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

Phase 3

Completed

Conditions: Neoplasms, Breast

Interventions: Drug: Lapatinib (GW572016) oral tablets
Drug: Paclitaxel infusion
Drug: Placebo

Registration Number: NCT00281658

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: 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: 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 Subjects who were no longer receiving active treatment were withdrawn from the study.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 444

Inclusion Criteria

Not provided

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Paclitaxel and Lapatinib (Blinded)	Lapatinib (GW572016) oral tablets	Paclitaxel and Lapatinib (Blinded)
Paclitaxel and Lapatinib (Blinded)	Paclitaxel infusion	Paclitaxel and Lapatinib (Blinded)
Paclitaxel and Placebo (Blinded)	Placebo	Paclitaxel and Placebo (Blinded)
Open Label - Monotherapy (Extension Phase)	Lapatinib (GW572016) oral tablets	Open Label - Monotherapy (Lapatinib)
Open Label - Combination Therapy (Extension Phase)	Lapatinib (GW572016) oral tablets	Open Label - Combination Therapy (Lapatinib and Paclitaxel)
Open Label - Combination Therapy (Extension Phase)	Paclitaxel infusion	Open Label - Combination Therapy (Lapatinib and Paclitaxel)
Paclitaxel and Placebo (Blinded)	Paclitaxel infusion	Paclitaxel and Placebo (Blinded)

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS) at 53 Months	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)	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.

Secondary Outcome Measures

Name	Time	Method
Overall Response Rate (ORR) by Investigator Assessment	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)	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.
Duration of Response (DOR)	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)	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.
Number of Participants With a CR or PR at Weeks 8, 12, 16, 24, 32, 40, 48, 56, 64, and 72	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.
Number of Tumors Evaluable for PIK3CA Mutations	Baseline	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.
Number of Participants With Tumors Evaluable for PTEN	Baseline	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.
Predictive Effect of PIK3CA Mutations Status on Overall Response Rate (ORR)	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)	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.
Overall Survival (OS) at 190 Months	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)	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.
Progression-free Survival (PFS) by Investigator Assessment	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)	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.
Clinical Benefit Rate (CBR)	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)	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.
Predictive Effect of PTEN Low on Overall Response Rate (ORR)	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)	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.
Predictive Effect of PIK3CA Mutations Status on Clinical Benefit Rate (CBR)	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)	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.
Predictive Effect of PTEN Low on Clinical Benefit Rate (CBR)	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)	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.