Entinostat and Lapatinib Ditosylate in Patients With Locally Recurrent or Distant Relapsed Metastatic Breast Cancer Previously Treated With Trastuzumab
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Purpose
This phase I/II trial studies the side effects and the best dose of entinostat when given together with lapatinib ditosylate and how well it works 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. Giving entinostat together with lapatinib ditosylate may kill more tumor cells
| Condition | Intervention | Phase |
|---|---|---|
|
HER2-positive Breast Cancer Inflammatory Breast Cancer Male Breast Cancer Recurrent Breast Cancer Stage IV Breast Cancer |
Drug: entinostat Drug: lapatinib ditosylate Genetic: protein expression analysis Other: circulating tumor cell analysis Other: diagnostic laboratory biomarker analysis |
Phase 1 Phase 2 |
| 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/II Study of Entinostat and Lapatinib in Patients With HER2-Positive Metastatic Breast Cancer in Whom Trastuzumab Has Failed |
- RP2D for entinostat in combination with lapatinib ditosylate (Phase I) [ Time Frame: Up to 28 days ] [ Designated as safety issue: No ]
- Clinical tumor response (complete and partial remission) (Phase II) [ Time Frame: 4 months ] [ Designated as safety issue: No ]Will be calculated and presented with its 95% confidence interval (CI).
- Irreversible grade III or IV toxicities graded according to CTCAE version 4 (Phase I/II) [ Time Frame: Up to 28 days ] [ Designated as safety issue: Yes ]Toxicity rate will also be calculated and presented with its 95% CI. Incidences of irreversible grade 3-4 toxicities will be tabulated for all patients.
- Time to tumor progression (Phase II) [ Time Frame: Up to 28 days ] [ Designated as safety issue: No ]Will be estimated using the Kaplan-Meier estimator.
- Time to tumor response (Phase II) [ Time Frame: Up to 28 days ] [ Designated as safety issue: No ]Will be estimated using the Kaplan-Meier estimator.
- PFS (Phase II) [ Time Frame: 2 years ] [ Designated as safety issue: No ]Will be estimated using the Kaplan-Meier estimator.
| Estimated Enrollment: | 70 |
| Study Start Date: | January 2012 |
| Estimated Primary Completion Date: | May 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Arm I
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.
|
Drug: entinostat
Given PO
Other Names:
Drug: lapatinib ditosylate
Given PO
Other Names:
Genetic: protein expression analysis
Other: circulating tumor cell analysis
Other Name: CTC analysis
Other: diagnostic laboratory biomarker analysis
|
Detailed Description:
PRIMARY OBJECTIVES:
I. To determine the recommended phase II dose (RP2D) for entinostat in combination with lapatinib ditosylate in patients who have received trastuzumab for HER2+ metastatic breast cancer.
II. To determine the tumor response to entinostat in combination with lapatinib ditosylate in patients who have received trastuzumab for HER2+ metastatic breast cancer in the non-inflammatory breast cancer (IBC) cohort.
SECONDARY OBJECTIVES:
I. To determine the toxicity of combination therapy with entinostat and lapatinib ditosylate in patients who have received trastuzumab for HER2+ metastatic breast cancer.
II. To determine time to tumor progression, time to tumor response, and progression-free survival (PFS) up to 2 years. (Phase II) III. To determine overall survival at 2 years in patients who have received trastuzumab for HER2+ metastatic breast cancer.
IV. To determine the toxicity of combination therapy with entinostat and lapatinib ditosylate in patients who have received trastuzumab for HER2+ metastatic breast cancer.
EXPLORATORY OBJECTIVES:
I. Determine whether the 2-drug combination modulates the expression of HER2, phosphorylated HER2 (pHER), EGFR, phosphorylated EGFR (pEGFR), Akt, and phosphorylated Akt (pAkt) in breast tumors and/or circulating tumor cells (CTCs).
OUTLINE: This is a phase I, dose-escalation study of entinostat followed by a phase II study.
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. Tumor tissue samples collected at diagnosis and blood samples collected at baseline and after treatment are analyzed for pEGFR/EGFR, pHER2/HER2, and pAkt/Akt expression.
After completion of study therapy, patients are followed up for 28 days or until toxicities are resolved.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Patients have histological confirmation of invasive breast carcinoma
- Patients have locally recurrent or distant relapsed metastatic disease (Phase I portion of the study-any metastatic breast cancer; Phase II portion of the study including non-inflammatory breast cancer [IBC] only)
- Patients have positive HER2 expression by IHC (3+) or fluorescence in situ hybridization (FISH) testing (> 2.2 ratio)
- Patients must have received prior trastuzumab for > 2-month period before disease recurrence or progression while on trastuzumab-based 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, allowed
- ECOG performance status 0-1
- Menopause status unspecified
- Patients are able to swallow and retain oral medication (i.e., no uncontrolled vomiting, inability to swallow, or diagnosis of chronic malabsorption)
- 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
No abnormal liver functions consisting of any of the following:
- Serum bilirubin ≥ 1.5 times upper limit of normal (ULN)
- ALT and AST ≥ 3 times ULN (with or without liver metastasis)
- ANC < 1,500/mm³
- Hemoglobin ≤ 9 g/dL
- Platelet count ≤ 75,000/mm³
- Serum creatinine > 2.0 mg/dL
- No patients who have an active infection requiring IV or oral antibiotics
- No cardiac arrhythmia requiring maintenance medication
- No history of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug
- No patients who 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
- Drugs that may prolong the QT/QTc interval are prohibited during treatment
- No patients who are receiving concurrent anti-cancer therapy (chemotherapy, immunotherapy, biological therapy, and hormonal therapy) while taking study medication
Contacts and Locations| United States, Texas | |
| M D Anderson Cancer Center | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Naoto T. Ueno 713-792-2817 nueno@mdanderson.org | |
| Principal Investigator: Naoto T. Ueno | |
| Principal Investigator: | Naoto Ueno | M.D. Anderson Cancer Center |
More Information
No publications provided
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT01434303 History of Changes |
| Other Study ID Numbers: | NCI-2011-03222, 2010-0842, U01CA062461 |
| Study First Received: | September 13, 2011 |
| Last Updated: | March 4, 2013 |
| Health Authority: | United States: Food and Drug Administration |
Additional relevant MeSH terms:
|
Breast Neoplasms, Male Breast Neoplasms Inflammatory Breast Neoplasms Neoplasms by Site Neoplasms Breast Diseases Skin Diseases Trastuzumab |
Lapatinib Histone Deacetylase Inhibitors Antineoplastic Agents Therapeutic Uses Pharmacologic Actions Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |
ClinicalTrials.gov processed this record on June 18, 2013