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

Primary Purpose

Breast Cancer

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Lapatinib
Herceptin
Sponsored by
Nancy Lin, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer focused on measuring HER2-positive breast cancer, Herceptin, trastuzumab

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University fo Alabama at Birmingham
  • University of Chicago
  • Dana-Farber at Faulkner Hospital
  • Beth Israel Deaconess Medical Center
  • Dana-Farber Cancer Institute
  • Mayo Clinic
  • University of North Carolina
  • Vanderbilt University
  • Baylor College of Medicine

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Cohort 1

Cohort 2

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.
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.
PI3K Pathway Alteration Rate
The alteration rate of the PI3K pathway is the percentage of participants having either PTEN loss or a PIK3CA mutation. Participants will be split into two groups: 1) Participants who have never been treated with trastuzumab for metastatic breast cancer. 2) Participants who have been treated with one or two therapies containing trastuzumab for metastatic breast cancer. The alteration rate will be determined for each group and they will compared with each other. To evaluate the relationship between pathway alteration and response, patients will be grouped by RECIST response (responder vs. non-responder with response considered to be CR or PRI) and the alteration rate will be determined by group, combining the cohorts. Both analyses will use a 2-sided 0.05 level Fisher's exact test.

Full Information

First Posted
May 7, 2007
Last Updated
May 19, 2023
Sponsor
Nancy Lin, MD
Collaborators
GlaxoSmithKline, Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT00470704
Brief Title
Lapatinib in Combination With Trastuzumab in Patients With HER2-Positive, Metastatic Breast Cancer
Official Title
A Phase 2 Study of Lapatinib in Combination With Trastuzumab in Patients With HER2-Positive, Metastatic Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
May 14, 2007 (Actual)
Primary Completion Date
November 30, 2013 (Actual)
Study Completion Date
December 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Nancy Lin, MD
Collaborators
GlaxoSmithKline, Novartis

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer
Keywords
HER2-positive breast cancer, Herceptin, trastuzumab

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
87 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort 1
Arm Type
Other
Arm Description
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
Arm Title
Cohort 2
Arm Type
Other
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Lapatinib
Other Intervention Name(s)
Tykerb
Intervention Type
Drug
Intervention Name(s)
Herceptin
Other Intervention Name(s)
trastuzumab
Primary Outcome Measure Information:
Title
Objective Response Rate
Description
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.
Time Frame
8 weeks
Secondary Outcome Measure Information:
Title
Top 3 Most Common Treatment RelatedToxicities
Description
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.
Time Frame
Up to 93 months
Title
Sites of First Progression
Description
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.
Time Frame
Up to 93 months
Title
Clinical Benefit Rate
Description
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.
Time Frame
Up to 93 months
Title
3-Year Overall Survival
Description
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.
Time Frame
Up to 93 months
Title
Median Time to Progression
Description
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.
Time Frame
Up to 93 months
Title
PI3K Pathway Alteration Rate
Description
The alteration rate of the PI3K pathway is the percentage of participants having either PTEN loss or a PIK3CA mutation. Participants will be split into two groups: 1) Participants who have never been treated with trastuzumab for metastatic breast cancer. 2) Participants who have been treated with one or two therapies containing trastuzumab for metastatic breast cancer. The alteration rate will be determined for each group and they will compared with each other. To evaluate the relationship between pathway alteration and response, patients will be grouped by RECIST response (responder vs. non-responder with response considered to be CR or PRI) and the alteration rate will be determined by group, combining the cohorts. Both analyses will use a 2-sided 0.05 level Fisher's exact test.
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nancy Lin, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
University fo Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
University of Chicago
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60452
Country
United States
Facility Name
Dana-Farber at Faulkner Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02130
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
University of North Carolina
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
26169615
Citation
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.
Results Reference
derived

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

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