Lapatinib in Combination With Capecitabine in Japanese Patients With Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This study is to evaluate the safety and efficacy of lapatinib taken together with capecitabine in Japanese patients. The study will proceed in two phases; the first phase(Part1) will lead to an evaluation of the mainly tolerability as well as PK parameters. If there are no major safety concerns in Part 1, the study will move into the second phase (Part 2) to further evaluate the safety and clinical activity.

Official Title
-----------------
Clinical Evaluation of Lapatinib Administered With Capecitabine in Japanese Patients With ErbB2 Overexpressing Advanced or Metastatic Breast Cancer

Conditions
-----------------
Metastatic Breast Cancer, Neoplasms, Breast

Intervention / Treatment
-----------------
* Drug: Lapatinib
* Drug: capecitabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Subjects eligible for enrolment in the study must meet all of the following criteria: Patients who have consent to this study participation and signed into Informed consent form. Subjects must have histologically confirmed invasive breast cancer with stage IIIB, stage IIIC with T4 lesion, or stage IV disease. Documentation of ErbB2 overexpression [IHC3+ or IHC2+ with FISH confirmation] is required based on local laboratory. Subjects must have documented progressive advanced or metastatic breast cancer. Subjects must have refractory breast cancer defined as progression in the locally advanced or metastatic setting or relapse within 6 months of completing adjuvant therapy. Prior therapies must include, but are not limited to: Taxane containing regimen for at least 4 cycles or 2 cycles provided disease progression occurred while on taxane. Anthracycline containing regimen for at least 4 cycles or 2 cycles provided disease progression occurred while on anthracycline. Subjects who relapse >6 months after completion of adjuvant anthracycline-containing chemotherapy, and for whom further anthracycline is not indicated, will be considered to have met the anthracycline prior exposure requirement. Taxanes and anthracyclines may have been administered concurrently or separately. Prior treatment with capecitabine is not permitted. Prior treatment must have contained trastuzumab alone or in combination with other chemotherapy for at least 6 weeks of standard doses in the adjuvant or advanced/metastatic setting. Subjects with hormone receptor positive tumors must have disease progression following hormonal therapy unless intolerant to hormonal therapy or hormonal therapy is not considered to be clinically appropriate. Subjects with stable CNS metastases (asymptomatic, and off systemic steroids and anticonvulsants for at least 3 months) are eligible. Measurable disease according to modified RECIST (Response Evaluation Criteria in Solid Tumors) (see Section 6.2, Efficacy p.49). Subjects must have archived tumor tissue available for biomarker assessment. Female subjects must be ≥20 ECOG Performance Status of 0 or 1. Life expectancy of ≥12 weeks. Measurable lesions may be in the field of prior irradiation. However, there must be at least a 4-week period between the last radiation treatment and the baseline scan documenting disease status for the lesion to be measurable. Cardiac ejection fraction within the institutional range of normal as measured by ECHO (or MUGA if ECHO is not available). If no institutional range is available, cardiac ejection fraction must be ≥50%. Adequate hematologic value, hepatic and renal function as defined below. Hematologic ANC (absolute neutrophil count) ≥1.5×109/L Hemoglobin ≥9 g/dL Platelets ≥100× 109/L Hepatic Serum bilirubin ≤1.5×ULN 2.5×ULN if subject has Gilbert's syndrome AST and ALT ≤5×ULN if documented liver metastases 3×ULN without liver metastases Renal Serum creatinine Creatinine clearance* ≤50 mL/min Calculated by the Cockcroft and Gault Method Exclusion criteria: Subjects meeting any of the following criteria must not be enrolled in the study: Pregnant or lactating females. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. In addition, subjects with ulcerative colitis are excluded. History of other malignancy. Subjects who have been disease-free for at least 5 years or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior anticancer therapy. Active or 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, arrhythmia or congestive heart failure. No prior anti-ErbB1/ErbB2 inhibitor for breast cancer other than trastuzumab. Known history or clinical evidence of leptomeningeal carcinomatosis. Concurrent anticancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, or tumor embolization) other than capecitabine. Bisphosphonates for the treatment of bone metastases should not be initiated following the first dose of study medication. Prophylactic use of bisphosphonate in subjects without bone disease is not permitted, except for prevention of osteoporosis. Use of an investigational drug within 30 days or 5 half-lives, whichever is longer, preceding the first dose of study medication. Participation in other studies or use of other investigational drugs during this study. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to lapatinib or excipients of lapatinib. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to capecitabine, fluorouracil or any excipients. Known dihydropyrimidine dehydrogenase (DPD) deficiency. Patients who an investigator judges ineligible to this study in consideration of patient's safety (e.g., complications).

Ages Eligible for Study
-----------------
Minimum Age: 20 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib+capecitabine<br>Lapatinib 1250mg once daily +capecitabine 2000mg/m^2 twice daily (14 days out of 21 days) | Drug: Lapatinib<br>* 1250mg once daily<br>Drug: capecitabine<br>* 2000mg/m^2 twice daily (14 days out of 21 days)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Response (Independent Reviewer-assessed) | CBR is defined as the percentage of participants receiving at least one dose of study medication who achieved a best overall response classified as a complete or partial (confirmed) tumor response or stable disease for at least 6 months (24 weeks). A complete response is defined as the disappearance of all target or non-target lesions, partial response and disease progression as at least a 30% decrease and at least a 20% increase, respectively, in the sum of the longest diameter of target lesions, and stable disease as neither partial response nor disease progression. | Baseline, every 6 weeks until Week 24 and then every 12 weeks until disease progression (up to Week 119) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Progression (Independent Reviewer-assessed) | Time to progression is defined as the interval between the start of treatment and the earliest date of disease progression or death due to breast cancer, if sooner. Time to progression was calculated by using the Kaplan Meier estimate. | Baseline, every 6 weeks until Week 24 and then every 12 weeks until disease progression or death due to breast cancer (up to Week 119) | 
| Progression-free Survival (PFS) (Independent Reviewer-assessed) | PFS is defined as the interval between the start of treatment and the earliest date of disease progression or death of any cause, if sooner. | Baseline, every 6 weeks until Week 24 and then every 12 weeks until disease progression or death (up to Week 119) | 
| 6-Month Progression-free Survival (Independent Reviewer-assessed) | 6-Month progression-free survival is defined as the percentage of participants surviving without progressive disease at 6 months (24 weeks) after the start of treatment. Progressive disease is defined as at least a 20% increase in the sum of the longest diameter of target lesions. | Baseline and then every 6 weeks until Month 6 (Week 24) | 
| Objective Response (Independent Reviewer-assessed) | Objective response is defined as the percentage of participants achieving a best overall response classified as a complete or partial (confirmed) tumor response. Complete response is defined as the disappearance of all target or non-target lesions, and partial response is defined as at least a 30% decrease in the sum of the longest diameter of target lesions. | Baseline every 6 weeks until Week 24 and then every 12 weeks until disease progression or death (up to Week 119) | 
| Overall Survival (Independent Reviewer-assessed) | Overall survival is defined as the time from the start of treatment until death regardless of cause. For participants who did not die, time to death was censored at the time of last confirmation of survival. | Baseline and then followed every 4 weeks until death (up to Week 157.9) while on treatment. After treatment termination, followed every 12 weeks until death (up to Week 157.9) | 
| Time to Response (Independent Reviewer-assessed) | Time to response is defined as the time from the start of treatment until the first documented evidence of complete response or partial response. | Baseline, every 6 weeks until Week 24 and then every 12 weeks until disease progression or death (up to Week 119) | 
| Duration of Response (Independent Reviewer-assessed) | For the subset of participants who showed a complete or partial response, duration of response is defined as the time from the first documented evidence of partial or complete tumor response until the first documented sign of disease progression or death due to breast cancer, if sooner. | Baseline, every 6 weeks until Week 24 and then every 12 weeks until disease progression or death (up to Week 119) | 
| Maximum Plasma Concentration (Cmax) of Lapatinib | Pharmacokinetic (PK) samples were collected at pre-dose, and at 1, 2, 3, 4 (plus or minus 15 minutes), 6, 8, 10, 12, and 24 hours (hr) (plus or minus 30 minutes) after dosing. Cmax is defined as the maximum concentration of lapatinib. | Week 2 | 
| Time to Maximum Plasma Concentration (Tmax) of Lapatinib | PK samples were collected at pre-dose, and at 1, 2, 3, 4 (plus or minus 15 minutes), 6, 8, 10, 12, and 24 hr (plus or minus 30 minutes) after dosing. Tmax is defined as the time to peak concentration from initiation of lapatinib dosing. | Week 2 | 
| Terminal Elimination Half-life (t1/2) of Lapatinib | Terminal elimination half-life is defined as the duration until observation of half of the maximum concentration. PK samples were collected at pre-dose, and at 1, 2, 3, 4 (plus or minus 15 minutes), 6, 8, 10, 12, and 24 hr (plus or minus 30 minutes) after dosing. | Week 2 | 
| Area Under the Plasma Concentration-time Curve Within the Dosing Interval AUC0-tau of Lapatinib | PK samples were collected at pre-dose, and at 1, 2, 3, 4 (plus or minus 15 minutes), 6, 8, 10, 12, and 24 hr (plus or minus 30 minutes) after dosing. AUC is defined as the area under the concentration-time curve from 0 to last quantifiable concentration (AUC 0-tau). AUC is a measure of exposure. | Week 2 | 
| Area Under the Plasma Concentration-time Curve From Zero to 24 Hours AUC0-24 of Lapatinib | PK samples were collected at pre-dose, and at 1, 2, 3, 4 (plus or minus 15 minutes), 6, 8, 10, 12, and 24 hr (plus or minus 30 minutes) after dosing. AUC is defined as the area under the concentration-time curve from 0 to 24 hour after dosing (AUC 0-24). AUC is a measure of exposure. | Week 2 | 
| Cmax of Capecitabine, 5'-Fluorouracil (5-FU), and Alpha-fluoro-beta-alanine (FBAL) | PK samples were collected at pre-dose, and at 0.5 (plus or minus 5 minutes), 1, 2, 3, 4 (plus or minus 15 minutes), 6, 8, and 10 hr (plus or minus 30 minutes) after dosing. Cmax is defined as the maximum concentration of drug. 5-FU and FBAL were evaluated because of the following reasons: (1) capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors; (2) FBAL is an inactive major metabolite of capecitabine, and metabolites of capecitabine are excreted mainly in urine. | Week 2 | 
| Tmax of Capecitabine, 5'-Fluorouracil (5-FU), and Alpha-fluoro-beta-alanine (FBAL) | PK samples were collected at pre-dose, and at 0.5 (plus or minus 5 minutes), 1, 2, 3, 4 (plus or minus 15 minutes), 6, 8, and 10 hr (plus or minus 30 minutes) after dosing. Tmax is defined as the time to peak concentration from initiation of dosing. 5-FU and FBAL were evaluated because of the following reasons: (1) capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors; (2) FBAL is an inactive major metabolite of capecitabine, and metabolites of capecitabine are excreted mainly in urine. | Week 2 | 
| t1/2 of Capecitabine, 5'-Fluorouracil (5-FU), and Alpha-fluoro-beta-alanine (FBAL) | Terminal elimination half-life is defined as the duration until observation of half of the maximum concentration. PK samples were collected at pre-dose, and at 0.5 (plus or minus 5 minutes), 1, 2, 3, 4 (plus or minus 15 minutes), 6, 8, and 10 hr (plus or minus 30 minutes) after dosing. 5-FU and FBAL were evaluated because of the following reasons: (1) capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors; (2) FBAL is an inactive major metabolite of capecitabine, and metabolites of capecitabine are excreted mainly in urine. | Week 2 | 
| AUC0-tau of Capecitabine, 5'-Fluorouracil (5-FU), and Alpha-fluoro-beta-alanine (FBAL) | PK samples were collected at pre-dose, and at 0.5 (plus or minus 5 minutes), 1, 2, 3, 4 (plus or minus 15 minutes), 6, 8, and 10 hr (plus or minus 30 minutes) after dosing. AUC is defined as the area under the concentration-time curve from 0 to last quantifiable concentration (AUC 0-tau). 5-FU and FBAL were evaluated because of the following reasons: (1) capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors; (2) FBAL is an inactive major metabolite of capecitabine, and metabolites of capecitabine are excreted mainly in urine. | Week 2 | 
| Area Under the Plasma Concentration-time Curve From Zero to 12 Hours (AUC0-12) of Capecitabine, 5'-Fluorouracil (5-FU), and Alpha-fluoro-beta-alanine (FBAL) | PK samples were collected at pre-dose, and at 0.5 (plus or minus 5 minutes), 1, 2, 3, 4 (plus or minus 15 minutes), 6, 8, and 10 hr (plus or minus 30 minutes) after dosing. AUC is defined as the area under the concentration-time curve from 0 to 12 hours after dosing (AUC 0-12). 5-FU and FBAL were evaluated because of the following reasons: (1) capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors; (2) FBAL is an inactive major metabolite of capecitabine, and metabolites of capecitabine are excreted mainly in urine. | Week 2 | 
| Trough Concentration of Lapatinib | PK samples were collected at pre-dose on Day 14 and Day 21 (minus 2 days). Trough concentration is defined as the minimum serum concentration at steady state after a repeated dose of lapatinib. | Week 2 | 
| Trough Concentration of Capecitabine, 5-FU, and FBAL | PK samples were collected at pre-dose on Day 14 (minus 2 days). Trough concentration is defined as the minimum serum concentration at steady state after a repeated dose. 5-FU and FBAL were evaluated because of the following reasons: (1) capecitabine is an orally administered fluoropyrimidine carbamate selectively activated to fluorouracil (5-FU) in tumors; (2) FBAL is an inactive major metabolite of capecitabine, and metabolites of capecitabine are excreted mainly in urine. | Week 2 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
dual kinase inhibitor,, EGFR/ErbB1,, ErbB2-overexpressing,, GW572016,, advanced/metastatic breast cancer, Lapatinib,, HER-2/new,, pharmacokinetics