trastuzumab in Treating Patients With Locally Recurrent or Distant Relapsed Metastatic Breast Cancer Previously Treated With Trastuzumab Only
  • Official Title: Phase I and Phase I Trastuzumab Cohort Study of Entinostat, Lapatinib and Trastuzumab in Patients With HER2-Positive Metastatic Breast Cancer in Whom Trastuzumab Has Failed

Clinical Trial IDs

  • ORG STUDY ID: NCI-2011-03222
  • SECONDARY ID: NCI-2011-03222
  • SECONDARY ID: NCI 8871
  • SECONDARY ID: 2010-0842
  • SECONDARY ID: CDR0000710891
  • SECONDARY ID: 2010-0842
  • SECONDARY ID: 8871
  • SECONDARY ID: P30CA016672
  • SECONDARY ID: U01CA062461
  • SECONDARY ID: UM1CA186688
  • NCT ID: NCT01434303

Conditions

  • HER2/Neu Positive
  • Invasive Breast Carcinoma
  • Recurrent Breast Carcinoma
  • Stage IV Breast Cancer AJCC v6 and v7

Interventions

DrugSynonymsArms
EntinostatHDAC inhibitor SNDX-275, MS 27-275, MS-275, SNDX-275Treatment (entinostat, lapatinib ditosylate and trastuzumab)
Lapatinib DitosylateTykerbTreatment (entinostat, lapatinib ditosylate and trastuzumab)
TrastuzumabABP 980, Anti-c-ERB-2, Anti-c-erbB2 Monoclonal Antibody, Anti-ERB-2, Anti-erbB-2, Anti-erbB2 Monoclonal Antibody, Anti-HER2/c-erbB2 Monoclonal Antibody, Anti-p185-HER2, c-erb-2 Monoclonal Antibody, HER2 Monoclonal Antibody, Herceptin, Herceptin Biosimilar PF-05280014, Herceptin Trastuzumab Biosimilar PF-05280014, MoAb HER2, Monoclonal Antibody c-erb-2, Monoclonal Antibody HER2, Ogivri, PF-05280014, rhuMAb HER2, RO0452317, Trastuzumab Biosimilar ABP 980, Trastuzumab Biosimilar PF-05280014, Trastuzumab-dkstTreatment (entinostat, lapatinib ditosylate and trastuzumab)

Purpose

This phase I trial studies the side effects and best dose of entinostat when given together with lapatinib ditosylate and trastuzumab in treating patients with breast cancer that has spread from the original (primary) tumor to distant organs or distant lymph nodes or has recurred (come back) at or near the same place as the original (primary) tumor, usually after a period of time during which the cancer could not be detected. Entinostat and lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as trastuzumab, may interfere with the ability of tumor cells to grow and spread. Giving entinostat together with lapatinib ditosylate and trastuzumab may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the recommended phase II dose (RP2D) for entinostat in combination with
      lapatinib (lapatinib ditosylate) in patients whom trastuzumab has failed for human epidermal
      growth factor receptor 2+ (HER2+) metastatic breast cancer (Phase I).

      II. To determine the maximum tolerated dose (MTD) for entinostat in combination with
      lapatinib and trastuzumab in patients whom trastuzumab has failed for HER2+ metastatic breast
      cancer (Phase I Trastuzumab Cohort).

      SECONDARY OBJECTIVES:

      I. To determine the toxicity of combination therapy with entinostat and lapatinib in patients
      whom trastuzumab has failed for HER2+ metastatic breast cancer (Phase I).

      II. To determine the toxicity of entinostat in combination with lapatinib and trastuzumab in
      patients whom trastuzumab has failed for HER2+ metastatic breast cancer (Phase I Trastuzumab
      Cohort).

      EXPLORATORY OBJECTIVES:

      I. Determine whether the 2-drug combination modulates the expression of HER2, phosphorylated
      HER2 (pHER), epidermal growth factor receptor (EGFR), phosphorylated EGFR (pEGFR), v-akt
      murine thymoma viral oncogene homolog 1 (Akt), and phosphorylated Akt (pAkt) in breast tumors
      and/or circulating tumor cells (CTCs).

      OUTLINE: This is a dose-escalation study of entinostat.

      Patients receive entinostat orally (PO) on days 1 and 15 and lapatinib tosylate PO on days
      1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable
      toxicity. Patients in the Phase I trastuzumab cohort also receive maintenance dose of
      trastuzumab intravenously (IV) over 30-90 minutes every 3 weeks.

      After completion of study treatment, patients are followed up for 28 days or until toxicities
      are resolved.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (entinostat, lapatinib ditosylate and trastuzumab)ExperimentalPatients receive entinostat PO on days 1 and 15 and lapatinib tosylate PO on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients in the Phase I Trastuzumab Cohort also receive maintenance dose of trastuzumab IV over 30-90 minutes every 3 weeks.
  • Entinostat
  • Lapatinib Ditosylate

Eligibility Criteria

        Inclusion Criteria:

          -  Patients have histological confirmation of invasive breast carcinoma

          -  Patients have locally recurrent or distant relapsed metastatic disease

          -  Patients have positive HER2 expression by immunohistochemistry (IHC) (3+) or
             fluorescence in situ hybridization (FISH) testing (> 2.0 ratio)

          -  Patients are able to swallow and retain oral medication (i.e., no uncontrolled
             vomiting, inability to swallow, or diagnosis of chronic malabsorption)

          -  Patients have Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Patients must have received prior trastuzumab for > 2 month period before disease
             recurrence or recurrence or progression while on trastuzumab-based therapy

          -  Patients have ability and willingness to sign written informed consent

          -  Female patients of childbearing potential (a female not free from menses > 2 years or
             not surgically sterilized) must be willing to use an adequate barrier method of
             contraception to prevent pregnancy or agree to abstain from heterosexual activity
             throughout the study; male patients who are able to father children must use an
             adequate barrier method of contraception

          -  Female patients of childbearing potential must have negative serum pregnancy test
             within 14 days of starting protocol therapy

          -  Patients with brain metastasis have no signs of progressive disease 4 months after the
             completion of brain metastasis treatment (radiation therapy, surgery, etc.) do not
             require anticonvulsants or corticosteroids, and have been off such drugs for at least
             7 days

          -  Both men and women and members of all races and ethnic groups are eligible for this
             trial

        Exclusion Criteria:

          -  Patients are receiving concurrent anti-cancer therapy (chemotherapy, immunotherapy,
             biological therapy and hormonal therapy) while taking study medication

          -  Serum bilirubin >= 1.5 x upper limit of normal (ULN)

          -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >= 3 x ULN (with
             or without liver metastasis [mets])

          -  Absolute neutrophil count (ANC) < 1.5

          -  Hemoglobin =< 9

          -  Platelet =< 140,000

          -  Patients have an active infection and require intravenous (IV) or oral antibiotics

          -  Cardiac arrhythmia requiring maintenance medication

          -  History of gastrointestinal disorders (medical disorders or extensive surgery) which
             may interfere with the absorption of the study drug

          -  Patients have a concurrent disease or condition that would make them inappropriate for
             study participation, or any serious medical disorder that would interfere with
             patients' safety

          -  Serum creatinine > 2.0 mg/dL
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:RP2D for entinostat in combination with lapatinib ditosylate defined as the highest dose level in which 6 patients have been treated with at most 1 patient experiencing dose limiting toxicity
Time Frame:Up to 28 days
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Incidence of grade III or IV toxicities, graded according to Common Terminology Criteria for Adverse Events version 4
Time Frame:Up to 28 days
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

January 15, 2018