Capecitabine, Cyclophosphamide, Lapatinib Ditosylate, and Trastuzumab in Treating Patients With HER2-Positive Metastatic Breast Cancer

• Sponsor: University of Southern California
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): University of Southern California

Study Description

Brief Summary:

This phase II trial studies how well capecitabine, cyclophosphamide, lapatinib ditosylate, and trastuzumab work in treating patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Drugs used in chemotherapy, such as capecitabine and cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving capecitabine and cyclophosphamide daily may kill more tumor cells. Lapatinib ditosylate may stop the growth of tumor cells by blocking some of the enzymes needed for growth. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of the tumor to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving capecitabine, cyclophosphamide, lapatinib ditosylate, and trastuzumab together may be an effective treatment for breast cancer.

Condition or disease	Intervention/treatment	Phase
HER2-positive Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer	Drug: capecitabine; Drug: cyclophosphamide; Drug: lapatinib ditosylate; Biological: trastuzumab; Other: laboratory biomarker analysis	Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the progression free survival (PFS).

SECONDARY OBJECTIVES:

I. To evaluate the overall response rate (ORR).

II. To evaluate the clinical benefit rate (CBR; complete response, partial response, and stable disease for >= 24 weeks).

III. To estimate the overall survival (OS).

IV. To assess the safety and tolerability.

OUTLINE:

Patients receive capecitabine orally (PO) once daily (QD), cyclophosphamide PO QD, and lapatinib ditosylate PO QD on days 1-21 and trastuzumab intravenously (IV) on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Metronomic Capecitabine and Cyclophosphamide With Lapatinib and Trastuzumab in Patients With HER2 Positive Metastatic Breast Cancer Who Have Progressed on a Previous Trastuzumab-Based Regimen
• Actual Study Start Date: July 29, 2013
• Estimated Primary Completion Date: July 27, 2020
• Estimated Study Completion Date: July 27, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment (chemotherapy, lapatinib ditosylate, trastuzumab); Patients receive capecitabine PO QD, cyclophosphamide PO QD, and lapatinib ditosylate PO QD on days 1-21 and trastuzumab IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: capecitabine; Given PO; Other Names: CAPE; Ro 09-1978/000; Xeloda; Drug: cyclophosphamide; Given PO; Other Names: CPM; CTX; Cytoxan; Endoxan; Endoxana; Drug: lapatinib ditosylate; Given PO; Other Names: GSK572016; GW-572016; GW2016; Lapatinib; Tykerb; Biological: trastuzumab; Given IV; Other Names: anti-c-erB-2; Herceptin; MOAB HER2; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures :

1. PFS [ Time Frame: From the date of registration to date of first documentation of progression or symptomatic deterioration or death due to any cause, assessed up to 1 year ]
   One-sided one-sample logrank test will be used to evaluate the improvement in PFS compared to the reported historical PFS rate.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histologically confirmed HER2-positive metastatic breast cancer
• HER2 overexpression of tumor by either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH); tumors tested by IHC must be 3+ positive; tumors tested by FISH must have a ratio of HER2:CEP17 > 2.0; when both tests are performed, the FISH result must be positive
• Prior trastuzumab use in the adjuvant or metastatic setting
• No more than two prior cytotoxic chemotherapeutic regimens for metastatic breast cancer. In addition, prior Trastuzumab emtansine (TDM-1, Kadcyla) is allowed.
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
• Absolute neutrophil count (ANC) >= 1500/mm^3
• Platelets >= 100,000/mm^3
• Hemoglobin >= 9 g/dL
• Bilirubin =< 1.5 x upper limit of normal (ULN)
• Serum creatinine =< 1.5 x ULN or calculated creatinine clearance >= 60 ml/min
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN
• Fully recovered from toxicity due to prior therapy
• Capable of understanding the informed consent and complying with the protocol and signed the informed consent document prior to any study-specific screening procedures or evaluations being performed
• Must be able to swallow pills
• May have either measurable or non-measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
• Sexually active participants must agree to use a medically accepted barrier method of contraception (i.e. male condom or female condom) during the course of the study and for 3 months following discontinuation of study treatments; for participants of childbearing potential, a barrier method and a second method of contraception must be used
• Participants of childbearing potential must have a negative pregnancy test at screening and enrollment; participants of childbearing potential are defined as premenopausal females capable of becoming pregnant, i.e. females who have had any evidence of menses in the past 12 months with the exception of those who had prior hysterectomy (oophorectomy or surgical sterilization); however, women who have been amenorrheic for >= 12 months are still considered to be of childbearing potential if the amenorrhea is possibly due to any other cause including prior chemotherapy, antiestrogens, or ovarian suppression

Exclusion Criteria:

• Prior treatment with capecitabine or lapatinib
• Radiation therapy within 2 weeks before the first dose of study treatment
• Hormonal therapy within 2 weeks before the first dose of study treatment
• Cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) within 3 weeks before the first dose of study treatment
• Biologic therapy (including antibodies [other than trastuzumab], immune modulators, cytokines) within 4 weeks before the first dose of study treatment; Note: there is no washout period required for trastuzumab
• Any other type of investigational agent within 4 weeks before the first dose of study treatment
• Major surgery, or not recovered from major surgery within 4 weeks before the first dose of study treatment
• Untreated, symptomatic, or progressive brain metastases; participants must have no radiographic or other signs of progression in the brain for >= 1 month after completion of local therapy; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 4 weeks prior to first study treatment
• Uncontrolled significant intercurrent illness that would preclude the patient from study participation per investigator assessment
• Left ventricular ejection fraction (LVEF) =< 50% as documented by multi gated acquisition scan (MUGA) or echocardiogram performed within 28 days prior to the first study treatment
• Currently receiving anticoagulation with therapeutic doses of warfarin (low-molecular weight heparin is permitted)
• Pregnant or breastfeeding
• Known to be positive for the human immunodeficiency virus (HIV) (a test for HIV at screening is not required)
• Have acute or currently active/requiring anti-viral therapy hepatic or biliary disease (with the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
• Previously identified allergy or hypersensitivity or intolerance to components of the study treatment formulation (cyclophosphamide, capecitabine, lapatinib [lapatinib ditosylate], trastuzumab)
• Any other diagnosis of malignancy or evidence of malignancy (except non-melanoma skin cancer, in-situ carcinoma of the cervix) within 2 years prior to screening for this study
• Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee

Contacts and Locations

Locations

United States, California

USC Norris Comprehensive Cancer Center

Los Angeles, California, United States, 90033

Sponsors and Collaborators

University of Southern California

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Darcy V Spicer, MD; University of Southern California

More Information

• Responsible Party: University of Southern California
• ClinicalTrials.gov Identifier: NCT01873833 History of Changes
• Other Study ID Numbers: 1B-12-10; NCI-2013-01086 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); P30CA014089 ( U.S. NIH Grant/Contract )
• First Posted: June 10, 2013
• Last Update Posted: May 14, 2019
• Last Verified: May 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Cyclophosphamide; Capecitabine; Trastuzumab; Lapatinib; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Enzyme Inhibitors