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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

Primary Purpose

HER2/Neu Positive, Invasive Breast Carcinoma, Recurrent Breast Carcinoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Entinostat
Laboratory Biomarker Analysis
Lapatinib Ditosylate
Trastuzumab
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for HER2/Neu Positive

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • M D Anderson Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (entinostat, lapatinib ditosylate and trastuzumab)

Arm Description

Patients 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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Incidence of grade III or IV toxicities, graded according to Common Terminology Criteria for Adverse Events version 4

Full Information

First Posted
September 13, 2011
Last Updated
May 17, 2019
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01434303
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
January 10, 2012 (Actual)
Primary Completion Date
February 16, 2016 (Actual)
Study Completion Date
February 16, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HER2/Neu Positive, Invasive Breast Carcinoma, Recurrent Breast Carcinoma, Stage IV Breast Cancer AJCC v6 and v7

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
37 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment (entinostat, lapatinib ditosylate and trastuzumab)
Arm Type
Experimental
Arm Description
Patients 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.
Intervention Type
Drug
Intervention Name(s)
Entinostat
Other Intervention Name(s)
HDAC inhibitor SNDX-275, MS 27-275, MS-275, SNDX-275
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Lapatinib Ditosylate
Other Intervention Name(s)
Tykerb
Intervention Description
Given PO
Intervention Type
Biological
Intervention Name(s)
Trastuzumab
Other Intervention Name(s)
ABP 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 HLX02, Trastuzumab Biosimilar PF-05280014, Trastuzumab-dkst
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
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
Secondary Outcome Measure Information:
Title
Incidence of grade III or IV toxicities, graded according to Common Terminology Criteria for Adverse Events version 4
Time Frame
Up to 28 days
Other Pre-specified Outcome Measures:
Title
Changes in CTCs levels before and after the combination treatment of entinostat, lapatinib ditosylate and trastuzumab
Description
Summary statistics (mean, standard deviation, median, quartiles) will be summarized for these changes in CTCs and biomarkers by patient tumor response status (yes vs. no). Changes will be compared between the two groups of patients (yes vs. no tumor response) using the two-sample t-test. If the data is skewed, Wilcoxon rank-sum test will be used.
Time Frame
Baseline up to 28 days after completion of study treatment
Title
Changes in phosphorylated Akt levels before and after the combination treatment of entinostat, lapatinib ditosylate and trastuzumab.
Description
Summary statistics (mean, standard deviation, median, quartiles) will be summarized for these changes in CTCs and biomarkers by patient tumor response status (yes vs. no). Changes will be compared between the two groups of patients (yes vs. no tumor response) using the two-sample t-test. If the data is skewed, Wilcoxon rank-sum test will be used.
Time Frame
Baseline up to 28 days after completion of study treatment
Title
Changes in phosphorylated HER2 levels before and after the combination treatment of entinostat, lapatinib ditosylate and trastuzumab
Description
Summary statistics (mean, standard deviation, median, quartiles) will be summarized for these changes biomarkers by patient tumor response status (yes vs. no). Changes will be compared between the two groups of patients (yes vs. no tumor response) using the two-sample t-test. If the data is skewed, Wilcoxon rank-sum test will be used.
Time Frame
Baseline up to 28 days after completion of study treatment
Title
Changes in phosphorylated EGFR levels before and after the combination treatment of entinostat, lapatinib ditosylate and trastuzumab
Description
Summary statistics (mean, standard deviation, median, quartiles) will be summarized for these changes biomarkers by patient tumor response status (yes vs. no). Changes will be compared between the two groups of patients (yes vs. no tumor response) using the two-sample t-test. If the data is skewed, Wilcoxon rank-sum test will be used.
Time Frame
Baseline up to 28 days after completion of study treatment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Naoto T Ueno
Organizational Affiliation
M.D. Anderson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
M D Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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