Resumen

Este estudio comparará la actividad de la combinación de savolitinib y osimertinib frente a la combinación de savolitinib con placebo de osimertinib en pacientes con cáncer de pulmón de células no pequeñas (CPCNP) localmente avanzado o metastásico con mutación positiva del Receptor del Factor de Crecimiento Epidérmico (EGFR) y amplificación de MET, que hayan progresado tras tratamiento con osimertinib.

Descripción detallada

La resistencia a los inhibidores de la tirosina quinasa del EGFR (EGFR-TKIs) es un problema clínico. Uno de los mecanismos de resistencia a osimertinib es la amplificación del receptor tirosina quinasa MET, que activa la señalización intracelular corriente abajo de forma independiente del EGFR. Este estudio explorará la contribución individual de savolitinib a la resistencia a osimertinib mediada por MET, evaluando la respuesta al bloqueo dual de la vía EGFRm y MET para superar la resistencia mediada por MET a osimertinib versus la inhibición de la vía MET de forma aislada, investigando la eficacia de savolitinib más osimertinib frente a savolitinib más placebo de osimertinib (en adelante denominado placebo) en pacientes con EGFRm+ y CPCNP localmente avanzado o metastásico con amplificación de MET que hayan progresado tras tratamiento con osimertinib. Se trata de un estudio multicéntrico, de fase II, doble ciego y aleatorizado. Los pacientes serán aleatorizados en una proporción 1:1 para recibir tratamiento con savolitinib una vez al día más osimertinib una vez al día, o savolitinib una vez al día más placebo. La aleatorización se estratificará según el número de líneas de tratamiento previas (es decir, osimertinib en monoterapia como primera línea o ≥ segunda línea [que incluye pacientes que recibieron osimertinib en monoterapia antes o después de quimioterapia]). Todos los pacientes confirmados como elegibles iniciarán el tratamiento el Día 1 con savolitinib más osimertinib o savolitinib más placebo. El tratamiento continuará una vez al día en ciclos de 28 días hasta que se documente progresión objetiva de la enfermedad (PD) según RECIST 1.1, ocurra toxicidad inaceptable, se retire el consentimiento o se cumpla otro criterio de discontinuación. Tras la progresión, los pacientes podrán ser desciegos, y aquellos inicialmente asignados al brazo de savolitinib más placebo podrán cruzar a savolitinib más osimertinib en abierto tras la PD objetiva evaluada por el investigador, a fin de garantizar que todos los pacientes enrolados tengan la oportunidad de recibir la combinación de savolitinib más osimertinib.

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Patients must be ≥ 18 years of age at the time of signing the informed consent (≥ 20 years of age in Japan). All genders are permitted
Histologically or cytologically confirmed locally advanced or metastatic EGFRm+ NSCLC harbouring an EGFR mutation known to be associated with EGFR TKI sensitivity and that is permitted in the osimertinib national label (such as exon 19 deletion and/or L858R), which is not amenable to curative therapy.
Documented radiologic PD following treatment with osimertinib (osimertinib does not need to be the most recent therapy).
Have MET amplification as determined by central MET FISH testing on tumour specimen collected following progression on prior osimertinib treatment.
At least measurable target lesion
Patients must have received at least one but no more than 3 prior lines of therapy (including investigational therapy) in the locally advanced/metastatic setting.
Adequate haematological, liver and renal function
Eastern Cooperative Oncology Group/WHO performance status of 0 or 1 with no deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.
Females of childbearing potential should be willing to use adequate contraceptive measures, should not be breastfeeding, and must have a negative pregnancy test.
Male patients with a female partner of childbearing potential should be willing to use barrier contraception during the study and for 6 months following discontinuation of study intervention. Patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing study intervention.

Criterios de exclusión

Unresolved toxicities from any prior therapy greater than CTCAE Grade 1 at the time of starting study intervention with the exception of alopecia, haemoglobin ≥ 9 g/dL and Grade 2, prior platinum therapy related neuropathy.
As judged by the investigator, active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy.
Any of the following cardiac diseases currently or within the last 6 months:
Unstable angina pectoris
Congestive heart failure (NYHA Grade ≥ 2)
Acute myocardial infarction
Stroke or transient ischemic attack
Uncontrolled hypertension (BP ≥ 150/95 mmHg despite medical therapy).
Mean resting corrected QT interval (QTcF) \> 470 msec for women and \> 450 msec for men at Screening, obtained from 3 ECGs using the screening clinic ECG machine derived QTcF value.
Any factors that may increase the risk of QTcF prolongation or risk of arrhythmic events
Any clinically important abnormalities in rhythm, conduction or morphology of resting ECGs.
Acute coronary syndrome
Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤ 28 days or limited field radiation for palliation ≤ 7 days prior to starting study intervention or has not recovered from side effects of such therapy.
Major surgical procedures ≤ 28 days of beginning study intervention or minor surgical procedures ≤ 7 days. No waiting is required following port-a-cath placement.
As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including renal transplant or active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to enter the study or which would jeopardise compliance with the CSP.
Active HBV (positive HBsAg result) or HCV. Viral testing is not required for assessment of eligibility for the study.
Known serious active infection including, but not limited to, tuberculosis, or HIV (positive HIV 1/2 antibodies). Testing is not required for assessment of eligibility for the study.
Presence of other active cancers, or history of treatment for invasive cancer, within the last 5 years. Patients with Stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (ie, non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.
Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 2 weeks prior to start of study intervention.
Past medical history of ILD, drug-induced ILD, radiation pneumonitis, which required steroid treatment, or any evidence of clinically active ILD.
Prior or current treatment with a 3rd generation EGFR-TKI other than osimertinib.
Prior or current treatment with savolitinib or another MET inhibitor (for example, foretinib, crizotinib, cabozantinib, onartuzumab, capmatinib).
Patients who have received ≥ 4 lines of systemic therapy for NSCLC
Any cytotoxic chemotherapy, investigational agents or other anti cancer drugs for the treatment of advanced NSCLC from a previous treatment regimen or clinical study within 14 days prior to the first dose of study intervention with the exception of monotherapy osimertinib which may continue uninterrupted during screening.
Patients currently receiving (or unable to stop use prior to receiving the first dose of study intervention) medications or herbal supplements known to be strong inducers of CYP3A4 or strong inhibitors of CYP1A2, or CYP3A4 substrates which have a narrow therapeutic range within 2 weeks of the first dose of study intervention (3 weeks for St John's Wort) will be excluded. All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4 during the study and for 3 months later the last dose intake.
Participation in another clinical study with a cytotoxic, investigational product, or other anti cancer drug for the treatment of advanced NSCLC if received study intervention from that study within 14 days of the first dose of study intervention.
Known hypersensitivity to the active or inactive excipients of osimertinib or savolitinib or drugs with a similar chemical structure or class.

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

Osimertinib + Savolitinib

Savolitinib + Placebo

Ubicaciones

Research Site

Patrocinadores