Tivantinib in Treating Patients With Recurrent or Metastatic Breast Cancer

Phase 2

Completed

Conditions: Estrogen Receptor Negative
Recurrent Breast Carcinoma
HER2/Neu Negative
Progesterone Receptor Negative
Stage IV Breast Cancer
Triple-Negative Breast Carcinoma

Interventions: Other: Laboratory Biomarker Analysis
Drug: Tivantinib

Registration Number: NCT01575522

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial studies how well tivantinib works in treating patients with recurrent or metastatic breast cancer. Tivantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description: PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

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
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 study
- Participant must not have received radiation to > 25% of his or her bone marrow within 30 days of starting study treatment
Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
Hemoglobin >= 9.0 g/dL
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/1.73 m^2 for participants with creatinine levels above institutional normal
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
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
Female subjects of childbearing potential must have a negative serum pregnancy test within 21 days of cycle 1 day 1
Participants on bisphosphonates may continue receiving bisphosphonate therapy during study treatment; bisphosphonate therapy may also be initiated on study treatment if needed
Confirmed availability of formalin-fixed, paraffin-embedded (FFPE) tumor tissue
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Participants who have received chemotherapy, biologic, investigational, or radiotherapy within 14 days prior to entering the study
Participants who are receiving any other investigational agents
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 computed tomography [CT] scan) during the screening period
  - Treatment for brain metastases may include whole-brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician
- Participants may be taking anti-convulsant medications, which must be non-enzyme-inducing anti-epileptic drugs
History of allergic reactions attributed to compounds of similar chemical or biologic composition to ARQ 197
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) Common Terminology Criteria for Adverse Events (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)
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
Pregnant women are excluded from this study
Human immunodeficiency virus (HIV)-positive participants on combination antiretroviral therapy are ineligible

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (tivantinib)	Tivantinib	Patients receive tivantinib 360 mg PO 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 FISH and IHC. Archived tumor tissue samples are also analyzed.
Treatment (tivantinib)	Laboratory Biomarker Analysis	Patients receive tivantinib 360 mg PO 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 FISH and IHC. Archived tumor tissue samples are also analyzed.

Primary Outcome Measures

Name	Time	Method
PFS Status	Time from start of treatment to time of progression or death, assessed up to 6 months	Analyzed using the Kaplan-Meier method. 95% confidence intervals (CI) will be determined. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Secondary Outcome Measures

Name	Time	Method
To Evaluate the Incidence of c-Met Positive Circulating Tumor Cells.	Baseline
Overall Response Using RECIST v1.1	Up to 1 year	The 95% confidence intervals should be provided. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by Conventional CT or MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>/=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
To Evaluate c-Met Expression in Archival Tumor Tissue.	Baseline	Assessment of ploidy status was done by visual screening of all tumor area; cells with maximum number of signals were recorded. MET amplification was defined as a MET/CEP7 ratio ≥ 2. Samples having a MET/CEP7 ratio from 1.5 and up to 2 were defined as having relative MET gain. Samples with a MET/CEP7 ratio of 1 but with more than two copies of each probe were defined as having polysomy of chromosome 7.
To Evaluate Phospho c-Met Expression in Archival Tumor Tissue.	Baseline	MET amplification was defined as a MET/CEP7 ratio ≥ 2. Samples having a MET/CEP7 ratio from 1.5 and up to 2 were defined as having relative MET gain. Samples with a MET/CEP7 ratio of 1 but with more than two copies of each probe were defined as having polysomy of chromosome 7.

Trial Locations

Locations (2): Dana-Farber Cancer Institute Faulkner Hospital
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Boston, Massachusetts, United States
Dana-Farber Cancer Institute
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Boston, Massachusetts, United States