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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Lapatinib
* Drug: Herceptin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Cohort 1<br>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: Lapatinib<br> <br> * Other names: Tykerb;Drug: Herceptin<br> <br> * Other names: trastuzumab;|
| Other: Cohort 2<br>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: Lapatinib<br> <br> * Other names: Tykerb;Drug: Herceptin<br> <br> * Other names: trastuzumab;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-positive breast cancer, Herceptin, trastuzumab