Resumen

A pesar de estas señales positivas iniciales en las estadísticas recientes, el cáncer de mama continúa cobrando un número sustancial de vidas, aproximadamente 500.000 muertes en todo el mundo en 2005. Por lo tanto, el paradigma de tratamiento actual —cirugía, radioterapia y quimioterapia sistémica y/o terapia hormonal y terapias biológicas— aún no logra curar a un número significativo de mujeres con cáncer de mama temprano, y se necesitan nuevas estrategias de tratamiento para mejorar los resultados actuales tanto en la enfermedad temprana como avanzada. El cáncer de mama recurrente o metastásico es una neoplasia maligna incurable con una mediana de supervivencia de 20 a 24 meses [Hortobagyi, 1998], y esto no ha cambiado significativamente en la última década, con menos del 20% de las pacientes vivas a los 5 años después del diagnóstico de recurrencia. Aunque ha habido pequeñas mejoras en la supervivencia con las nuevas terapias, el cáncer de mama metastásico sigue siendo una enfermedad incurable y, en última instancia, fatal. La introducción de terapias combinadas novedosas tiene el potencial de dirigirse a diferentes vías en la célula cancerosa, lo que conduciría a una mejor eficacia. Estudios adicionales para optimizar la terapia combinada, mientras se mitigan los eventos adversos, son de importancia crítica para las pacientes con cáncer de mama metastásico. Lapatinib es un inhibidor oral de la tirosina quinasa que inhibe potentemente tanto EGFR como HER2 [Spector, 2005]. Lapatinib en combinación con capecitabina está aprobado en más de 20 países para el tratamiento de pacientes con cáncer de mama avanzado o metastásico cuyos tumores sobreexpresan HER2. Todas las pacientes en el ensayo clínico que condujo a la aprobación de lapatinib habían recibido terapia previa incluyendo una antraciclina, un taxano y trastuzumab. La relevancia del blanco HER2/neu en el cáncer de mama, combinada con los datos preclínicos y clínicos prometedores respecto al uso de lapatinib, proporcionan la justificación para una evaluación formal de este agente combinado con otros agentes no taxanos como gemcitabina o vinorelbina después de la progresión con terapias basadas en taxanos y trastuzumab en el contexto de enfermedad metastásica, ya que estas opciones de quimioterapia se utilizan en la práctica diaria en este subgrupo de pacientes. Este es un ensayo clínico de fase II, aleatorizado, abierto, multicéntrico, internacional, con 3 brazos de tratamiento, en pacientes con cáncer de mama metastásico HER2+ confirmado después de progresión con taxanos. El objetivo principal es investigar la tasa de beneficio clínico (TBC) y la seguridad en 3 combinaciones diferentes de terapia con lapatinib (más capecitabina, gemcitabina o vinorelbina) y determinar si una o ambas combinaciones de lapatinib/vinorelbina o lapatinib/gemcitabina pueden considerarse una alternativa razonable a la combinación estándar establecida de lapatinib/capecitabina. La decisión sobre si estudiar alguna de las nuevas combinaciones en mayor profundidad se basará tanto en el perfil de toxicidad como en el de eficacia.

Descripción detallada

En áreas donde trastuzumab está disponible sin barreras de acceso, todas las pacientes deben haber recibido trastuzumab en el contexto adyuvante o metastásico. Sin embargo, en países donde trastuzumab no está aprobado o no está disponible para las pacientes debido al reembolso u otras consideraciones, se permiten pacientes sin exposición previa a trastuzumab, considerando los datos de eficacia de lapatinib en este subgrupo de pacientes. Este ensayo clínico utiliza un diseño para asegurar la selección de una o más de las mejores combinaciones de tratamiento para evaluación clínica adicional. Aproximadamente 165 pacientes que cumplan los criterios para el análisis de eficacia según la definición establecida serán incluidas en el ensayo clínico en un proceso de una sola etapa. El tamaño de la muestra se reclutará en 16 meses, con seguimiento adicional durante un período de estudio de 24 meses desde la aleatorización o hasta la progresión. El ensayo clínico incluye un período de selección/basal, un período de tratamiento y un período de seguimiento posterior al tratamiento. Las pacientes continuarán recibiendo los productos en investigación hasta la progresión de la enfermedad o la discontinuación temprana del producto en investigación por otros motivos. Las pacientes que discontinúen el/los producto(s) en investigación sin progresión de la enfermedad continuarán siendo evaluadas para eficacia hasta la progresión o hasta recibir la primera terapia anticancerosa subsiguiente. Una vez documentada la progresión, todas las pacientes serán seguidas para supervivencia a intervalos de aproximadamente 3 meses hasta el fallecimiento.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Signed informed consent must be obtained according to local ethical committee requirements.
Subjects must be older than 18 years old.
Histologically confirmed invasive adenocarcinoma of the breast which is stage IIIb, stage IIIc with T4 lesion, or stage IV disease \[according to AJCC 6th edition\]
Documented progression after taxane based treatment for ErbB2 positive patients for 1st line metastatic breast cancer or documented progression after taxane based regimens as adjuvant or neo-adjuvant therapy. Patients may have had a maximum of one prior treatment with a chemotherapy regimen for metastatic disease.
Patients must have at least 1 measurable lesion defined by RECIST as follows:
X-ray, physical exam \> 20 mm.
Conventional CT scan \> 20 mm.
Spiral CT scan \> 10 mm.
Measurable lesions must be outside a previous radiotherapy field if they are the sole site of disease.
Local laboratory confirmed HER2/neu over expressing and/or amplified disease in the invasive component of the primary or metastatic lesion as defined by at least one of the following based local results:
+ overexpression by IHC (\> 30% of invasive tumour cells).
+ or 3+ (in 30% or \< % of neoplastic cells) over expression by IHC AND in situ hybridization (FISH/CISH) test demonstrating HER2 gene amplification.
HER2 gene amplification by FISH or CISH. (\> 6 HER2 gene copies per nucleus, or a FISH ratio (HER2 gene copies to chromosome 17 signals) of \> than 2.2.
Prior therapy must have included a taxane regimen. Patients must have received either:
Prior adjuvant treatments with taxanes-containing chemotherapy regimens providing that at least 6 months has elapsed from the last dose of adjuvant or neoadjuvant chemotherapy and all treatment related adverse events are \< grade 1 at the time of randomization; OR
Prior treatment with taxane based chemotherapeutic regimens for first line metastatic breast cancer or prior taxane based neoadjuvant regimens for locally advanced disease providing that at least 4 weeks has elapsed since the last dose of therapy for metastatic disease and all treatment related adverse events are \< grade 1 at the time of randomization.
In regions where trastuzumab is available with no barriers to access, patients must have also received prior trastuzumab alone or in combination with chemotherapy in order to be eligible as follows:
Prior treatment with Trastuzumab includes only first line metastatic setting; OR
Prior trastuzumab treatment in neoadjuvant / adjuvant setting provided that at least 6 months has elapsed from last dose of adjuvant / neoadjuvant Trastuzumab , and all treatment related adverse events are \< grade 1 at the time of randomization.
Prior treatment with anthracyclines in the adjuvant or first line metastatic setting are permitted provided that therapy has been discontinued before randomization, and all treatment related adverse events are \< grade 1 at the time of randomization.
Prior treatment with endocrine therapy in the adjuvant or metastatic setting are permitted provided that therapy has been discontinued before randomization, and all treatment related adverse events are \< grade 1 at the time of randomization.
Prior treatments with radiation therapy for palliative management of metastatic disease , to a limited area (e.g., palliative treatment for painful disease) other than the sole site of measurable and assessable disease is allowed however, subjects must have completed treatment at least 4 weeks of the last dose of radiotherapy prior to starting study drugs, and must have recovered from all treatment-related toxicities prior to Day 1.
\. Life expectancy of at least 6 months.
\. ECOG PS 0-2.
\. Patients must have normal organ and marrow function measured within 14 days prior to randomization as defined below:
System Laboratory Values
Hematologic
Absolute neutrophil count (ANC) \> 1.5 X 109/L
Hemoglobin1 \> 9 g/dL
Platelets \> 100 X 109/L
Hepatic
Albumin \> 2.5 gr /dl
Total bilirubin \> 1.5 X upper limit of normal (ULN)
AST and ALT \> 2.5 X ULN
Renal
Serum Creatinine \> 1.5 mg/dL o 132.6 micromol/L
Or, if serum creatinine \> 1.5 mg/dL, Calculated creatinine clearance \> 50 mL/min
Patients may not have had a transfusion within 7 days of screening assessment
\. CT head/MRI within 4 weeks prior to randomization.
\. Women of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 7 days prior to registration.
\. Patients must have at least 1 measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST, Therasse, 2000). Measurable lesions may be in the field of prior adjuvant irradiation. However, there must be at least a 4 week period between the last radiation treatment and the baseline scan documenting disease status. Documented progression of the irradiated lesion is also required for the lesion to be considered measurable.
\. Subjects must have a cardiac ejection fraction within the institutional range of normal as measured by ECHO (echocardiogram) or alternatively by MUGA (Multigated Acquisition) scan. Cardiac ejection fraction \> 50% and within the institutional range of normal as demonstrated by echocardiogram or alternatively by MUGA scan within 4 weeks of randomization Subjects with known uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure are NOT eligible;
\. Subjects must complete all screening assessments as outlined in the protocol.

Criterios de exclusión

Pregnant or lactating women.
Prior therapy with other anti Erbb1 or antiErbB2 targeted agent rather than Trastuzumab only limited to 1st line treatment of metastatic disease OR as adjuvant/neoadjuvant therapy.
Prior exposure to gemcitabine , vinorelbine and capecitabine for 1st line treatment of recurrent-metastatic disease OR as adjuvant / neoadjuvant therapy.
Treatment in the 14 days prior to randomization with anti-cancer therapy (tumor embolization, chemotherapy , immunotherapy, biological therapy, or hormonal therapy) or treatment with mitomycin within 6 weeks prior to randomization. Such treatment may not be resumed or begun after study entry. Note: Patients receiving bisphosphonate therapy prior to randomization may continue for the duration of study participation, however bisphosphonates should not be initiated following study entry.
Prophylactic use of bisphosphonates in subjects without bone disease is not permitted, except for the treatment of osteoporosis.
Active CNS metastases.
Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, serious non-healing wound/ulcer/bone fracture, or psychiatric illness/social situations that would limit compliance with study requirements.
Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis).
Have current active hepatic or biliary disease(with exception of patients with Gilbert syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment)
History of other malignancy. 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.
Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent.
Concurrent treatment with an investigational agent or participation in another clinical trial.
Used an investigational drug within 30 days or 3 half-lives, whichever is longer, preceding the first dose of therapy.
History of immediate or delayed hypersensitivity or idiosyncrasy to drugs chemically parented to Lapatinib or navelbine or capecitabine or gemcitabine and its excipients.

Intervenciones

drug

Lapatinib Vinorelbine

The starting dose of vinorelbine is 25 mg/m2/ IV days 1 and 8, every 21 days. A daily dose of Lapatinib is 5 tablets (1250 mg of Lapatinib) taken approximately at the same time each day.

drug

Lapatinib Capecitabine

The starting dose of capecitabine is 2000 mg/m2/day, to be divided and given twice daily orally, 12 hours apart, for 14 days, every 21 days. A daily dose of Lapatinib is 5 tablets (1250 mg of Lapatinib) taken approximately at the same time each day.

drug

Gemcitabine Lapatinib

The starting dose of gemcitabine is 1000mg/m2/ IV days 1 and 8, every 21 days. A daily dose of Lapatinib is 5 tablets (1250 mg of Lapatinib) taken approximately at the same time each day.

Estudio de fase II, aleatorizado, abierto, de lapatinib-capecitabina o lapatinib-vinorelbina o lapatinib-gemcitabina en sujetos con cáncer de mama metastásico con amplificación de HER2/neu con progresión después del tratamiento con taxanos

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

Lapatinib Vinorelbine

Lapatinib Capecitabine

Gemcitabine Lapatinib

Ubicaciones

Dr. Guillermo Lerzo

Dr. Eduardo Richardet

Dr. Adolfo Capó

Dr. Juan Lacava

Dra. Mirta Varela

Dr. Luis Fein

Dr. Jose Zarba

Dr. Cesar Blajman

Patrocinadores