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

This study is currently recruiting participants.
Verified January 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01434303
First received: September 13, 2011
Last updated: April 14, 2014
Last verified: January 2014

September 13, 2011
April 14, 2014
January 2012
May 2014   (final data collection date for primary outcome 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 (DLT) [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]
  • RP2D for entinostat in combination with lapatinib ditosylate (Phase I) [ Designated as safety issue: No ]
  • Clinical tumor response (complete and partial remission) at 4 months (Phase II) [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01434303 on ClinicalTrials.gov Archive Site
  • Incidence of grade III or IV adverse events graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4 [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]
    Toxicity rate will also be calculated and presented with its 95% confidence interval (CI). Incidences of irreversible grade 3-4 toxicities will be tabulated for all patients.
  • Changes in phosphorylated HER2 levels before and after the combination treatment of entinostat, lapatinib and trastuzumab [ Time Frame: Baseline up to 28 days after completion of study treatment ] [ Designated as safety issue: No ]
    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.
  • Toxicity of combination therapy (Phase I/II) [ Designated as safety issue: Yes ]
  • Time to tumor progression, time to tumor response, and PFS at 2 years (Phase II) [ Designated as safety issue: No ]
  • Changes in CTCs levels before and after the combination treatment of entinostat, lapatinib and trastuzumab [ Time Frame: Baseline up to 28 days after completion of study treatment ] [ Designated as safety issue: No ]
    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.
  • Changes in phosphorylated Akt levels before and after the combination treatment of entinostat, lapatinib and trastuzumab. [ Time Frame: Baseline up to 28 days after completion of study treatment ] [ Designated as safety issue: No ]
    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.
  • Changes in phosphorylated EGFR levels before and after the combination treatment of entinostat, lapatinib and trastuzumab [ Time Frame: Baseline up to 28 days after completion of study treatment ] [ Designated as safety issue: No ]
    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.
Not Provided
 
Entinostat, Lapatinib Ditosylate and Trastuzumab in Treating Patients With Locally Recurrent or Distant Relapsed Metastatic Breast Cancer Previously Treated With Trastuzumab Only
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

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 locally recurrent or distant relapsed metastatic breast cancer. 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, can block tumor growth in different ways. Some block the ability of tumor to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving entinostat together with lapatinib ditosylate and trastuzumab may kill more tumor cells.

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.

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • HER2-positive Breast Cancer
  • Male Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Drug: entinostat
    Given PO
    Other Names:
    • HDAC inhibitor SNDX-275
    • SNDX-275
  • Drug: lapatinib ditosylate
    Given PO
    Other Names:
    • GSK572016
    • GW-572016
    • GW2016
    • Lapatinib
    • Tykerb
  • Biological: trastuzumab
    Given IV
    Other Names:
    • anti-c-erB-2
    • Herceptin
    • MOAB HER2
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (entinostat, lapatinib ditosylate and trastuzumab)
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.
Interventions:
  • Drug: entinostat
  • Drug: lapatinib ditosylate
  • Biological: trastuzumab
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
37
Not Provided
May 2014   (final data collection date for primary outcome measure)

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 (> 2.2 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 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 who 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 =< 75,000
  • 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
Both
18 Years and older
No
Not Provided
United States
 
NCT01434303
NCI-2011-03222, NCI-2011-03222, CDR0000710891, 2010-0842, 8871, U01CA062461, P30CA016672
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Naoto Ueno M.D. Anderson Cancer Center
National Cancer Institute (NCI)
January 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP