Study In Women And Men With Metastatic Breast Cancer That Have Overexpression Of ErbB2

Study Overview
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Brief Summary
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This was a randomized, double-blind, placebo-controlled, multicenter, Phase III study to evaluate and compare the efficacy and safety of Lapatinib + Paclitaxel versus Placebo + Paclitaxel in men and women with ErbB2 amplified metastatic (Stage IV) breast cancer who had not received prior therapy for metastatic disease.

Detailed Description
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Subjects were randomized to receive either Lapatinib (1500 mg once daily) + Paclitaxel (80 mg/m2 IV weekly for 3 weeks every 4 weeks) or Placebo (once daily) + Paclitaxel (80 mg/m2 IV weekly for 3 weeks every 4 weeks). Subjects who progressed while on study and were on the placebo+paclitaxel arm were permitted to enter an extension phase of open label monotherapy therapy with lapatinib or open label combination therapy with lapatinib+paclitaxel and followed for response, progression and survival. Based on the positive results in the primary analysis, Protocol Amendment 02 (dated 09 May 2011) discontinued further entry into the lapatinib monotherapy extension phase, and ongoing subjects taking placebo were permitted to replace it with open label lapatinib therapy (with or without continued paclitaxel therapy). Following the primary Overall Survival (OS) analysis and subsequent implementation of Protocol Amendment 03, subjects who were still receiving active treatment entered the Long-term follow-up (LTFU) phase of the study. Reporting requirements in the LTFU phase were limited to Adverse events of special interest (AESI), Serious adverse events (SAEs) and pregnancy, and the subjects continued to receive treatment until the occurrence of unacceptable toxicity or disease progression (as determined by the investigator) or permanent withdrawal from treatment for any reason. Subjects who were no longer receiving active treatment were withdrawn from the study.

Official Title
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A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Phase III Study of Lapatinib (GW572016) in Combination With Paclitaxel Versus Paclitaxel Plus Placebo in Subjects With ErbB2 Amplified Metastatic Breast Cancer

Conditions
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Neoplasms, Breast

Intervention / Treatment
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* Drug: Lapatinib (GW572016) oral tablets
* Drug: Paclitaxel infusion
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Signed informed consent; Male or female ≥18 years; Histologically confirmed invasive breast cancer with stage IV disease; If the disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology or histology. Documented amplification of ErbB2 by fluorescence in situ hybridization (FISH) in primary or metastatic tumor tissue by the central laboratory for randomization into the study; If a taxane was administered in the neoadjuvant or adjuvant setting, progression must have occurred >12 months after completion of this treatment and the patient recovered from all associated toxicities; Measurable lesion(s) according to RECIST (Response Evaluation Criteria in Solid Tumors); Radiotherapy as palliative treatment for painful metastatic disease is permitted but must have been stopped within 2 weeks prior to initiation of any investigational treatment. All subjects must have recovered from all radiotherapy related toxicities prior to initiation of any investigational treatment. The site of radiotherapy must not be used as a site of measurable disease; Bisphosphonate therapy for bone metastases and is allowed; however, treatment must be initiated prior to the first dose of investigational treatment. Prophylactic use of bisphosphonates in subjects without bone disease is not permitted, except for the treatment of osteoporosis; For those patients whose disease is ER+ and/or PR+ the following criteria should be met: Patients with visceral disease that requires chemotherapy (eg., patients with liver or lung metastases) Rapidly progressing or life threatening disease, as determined by the investigator Patients who received hormonal therapy and are no longer benefiting from this therapy and the hormonal treatment must have been stopped before the first dose of investigational treatment; Cardiac ejection fraction within institutional range of normal as measured by echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive; ECOG Performance Status of 0 to 1; Life expectancy of ≥ 12 weeks; Able to swallow and retain oral medication; Archived tumor tissue available for testing; Women and men with potential to have children must be willing to practice acceptable methods of birth control during the study; Willing to complete all screening assessments as outlined in the protocol; Adequate organ function as defined in Table 1 Baseline Laboratory Values; Exclusion Criteria: Pregnant or lactating females at anytime during the study Subjects with only non-measurable metastatic sites of disease per RECIST, (e.g. bone metastases, pleural effusion, or ascites, etc. (Refer to Section 5.3 Efficacy for list sites considered to be non-measurable disease.); Received prior chemotherapy, immunotherapy, biologic therapy, or anti-ErbB1/ErbB2 therapy for metastatic disease. Prior therapy with an ErbB1 and/or ErbB2 inhibitor, other than trastuzumab in the adjuvant setting. If trastuzumab was administered in the adjuvant setting, then > 12 months must have elapsed since completion of trastuzumab therapy; Planned concurrent anti-cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy) while taking investigational treatment; Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment; Peripheral neuropathy of Grade 2 or greater; Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded; History of other malignancy. However, subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma, are eligible; Concurrent disease or condition that would make the subject inappropriate for study participation, or any serious medical disorder that would interfere with the subject's safety; Uncontrolled infection; Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent; Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure; Known history or clinical evidence of central nervous system (CNS) metastases or leptomeningeal carcinomatosis; Concurrent treatment with prohibited medications, including herbal remedies and Chinese traditional medicines; Concurrent treatment with an investigational agent or participation in another clinical trial involving investigational agents; Used an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of investigational treatment; Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to paclitaxel or lapatinib or their excipients.

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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paclitaxel and Lapatinib (Blinded)<br>Paclitaxel and Lapatinib (Blinded) | Drug: Lapatinib (GW572016) oral tablets<br>* 1500 mg oral daily continuously<br>Drug: Paclitaxel infusion<br>* Paclitaxel 80 mg/m2 every 3 weeks, 4th week rest for minimum 6 months<br>|
| Active Comparator: Paclitaxel and Placebo (Blinded)<br>Paclitaxel and Placebo (Blinded) | Drug: Paclitaxel infusion<br>* Paclitaxel 80 mg/m2 every 3 weeks, 4th week rest for minimum 6 months<br>Drug: Placebo<br>* Paclitaxel Matching Placebo<br>|
| Other: Open Label - Monotherapy (Extension Phase)<br>Open Label - Monotherapy (Lapatinib) | Drug: Lapatinib (GW572016) oral tablets<br>* 1500 mg oral daily continuously<br>|
| Other: Open Label - Combination Therapy (Extension Phase)<br>Open Label - Combination Therapy (Lapatinib and Paclitaxel) | Drug: Lapatinib (GW572016) oral tablets<br>* 1500 mg oral daily continuously<br>Drug: Paclitaxel infusion<br>* Paclitaxel 80 mg/m2 every 3 weeks, 4th week rest for minimum 6 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) at 53 Months | Overall Survival (OS) was defined as the interval of time (in months) between the date of randomization and the date of death due to any cause. | From date of randomization until date of death from any cause, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) at 190 Months | Overall Survival (OS) was defined as the interval of time (in months) between the date of randomization and the date of death due to any cause. | From date of randomization until date of death from any cause, assessed up to 190 months (Final OS analysis cut-off date = 23-Nov-2021) | 
| Progression-free Survival (PFS) by Investigator Assessment | Progression-free survival (PFS) during the randomized phase was defined as the interval of time (in months) between the date of randomization and the earlier of date of disease progression (radiological or clinical assessment of symptomatic progression), or date of death due to any cause. | From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021) | 
| Overall Response Rate (ORR) by Investigator Assessment | Overall response rate (ORR) during the randomized phase was evaluated per Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and defined as the percentage of subjects achieving either a Complete Response (CR) or a Partial Response (PR). Participants with unknown or missing responses were treated as non-responders. | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021) | 
| Clinical Benefit Rate (CBR) | Clinical benefit rate (CBR) was defined as the percentage of subjects with evidence of CR or PR or stable disease (neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of >=1 new lesions], taking as reference the smallest sum LD since treatment start) of >=24 weeks, based on confirmed responses from the investigator assessment of best overall response during the randomized phase. | From date of randomization until date of progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary analysis cut-off date = 18-Jun-2010) | 
| Duration of Response (DOR) | For subjects who show CR or PR, duration of response (DOR) was defined to be the time from first documented evidence of PR or CR until the first documented sign of disease progression (radiological or clinical assessment of symptomatic progression) or death due to any cause, if sooner during the randomized phase. | From date of confirmed CR or PR until date of progression or date of death from any cause, whichever comes first, assessed up to 190 months (Final analysis cut-off date = 23-Nov-2021) | 
| Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | The original outcome measure to be analyzed was Time to response (TTR) during the randomized phase defined as the time from randomization until first documented evidence of PR or CR (whichever status was recorded first); however, data were presented as the number of participants with a response at each nominal visit. Responses were based on the investigator's assessment, and only participants with a confirmed CR or PR were included in this analysis. | Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72 | 
| Number of Tumors Evaluable for PIK3CA Mutations | Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue. | Baseline | 
| Number of Participants With Tumors Evaluable for PTEN | Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression. | Baseline | 
| Predictive Effect of PIK3CA Mutations Status on Overall Response Rate (ORR) | ORR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving either CR or PR. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue. | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010) | 
| Predictive Effect of PTEN Low on Overall Response Rate (ORR) | ORR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving either CR or PR. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression. Tumors scored IHC 0/1+ were considered PTEN low. | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010) | 
| Predictive Effect of PIK3CA Mutations Status on Clinical Benefit Rate (CBR) | CBR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving CR or PR or stable disease. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. A PIK3CA mutation test kit was used to assess mutation status on genomic deoxyribonucleic acid (DNA) isolated from tumor tissue. | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010) | 
| Predictive Effect of PTEN Low on Clinical Benefit Rate (CBR) | CBR was evaluated per RECIST v1.1 and defined as the percentage of subjects achieving CR or PR or stable disease. Phosphatidylinositol 3-kinase (PI3K) pathway deregulation (that is PIK3CA mutations and/or phosphatase and tensin homolog (PTEN) loss) was studied to evaluate the predictive and prognostic value of PIK3CA mutations and/or PTEN low in HER2-positive patients receiving first-line treatment with paclitaxel alone or in combination with lapatinib. Immunohistochemistry (IHC) staining in an analytically validated assay was used in the assessment of PTEN protein expression on tumor tissue. Staining intensity was allocated a score of 0, 1+, 2+ or 3+. Tumors scored IHC 0 were considered as exhibiting an absence of PTEN expression whereas those scored ICH 1+, 2+ or 3+ were considered as exhibiting any PTEN expression, being 3+ the highest expression. Tumors scored IHC 0/1+ were considered PTEN low. | From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 53 months (Primary OS analysis cut-off date = 18-Jun-2010) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ErbB2 positive, human epidermal growth factor receptor 2 positive (Her2+), metastatic breast cancer, Fluorescence in situ hybridization (FISH) positive, Stage IV