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Pilot and Phase II- Vorinostat and Lapatinib in Patients With Advanced Solid Tumor Malignancies and Women With Recurrent Local-Regional or Metastatic Breast Cancer to Evaluate Response and Biomarkers of EMT and Breast Cancer Stem Cells

Phase 2
18 Years
Open (Enrolling)
Breast Cancer, Neoplasm Metastasis

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Trial Information

Pilot and Phase II- Vorinostat and Lapatinib in Patients With Advanced Solid Tumor Malignancies and Women With Recurrent Local-Regional or Metastatic Breast Cancer to Evaluate Response and Biomarkers of EMT and Breast Cancer Stem Cells

Lapatinib is an anti-cancer drug that is approved by the Food and Drug Administration (FDA)
for the treatment of metastatic HER2-positive breast cancer. HER2 is a protein involved in
the growth of some cancer cells. In lab tests and small clinical studies, lapatinib is also
found to kill other types of cancer that have another related protein called epidermal
growth factor receptor (EGFR). For participants who have other cancers, the use of lapatinib
in this study is investigational. This means the drug is not FDA approved for this use.

Vorinostat is only FDA approved for the treatment of cutaneous T cell lymphoma (a type of
cancer). Vorinostat is not currently FDA approved for breast cancer or any other type of
cancer. The use of vorinostat in this study is investigational.

Cancer cells can travel through the blood stream and spread to other organs. This process is
called metastasis. Lab tests and small clinical trials have shown that vorinostat kills some
cancer cells and prevents these cancer cells from traveling through the blood stream. These
trials have shown that vorinostat improves how well lapatinib kills cancer cells.

Newer studies have also shown that a subset of cells, called "cancer stem cells," can come
back, spread, and become resistant to the usual chemotherapy. In laboratory tests, we found
that vorinostat and lapatinib can reduce the number of cancer stem cells. We are looking at
combining vorinostat and lapatinib in the hope that we can reduce the number of cancer stem
cells and cancer cells traveling through the blood stream.

There are two parts to this study.

First part- We want to learn more about the best dose of vorinostat to be given with
lapatinib. We want to learn about how much vorinostat and lapatinib goes into the blood
during treatment. We also want to learn the side effects (safety) of the combination of
vorinostat and lapatinib. All patients will receive the FDA-approved dose of lapatinib. The
first group of patients will get a slightly lower dose of vorinostat than is given normally.
If the side effects are not too serious, the next group of patients will get the dose of
vorinostat that is given normally.

Second part- We will find out how well the combination of vorinostat and lapatinib works in
patients with HER2-positive metastatic breast cancer.

Inclusion Criteria:

- Age greater than or equal to 18 years.

- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.

- Consent for peripheral blood sampling for analysis of circulating tumor cells.

- Patients must have adequate organ and marrow function as defined by the protocol.

- Female patients with histologically confirmed adenocarcinoma of the breast with
recurrent local-regional disease, or metastatic disease that have progressed after
treatment with regimens that include an anthracycline, a taxane, or trastuzumab.

- Human Epidermal growth factor Receptor 2 (HER2) positive in the primary or secondary
tumor tissue as defined by:

- Grade 3plus staining intensity (on a scale of 0 to 3) by means of
Immunohistochemistry (IHC) analysis OR

- Gene amplification on fluorescence in situ hybridization (FISH) greater than or
equal to 2.2.

- Patients must have measurable disease by the Response Evaluation Criteria In Solid
Tumors (RECIST)criteria at the time of enrollment.

- Prior trastuzumab therapy is allowed. Trastuzumab should be stopped at least 4 weeks
prior to enrollment.

Exclusion Criteria:

- Patients receiving any other investigational agents.

- Prior exposure to lapatinib, vorinostat, or other Histone deacetylase (HDAC)
inhibitors. Prior valproic acid exposure is allowed providing this is a greater than
or equal to 30 days wash-out period.

- History of allergic reactions or hypersensitivity to compounds of similar chemical or
biologic composition to vorinostat or lapatinib.

- Patients with history of clinically significant or uncontrolled cardiac disease, as
defined by the protocol, or any significant cardiac condition that in the judgment of
the investigator is unsuitable.

- Significant chronic or recent (less than 30 days) acute gastrointestinal disorder
with diarrhea as a major symptom (e.g. Crohn's disease, malabsorption, or Grade 2 or
greater diarrhea of any etiology at baseline).

- Prior exposure to more than 360 mg/m2 doxorubicin or liposomal doxorubicin, more than
120 mg/m2 mitoxantrone, or more than 90 mg/m2 idarubicin, or elevated baseline
cardiac troponin T (more than upper limit of normal).

- Patients with active Central Nervous System (CNS) metastasis and/or carcinomatous
meningitis are excluded. Patients with CNS metastasis who have completed a course of
therapy would be eligible for the study provided they are clinically stable for 3
weeks prior to entry as defined as: (1) no evidence of new or enlarging CNS
metastasis and (2) off steroids and/or anticonvulsants, for at least 4 weeks before
an enrollment.

- Female patient that is pregnant or breastfeeding or expecting to conceive during the
study. Women able to have children must have a negative pregnancy test prior to
enrollment. All patients must use two effective methods of contraception (including a
barrier method) during treatment and for 12 weeks after stopping treatment.

- The patient is known to be Human immunodeficiency virus (HIV), Hepatitis B, or
Hepatitis C-positive (test results are not required in order to participate).

- Patients with current active hepatic or biliary disease (with exception of patients
with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic
liver disease per investigator assessment)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirement.

- Previous or current systemic malignancy within the past 3 years other than the
following: Female- breast cancer or adequately treated carcinoma in-situ of the
cervix, or Female and Male- basal/squamous carcinoma of the skin.

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Clinical benefit rate (Complete Response (CR), Partial Response (PR), and Stable Disease (SD) ≥ 6 months) of vorinostat in combination with lapatinib in patients with locally recurrent or metastatic breast cancer.

Outcome Time Frame:

Radiological evaluations are performed every 12 weeks to determine disease status

Safety Issue:


Principal Investigator

Saranya Chumsri, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Maryland


United States: Institutional Review Board

Study ID:




Start Date:

March 2010

Completion Date:

December 2014

Related Keywords:

  • Breast Cancer
  • Neoplasm Metastasis
  • lapatinib ditosylate
  • Zolinza (vorinostat)
  • Cancer Stem Cells
  • Breast Neoplasms
  • Neoplasms
  • Neoplasm Metastasis



University of Maryland Greenebaum Cancer Center Baltimore, Maryland  21201