Lapatinib in Combination With Trastuzumab in Patients With HER2-Positive, Metastatic Breast Cancer

A Phase 2 Study of Lapatinib in Combination With Trastuzumab in Patients With HER2-Positive, Metastatic Breast Cancer

In this research study we are studying the effects of the combination of lapatinib plus Herceptin in subjects with breast cancer that has spread outside of the breast. We are also studying whether positron emission tomography (PET/CT) scans can predict which participants will benefit from the study treatment. Finally, we are studying genes and proteins in the tumor tissue that may lead to sensitivity or resistance to Herceptin, and to the combination of Herceptin plus lapatinib. Lapatinib is a compound that may stop cancer cells from growing. Other research studies suggest that lapatinib in combination with Herceptin may help to shrink or stabilize breast cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Herceptin; Drug: Lapatinib

Detailed Description

• Participants will be asked to undergo a biopsy of an area of the body where the cancer has spread.
• Participants will be given a study medication-dosing calendar for each treatment cycle. Each treatment cycle lasts four weeks during which time you will be taking lapatinib, once per day.
• Participants will receive Herceptin once every week or once every 3 weeks through a vein.
• During all treatment cycles a physical exam will be performed and questions about the participants general health will be asked. Blood tests including chemistry and hematology will be performed to measure additional effect of the study drug and disease status. Photographs may be taken of the tumor to assess the response of the tumor to treatment.
• CT scans will be repeated every 8 weeks to assess the effect of the study treatment on the cancer. Either a MUGA scan or echocardiogram will be performed 8 weeks and 16 weeks after the participant starts the study treatment.
• Participants will remain on this research study for as long as they are benefiting from the study treatment.

• Study Type: Interventional
• Enrollment (Actual): 87
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University fo Alabama at Birmingham
  • Illinois
    • Chicago, Illinois, United States, 60452
      • University of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
    • Boston, Massachusetts, United States, 02130
      • Dana-Farber at Faulkner Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor college of medicine

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Histologically or cytologically confirmed invasive breast cancer, with stage IV disease
• HER2-positive breast cancer, defined as 3+ staining by IHC or gene amplification by FISH
• Measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension
• Willingness to undergo a research biopsy of recurrent or metastatic disease
• Prior chemotherapy treatment must be discontinued for at least 2 weeks prior to study entry.
• Completed radiation therapy at least 7 days prior to beginning protocol treatment
• Cohort 1: No prior chemotherapy for advanced breast cancer; no prior trastuzumab in the advanced breast cancer setting; nor prior treatment with lapatinib or other HER2-directed therapy other than trastuzumab
• Cohort 2: Up to two prior chemotherapy regimens for the treatment of advanced breast cancer; no prior treatment with lapatinib or other HER2-directed therapy except for trastuzumab
• 18 years of age or older
• Life expectancy of greater than 12 weeks
• ECOG Performance Status 0-2
• Normal organ and marrow function as outlined in protocol
• Cardiac ejection fraction, as assessed by either MUGA scan or echocardiogram greater than or equal to 50%
• Able to take oral medications

Exclusion Criteria:

• Patients may not be receiving any other investigational agents or concurrent chemotherapy or hormonal therapy for treatment of metastatic disease
• Active brain metastases
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to lapatinib or other agents used in this study
• Clinically significant malabsorption syndrome
• Uncontrolled intercurrent illness
• Pregnant or breastfeeding women
• Concurrent use of the medications listed in the protocol because of possible interaction with lapatinib

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Cohort 1; This cohort is made up of participants without prior trastuzumab for MBC. Adjuvant or neoadjuvant trastuzumab was allowed, if the interval from trastuzumab completion to recurrence exceeded 1 year. 1000 mg daily Lapatinib 2 mg/kg weekly or 6 mg/kg every 3 week dose of trastuzumab	Drug: Herceptin; Other Names: trastuzumab; Drug: Lapatinib; Other Names: Tykerb
Other: Cohort 2; This cohort is made up of participants with one to two lines of chemotherapy for metastatic disease with at least one trastuzumab-containing regimen or patients who recurred within 12 months of adjuvant or neoadjuvant trastuzumab with up to one line of metastatic trastuzumab-based therapy 1000 mg daily Lapatinib 2 mg/kg weekly or 6 mg/kg every 3 week dose of trastuzumab	Drug: Herceptin; Other Names: trastuzumab; Drug: Lapatinib; Other Names: Tykerb

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate	The objective response rate is the percentage of participants achieving complete response (CR) or partial response (PR) as the best response recorded on treatment based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CR and PR must meet the following lesion criteria without having any new lesions as well: Target Lesion: (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Non-Target Lesion: (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Non-CR/Non-Progressive Disease: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have PR in target lesion.	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Top 3 Most Common Treatment RelatedToxicities	Assessed by -Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Top 3 treatment-related all-grade adverse events in terms of incidence. Treatment Related is discerned as follows: Yes: There is a plausible temporal relationship between the onset of the AE and administration of atezolizumab or bevacizumab, and the AE cannot be readily explained by the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the AE follows a known pattern of response to atezolizumab or bevacizumab or with similar treatments; and/or the AE resolves upon discontinuation of the study drugs or dose reduction and, if applicable, reappears upon re-challenge. No: Evidence exists that the AE has an etiology other than the study drugs (e.g., pre existing medical condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE has no plausible temporal relationship to the study drugs administration.	Up to 93 months
Sites of First Progression	Progression is defined by Response Evaluation Criteria In Solid Tumors Criteria 1.1 (RECIST) as follows: - >20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including baseline if it's the smallest). The sum must also demonstrate an increase of >5 mm. OR -Appearance of new lesions and/or unequivocal progression of non-target lesions. It must be representative of overall disease status change, not a single lesion increase. For patients with PD at the first on-treatment imaging assessment, patients will be allowed to remain on study until confirmation at the next assessment at investigator discretion if patient is benefiting from treatment.	Up to 93 months
Clinical Benefit Rate	Clinical Benefit Rate is the percentage of participants who achieve clinical benefit from the study treatment. Clinical benefit is defined as at least 24 weeks of confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD). SD or better is achieved if the following are true: Target Lesions: -At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Non-target Lesions: No progression. No appearance new lesions or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.	Up to 93 months
3-Year Overall Survival	Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. 3-Year survival is calculated using Kaplan-Meier methods.	Up to 93 months
Median Time to Progression	Time to progression (TTP) is defined as the time from study entry to disease progression by RECIST. Subjects are considered to have progressed if they discontinue treatment due to clinical deterioration from breast cancer or die on-treatment of any cause. TTP is censored at the time of initiation of alternative therapy or time of last contact. The time to progression is calculated using a Kaplan-Meier emthods. Progression is defined by RECIST as: >20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including baseline if it's the smallest). The sum must also demonstrate an increase of >5 mm. OR Appearance of new lesions and/or unequivocal progression of non-target lesions. It must be representative of overall disease status change, not a single lesion increase.	Up to 93 months

Collaborators and Investigators

• Sponsor: Nancy Lin, MD
• Collaborators: GlaxoSmithKline; Novartis
• Investigators: Principal Investigator: Nancy Lin, MD, Dana-Farber Cancer Institute

Publications and helpful links

General Publications

• Lin NU, Guo H, Yap JT, Mayer IA, Falkson CI, Hobday TJ, Dees EC, Richardson AL, Nanda R, Rimawi MF, Ryabin N, Najita JS, Barry WT, Arteaga CL, Wolff AC, Krop IE, Winer EP, Van den Abbeele AD. Phase II Study of Lapatinib in Combination With Trastuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer: Clinical Outcomes and Predictive Value of Early [18F]Fluorodeoxyglucose Positron Emission Tomography Imaging (TBCRC 003). J Clin Oncol. 2015 Aug 20;33(24):2623-31. doi: 10.1200/JCO.2014.60.0353. Epub 2015 Jul 13.

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2007
• Primary Completion (Actual): November 30, 2013
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: May 7, 2007
• First Submitted That Met QC Criteria: May 7, 2007
• First Posted (Estimated): May 8, 2007

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 26, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: HER2-positive breast cancer; trastuzumab; Herceptin
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Trastuzumab; Lapatinib
• Other Study ID Numbers: 06-213

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED