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A Phase 2 Study of ARQ 197 in Metastatic Triple-negative Breast Cancer

Phase 2
18 Years
Open (Enrolling)
Estrogen Receptor-negative Breast Cancer, HER2-negative Breast Cancer, Progesterone Receptor-negative Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer, Triple-negative Breast Cancer

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Trial Information

A Phase 2 Study of ARQ 197 in Metastatic Triple-negative Breast Cancer


I. To evaluate the activity of tivantinib (ARQ-197) as defined by 6-month progression-free
survival (PFS) of participants with triple-negative metastatic breast cancer.


I. To evaluate objective response based on Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1 criteria.

II. To evaluate c-Met and phospho c-Met expression in archival tumor tissue. (Exploratory)
III. To evaluate the incidence of c-Met-positive circulating tumor cells at baseline.
(Exploratory) IV. To evaluate the effect of ARQ-197 on serum markers relevant to c-Met
pathway (hepatocyte growth factor [HGF] and vascular endothelial growth factor [VEGF]).
(Exploratory) V. To evaluate phosphatase and tensin homolog (PTEN) loss and PI3K mutations
in archival tumor tissue. (Exploratory) VI. To evaluate proportion of participants with
basal-like breast cancer. (Exploratory)

OUTLINE: This is a multicenter study.

Patients receive tivantinib orally (PO) twice daily (BID) on days 1-21. Courses repeat every
21 days in the absence of disease progression or unacceptable toxicity. Patients undergo
blood sample collection at baseline and periodically during study for c-Met expression,
relevant markers (HGF and VEGF), PTEN loss, and PI3K mutation analysis by fluorescent in
situ hybridization (FISH) and immunohistochemistry (IHC). Archived tumor tissue samples are
also analyzed.

After completion of study treatment, patients are followed up every 6 months.

Inclusion Criteria:

- Participants must have histologically or cytologically confirmed invasive breast
cancer, with recurrent or metastatic disease; participants without pathologic or
cytologic confirmation of metastatic disease should have unequivocal evidence of
metastasis from physical examination or radiologic evaluation

- Participants must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional
techniques or as ≥ 10 mm with spiral computed tomography (CT) scan

- Participants must have recent evidence of progressive disease

- Participants must have received 1-3 prior chemotherapeutic regimens for
metastatic breast cancer and must have been off treatment with chemotherapy for
at least 14 days before enrollment in the study

- Either the primary tumor and/or the metastasis must be triple-negative; the invasive
tumor must be hormone-receptor poor, defined as estrogen-receptor negative (ER-) and
progesterone-receptor negative (PR-), or staining < 10% by immunohistochemistry (IHC)

- Human epidermal growth factor receptor 2 (HER2) status: the invasive tumor must
be HER2-negative, defined as 0 or 1+ by IHC, or FISH < 2.0

- Confirmed availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue

- No known brain metastases that are untreated, symptomatic, or require therapy to
control symptoms

- Participants with a history of treated central nervous system (CNS) metastases
are eligible

- Treated brain metastases are defined as those having no evidence of
progression or hemorrhage for ≥ 2 months after treatment, and no ongoing
requirement for corticosteroids, as ascertained by clinical examination and
brain imaging (magnetic resonance imaging or CT scan) during the screening

- Treatment for brain metastases may include whole-brain radiotherapy,
radiosurgery, or a combination as deemed appropriate by the treating

- Participants may be taking anti-convulsant medications, which must be
non-enzyme-inducing anti-epileptic drugs

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)

- Hemoglobin ≥ 9.0 g/dL

- Leukocytes ≥ 3,000/mcL

- Absolute neutrophil count ≥ 1,500/mcL

- Platelets ≥ 100,000/mcL

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
≤ 2.5 times institutional ULN; for participants with documented liver metastases,
AST/ALT ≤ 5.0 times ULN

- Serum creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min

- Female subjects of childbearing potential must have a negative serum pregnancy test
within 21 days of cycle 1 day 1

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) during the study and for 90
days after the last investigational drug dose received

- Ability to understand and the willingness to sign a written informed consent document

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to ARQ 197

- No history of congestive heart failure defined as Class II to IV per New York Heart
Association (NYHA) classification; active coronary artery disease (CAD); clinically
significant bradycardia or other uncontrolled, cardiac arrhythmia defined as ≥ grade
3 according to National Cancer Institute (NCI) CTCAE version 4.0, or uncontrolled
hypertension; myocardial infarction occurring within 6 months prior to study entry
(myocardial infarction occurring > 6 months prior to study entry is permitted)

- No 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 requirements

- Not pregnant or nursing

- Human immunodeficiency virus (HIV)-positive participants on combination
antiretroviral therapy are ineligible

- See Disease Characteristics

- Any treatment-related toxicity should have resolved to ≤ grade 1 per Common
Terminology Criteria for Adverse Events (CTCAE)

- Participants must have discontinued all biologic therapy (including vaccines) at
least 14 days before enrollment in the study

- Participants must have discontinued any investigational therapy at least 14 days
before enrollment in the study

- Participants may have received prior radiation therapy in either the metastatic or
early-stage setting

- Radiation therapy must be completed at least 14 days before enrollment in the

- Participant must not have received radiation to > 25% of his or her bone marrow
within 30 days of starting study treatment

- Participants on bisphosphonates may continue receiving bisphosphonate therapy during
study treatment

- Bisphosphonate therapy may also be initiated on study treatment if needed

- No participants who have received chemotherapy, biologic, investigational, or
radiotherapy within 14 days prior to entering the study

- No participants who are receiving any other investigational agents

Type of Study:


Study Design:

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

Outcome Measure:

PFS status

Outcome Description:

Analyzed using the Kaplan-Meier method. 95% confidence intervals (CI) will be determined.

Outcome Time Frame:

Time from start of treatment to time of progression or death, assessed up to 6 months

Safety Issue:


Principal Investigator

Sara Tolaney

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute


United States: Food and Drug Administration

Study ID:




Start Date:

March 2012

Completion Date:

Related Keywords:

  • Estrogen Receptor-negative Breast Cancer
  • HER2-negative Breast Cancer
  • Progesterone Receptor-negative Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Triple-negative Breast Cancer
  • Breast Neoplasms



Dana-Farber Cancer Institute Boston, Massachusetts  02115