Evaluating Lapatinib + Capecitabine in Patients Aged 70 and Over With HER2 Metastatic Breast Cancer.

Study Overview
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Brief Summary
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GERICO 09/0907 is a Phase II multicentric trial evaluating the toxicity and activity of the combination of lapatinib and capecitabine in locally advanced or metastatic breast cancer over expressing HER2 for patients aged ≥ 70 who have failed after one line of chemotherapy in combination with trastuzumab. Due to the minimal participation of older people in clinical trials, there is a lack of data to make evidence-based decisions regarding chemotherapy in this indication. The study is designed to investigate whether elderly patients with locally advanced or metastatic breast cancer over-expressing HER2 could take advantage of the combination lapatinib and capecitabine in term of clinical benefit, and with no adverse effects and no detrimental impact on functional status (part of geriatric assessment). The main objective is to assess clinical benefit (defined at 4 months as complete response, partial response or stable disease), safety and preserved geriatric independence (main objective is a bi-criteria or composite criteria).

Detailed Description
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More than half of patients who have breast cancer with Her2-positive tumors treated with trastuzumab as a single agent develop resistance within one year of treatment initiation. Recent studies on this population of patients show that the use of Capecitabine combined with Lapatinib demonstrates an improvement of TTP without an increase of serious toxic effects. Our study is designed to investigate whether elderly patients with locally advanced or metastatic breast cancer over-expressing HER2 could take advantage of the combination lapatinib (1250mg/day) and capecitabine (1st cycle day 1 to day 14: 850mg/m2/day x2; next cycles day 1 to day 14: 1000 mg/m2/day x2) in term of clinical benefit, and with no adverse effects and no detrimental impact on functional status (part of geriatric assessment). Treatment will continue until disease progression or unacceptable toxicity occurence. This is a phase II multicentric trial associated to a pharmacokinetic study which aims to assess the effect of age modifications (absorption, distribution, metabolism and elimination) on the combination Lapatinib-Capecitabine by measuring the Cmin-Cmax of both components in elderly patients.

Official Title
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PHASE II STUDY Evaluating the Toxicity and Activity of the Combination Lapatinib + Capecitabine in Elderly Patients Aged 70 and Over With Metastatic Breast Cancer Over Expressing HER2

Conditions
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Metastatic Breast Cancer, 70 Years Old Patients and Over, After One Line of Chemotherapy With Trastuzumab

Intervention / Treatment
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* Drug: lapatinib + capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 70 Histological confirmed advanced breast cancer (metastatic or locally advanced) Tumor over expressing HER2 (HER2 3+ in IHC or IHC 2+ and Fish positive) in sample from the primary and/or secondary tumor WHO performance status (EGOG) from 0 to 2 MMS > 25 Measurable disease (RECIST criteria) Progression of disease after one metastatic line of chemotherapy associated with trastuzumab (must be stopped at least 3 weeks before beginning the trial) Adequate hematological function (Hb ≥ 10g/dl, ANC ≥ 1500/mm3, platelets ≥ 100 000/mm3) Adequate hepatic function (total bilirubine ≤ 1.5ULN, ASAT and ALAT ≤ 3ULN) Adequate renal function (measured or calculated creatinine clearance ≥ 40 ml/min - Cockroft) LVEF ≥ 50% (US or isotopic method) Absence of treatment by enzymatic inhibitors or inducers or any gastric pH modifying agent/drug within a 7-to-14 day period preceding the first administration of one of the trial's products and within the overall duration of the study (see medication list) Patients must be affiliated to a Social Security System Patient information and written informed consent form signed Exclusion Criteria: Life expectancy < 3 months Prior treatment with capecitabine or lapatinib Concomitant radiotherapy except for palliative reason and more than 25% of the BM Patients with pre-existing toxicity ≥ grade 2 (excepted alopecia) Patients with dysphagia, or inability to swallow the capsules. Patient with malabsorption syndrome or disease significantly affecting gastro-intestinal function or with major resection of stomach or proximal bowel that could affect absorption of oral drugs Patient already included in another therapeutic trial using an experimental drug within 30 days preceding entry into the study Individual deprived of liberty or placed under the authority of a tutor Patient with any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Ages Eligible for Study
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Minimum Age: 70 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lapatinib + Capecitabine<br>lapatinib 1250 mg/day (once daily) Capecitabine 2x850 mg/m2/day, days 1-14 during the first cycle and 2x1000 mg/m2/day, days 1-14, every 21 days for following cycles ( if no unacceptable toxicity is observed). | Drug: lapatinib + capecitabine<br>* For Lapatinib: 5 tablets of 250 mg each, once daily, until disease progression or unacceptable toxicity occurence. For Capecitabine: 850 mg/m2 twice a day from day 1 to 14 of cycle 1 and 1000 mg/m2 twice a day from day 1 to 14 of the next cycles.<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy assessment | Benefit is defined as complete response, partial response, or stable disease according to RECIST criteria (vers. 1.1). Efficacy criteria is the number of patients meeting this definition. Patients having stopped before this 4-months time point will be considered as non responders without clinical benefit. | at 4 months | 
| Tolerance criteria and impact on functional status | The criteria is the number of patients for whom a toxicity event (according to the NCI-CTC AE vers.4)and/or an impact on functional status (defined by the 8 items IADL assessment scale) has been observed during the first 4 months of treatment. | at 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of clinical benefit |  | from treatment start until disease progression | 
| Time to progression |  | from inclusion to disease progression or death due to breast cancer | 
| Overall response rate |  | from treatment start until end of treatment | 
| Progression free survival |  | from inclusion to disease progression or death due to any cause | 
| Overall survival |  | from inclusion until death due to any cause or last follow-up news (censored data) | 
| Time to treatment failure endpoint | Treatment stop can be due to toxicity, death, refusal to continue study, or progressive disease. | from inclusion to end of treatment | 
| Determination of toxicity of the combination (NCI-CTC vers.4) |  | from informed consent signature to one month after last study drug intake | 
| Geriatric Evaluation | Activities of daily Living (ADL)/ Instrumental ADL(IADL), Geriatric depression scale (GDS), Mini Mental States (MMS), comorbidities (CIRGS), G8 (oncodage), Vulnerable Elders Survey (VES13), QLQC30 item 29-30. | At baseline, at uneven cycles, at end of treatment and at follow-up visits (every 6 months) | 
| Determination of the minimal and maximal concentration of lapatinib and capecitabine | The samples time points are the followings: T0 : before administration of treatment (lapatinib is administered 1 hour before meal and capecitabine 30 min before meal) T1 : time for Cmax (2 hrs post-dose lapatinib and 90 min post-dose of capecitabine) | at Day1 Cycle1 and Day1 Cycle3 | 
| Number of patients treated with 3 and 6 cycles and % of dose administrated |  | From treatment start until 6 cycles of treament |