Lapatinib in Combination With Vinorelbine

Study Overview
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Brief Summary
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This is a randomized, parallel-arm, open-label, multi-centre, Phase II study to determine the efficacy and safety of lapatinib in combination with vinorelbine or capecitabine in women with ErbB2 overexpressing metastatic breast cancer (MBC) who have received no more than one chemotherapeutic regimen in the metastatic setting.

Detailed Description
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Approximately 105 subjects will be enrolled in the study and randomized 2:1 to one of the following regimens Arm A (n=70): Lapatinib 1250 mg orally once daily continuously plus Vinorelbine 20mg/m2 intravenously (IV) on day 1 and 8, every third week, or Arm B (n=35): Lapatinib 1250 mg orally once daily (QD) continuously plus Capecitabine 2000 mg/m2/day orally in 2 doses 12 hours apart on days 1-14 every third week. Randomization will be stratified according to the following variables: 1) Prior receipt of therapy for metastatic breast cancer (Yes or No), and 2) Site of metastatic disease (Visceral/Soft tissue or Bone-only). Subjects will receive randomized study treatment until disease progression or discontinuation of study treatment due to unacceptable toxicity, withdrawal of consent, lost to follow up, or death. All subjects who discontinue study treatment without documented progression will continue to be followed for progression according to protocol-schedule until new anti-cancer therapy is initiated and/or progression or death is documented. Survival data will be collected for all subjects to ensure a minimum of 18 months survival data. This study will include a safety run-in phase for approximately the first 30 subjects (20 randomized to lapatinib and vinorelbine; 10 to lapatinib and capecitabine).

Official Title
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A Phase II, Randomised, Multi-Centre Study Evaluating Lapatinib in Combination With Vinorelbine or Capecitabine in Women With ErbB2 Overexpressing Metastatic Breast Cancer

Conditions
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Cancer

Intervention / Treatment
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* Drug: Vinorelbine
* Drug: Lapatinib
* Drug: Capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria : Signed informed consent prior to registration. Considered by the investigator to have a life expectancy of ≥12 weeks. Subjects must be female and have histologically - confirmed invasive breast cancer with Stage IV disease at primary diagnosis or at relapse after curative - intent surgery. Documented overexpression of ErbB2 Subjects should have progressive disease following prior therapy which may include anthracyclines, taxanes, and trastuzumab. Females aged ≥18 years Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1. Subjects must have adequate organ and marrow function Subjects must have a cardiac ejection fraction of at least 50% and within the institutional range of normal. Radiotherapy prior to initiation of study medication is allowed to a limited area ( e . g . , palliative therapy ) , if it is not the sole site of disease. Subjects with stable central nervous system (CNS) metastases are permitted. Subject must be free of gastrointestinal diseases or any other conditions that impede swallowing, retaining, and absorption of oral medications. Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of study medication. Prophylactic use of bisphosphonates in subjects without bone disease, except for the treatment of osteoporosis, is not permitted. Exclusion Criteria: Subjects taking prohibited medications are not eligible for the study. Therapy with lapatinib, vinorelbine, or capecitabine prior to randomization into this study. Prior therapy with more than one chemotherapeutic regimen for metastatic breast cancer. Concurrent anticancer or concomitant radiotherapy treatment. History of uncontrolled or symptomatic angina; history of arrhythmias requiring medications ; clinically significant myocardial infarction < 6 months from study entry; uncontrolled or symptomatic congestive heart failure; ejection fraction below the institutional normal limit; or any other cardiac condition, which in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient. Have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment). Use of an investigational drug within 30 days or 5 half - lives, whichever is longer, preceding the first dose of investigational treatment, or, concurrent treatment with an investigational agent or participation in another clinical trial involving investigational agents. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to any of the agents used in this study or their excipients that in the opinion of the investigator or GSK Medical Monitor contraindicates their participation. Known deficiency for the enzyme dihydropyrimidine dehydrogenase (DPD). Known history of uncontrolled inter - current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia, or psychiatric illness / social situations that would limit compliance with study requirements. 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. Pregnant or lactating females at any time during the study (due to the potential teratogenic or abortifacient effects of lapatinib and breastfeeding). Subjects with diseases affecting gastrointestinal function resulting in an inability to take oral medication , including ; malabsorption syndrome, disease significantly affecting gastrointestinal function , or resection of the stomach , small bowel , or colon. Subjects with inflammatory bowel disease or ulcerative colitis are also excluded. Peripheral neuropathy of Grade 2 or greater. Unresolved or unstable, serious toxicity from prior administration of another investigational drug and / or of prior cancer treatment. Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Crossover Assignment
Interventional Model Description: After disease progression in the Randomized Phase (in which participants received lapatinib plus vinorelbine), participants were given the option of crossing over to the alternative treatment arm (lapatinib plus capecitabine), and continuing in a post-progression Cross-over Phase.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib + Vinorelbine<br>Lapatinib + Vinorelbine | Drug: Vinorelbine<br>* Vinorelbine<br>Drug: Lapatinib<br>* Lapatinib<br>|
| Active Comparator: Lapatinib + Capecitabine<br>Lapatinib + Capecitabine | Drug: Lapatinib<br>* Lapatinib<br>Drug: Capecitabine<br>* Capecitabine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) in the Randomized Phase | PFS is defined as the time from randomization until the earliest date of disease progression (PD) or death due to any cause, if sooner. PD is defined as at least a 20 % increase in the sum of the longest diameter (LD) of target lesions, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of >=1 new lesion. | From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Overall Response (OR), as Assessed by the Investigator in the Randomized Phase | OR is defined as the number of participants achieving either a confirmed complete response (CR: the disappearance of all target lesions [TLs]) or partial response (PR: a >=30% decrease in the sum of the longest diameter [LD] of the TLs, taking as reference the baseline sum LD) as assessed by the investigator as the best OR. | From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks) | 
| Overall Survival (OS) | OS is defined as the time from randomization to the date of death due to any cause. Participants who had not died were censored at the date of the last adequate tumor assessment at the time of the cut-off. | From the date of randomization until death (average of 55 study weeks) | 
| Duration of Response (DOR) in the Randomized Phase | DOR is defined as the time from the first documented evidence of response (CR or PR) until the first documented sign of disease progression (a >=20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since the treatment started or the appearance of >=1 new lesion) or death, if sooner. CR=the disappearance of all TLs. PR=a >=30% decrease in the sum of the LD of target lesions, taking as a reference the Baseline sum LD. | From the time of the first documented confirmed complete or partial response until disease progression or death, if sooner (average of 27 study weeks) | 
| Time to Response in the Randomized Phase | Time to response is defined as the time from randomization until the first documented evidence of CR (the disappearance of all TLs) or PR (a >=30% decrease in the sum of the LD of the TLs, taking as a reference the basline sum LD) (whichever status is recorded first). When tumor response was confirmed at a repeat assessment, the time to response was taken to be the first time that the response was observed. | From randomization until the time of the first documented confirmed CR or PR (average of 27 study weeks) | 
| Number of Participants With Clinical Benefit (CB) in the Randomized Phase | CB is defined as the the number of participants achieving either a confirmed CR or PR or having stable disease (SD) for at least 24 weeks (i.e., approximately 6 months). CR=the disappearance of all TLs. PR=a >=30% decrease in the sum of the LD of TLs, taking as a reference the Baseline sum LD. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD=at least a 20% increase in the sum of the LD of target lesions, taking as a reference the smallest sum LD recorded since the treatment started or the appearance of >=1 new lesion). Participants with unknown or missing responses were treated as non-responders. | From randomization until disease progression, death, or discontinuation from the study (average of 27 study weeks) | 
| Area Under the Concentration-time Curve Over the Dosing Interval (AUC-tau) for Vinorelbine | AUC-tau is defined as the area under the concentration-time curve over a dosing interval at steady state, where tau is the length of the dosing interval. The AUC is of particular use in estimating the bioavailability of drugs, by measuring the extent of absorption. Pharmacokinetic (PK) parameters were to be assessed in an optional sub-study. No participants were enrolled in this optional sub-study; thus, no PK data are available. | Days 1 and 8; 0 to 24 hours post-dose | 
| Maximum Concentration (Cmax) for Vinorelbine | Cmax is defined as the maximum observed plasma or serum concentration after administration of the drug. PK parameters were to be assessed in an optional sub-study. No participants were enrolled in this optional sub-study; thus, no PK data are available. | Days 1 and 8; 0 to 24 hours post-dose | 
| Number of Participants With Grade 4 and Grade 5 Adverse Events (AE) | An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grades: 0 = no AE or within normal limits; 1 = mild AE; 2 = moderate AE; 3 = severe and undesirable AE; 4 = life-threatening or disabling AE; 5 = death related to AE. | From randomization until disease progression, death, or discontinuation from the study (average of 55 study weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoplasms, Breast