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 goal of this clinical research study is to find the highest tolerable dose of entinostat and lapatinib that can be given in combination to patients with advanced or metastatic breast cancer. The effectiveness and safety of this dose combination will be studied. Researchers will also study the safety of the other dose combinations. Entinostat in an investigational drug and is not FDA approved or commercially available. It is currently being used for research purposes only. Lapatinib is approved by the FDA for certain kinds of breast cancer. The combination of these drugs is investigational.
Disease Group: Breast
Treatment Agent: Entinostat
Treatment Location: Only at MD Anderson
Sponsor: NCI will supply Entinostat and provide IND.
Primary Objectives Phase I: To determine the recommended phase II dose (RP2D) for entinostat in combination with lapatinib in patients who have received trastuzumab for HER2+ metastatic breast cancer. Phase I Trastuzumab Cohort: To determine the recommended phase II dose (RP2D) for entinostat in combination with lapatinib and trastuzumab in patients whom trastuzumab has Failed for HER2+ metastatic breast cancer. Secondary Objectives Phase I: To determine the toxicity of combination therapy with entinostat and lapatinib in patients who have received trastuzumab for HER2+ metastatic breast cancer. Phase I Trastuzumab Cohort: To determine the toxicity of entinostat in combination with lapatinib and trastuzumab in patients whom trastuzumab has Failed for HER2+ metastatic breast cancer. Exploratory Objectives 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).
IRB Review and Approval Date: 01/10/2012
Recruitment Status: Closed
Projected Accrual: N/A
1) Patients have histological confirmation of invasive breast carcinoma.
2) Patients have locally recurrent or distant relapsed metastatic disease.
3) Patients have positive HER2 expression by IHC (3+) or FISH testing (> 2.0 ratio)
4) Patients are able to swallow and retain oral medication (i.e. no uncontrolled vomiting, inability to swallow, or diagnosis of chronic malabsorption)
5) Patients have ECOG performance status 0-1
6) Patients must have received prior trastuzumab for > 2 month period before disease recurrence or recurrence or progression while on trastuzumab based therapy
7) Patients have ability and willingness to sign written informed consent
8) Patients are 18 years of age or older
9) 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.
10) Female patients of childbearing potential must have negative serum pregnancy test within 14 days of starting protocol therapy.
11) 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
12) Both men and women and members of all races and ethnic groups are eligible for this trial
1) Patients are receiving concurrent anti-cancer therapy (chemotherapy,
immunotherapy, biological therapy and hormonal therapy) while taking
2) Abnormal liver functions consisting of any of the following: Serum bilirubin >/= 1.5 x ULN, ALT and AST >/=3 x ULN (with or without liver mets) ANC < 1.5, Hemoglobin </=9, Platelet </= 140,000
3) Patients have an active infection and require IV or oral antibiotics
4) Cardiac arrhythmia requiring maintenance medication
5) History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug
6) 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
7) Inadequate renal function: Serum creatinine > 2.0 mg/dL.