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Background The combination of a CDK4/6 inhibitor (CDK4/6i) with letrozole (LET) or fulvestrant (FUL) is the most active first–line (1L) treatment for patients (pts) with HR[+]/HER2[-] ABC. Although endocrine sensitivity persists beyond progression, preliminary findings suggest more adaptive resistance mechanisms to endocrine therapy (ET) than to CDK4/6i. At present, there are no data about prolonging CDK4/6 blockade beyond progression on a CDK4/6i. The aim of this study is to determine whether palbociclib rechallenge combined with second–line ET upon progression to a prior palbociclib–based therapy will improve progression–free survival (PFS) over ET alone in HR[+]/HER2[-] ABC pts. Trial design This is an international, open–label, randomized phase II trial. A total of 198 pts will be randomized (2:1) to palbociclib plus ET (LET or FUL) or ET alone, until progressive disease (PD) or unacceptable toxicity. Pts will be stratified by 1L ET and presence of visceral metastasis. Main selection criteria include: (1) Pre– and post–menopausal women with HR[+]/HER2[-] ABC; (2) Evidence of PD on a 1L combination of palbociclib plus LET or FUL after obtaining clinical benefit (secondary resistance); (3) Pts relapsing on or within the first year of a palbociclib–based adjuvant regimen; (4) Measurable and biopsable disease or non–measurable disease with bone lesion. The primary objective is to assess PFS of palbociclib plus ET versus ET alone. The 1st co-primary endpoint is the PFS in the combination arm only. If this objective is achieved, we will compare PFS between the two arms (2nd co-primary endpoint). With 128 events, the 1st and 2nd analyses have an 80% power to detect a 1.4–month (hazard ratio [HR]=0.74) or 2.74–month (HR = 0.6) increase over 4–month median PFS for ET arm, respectively. The nominal alpha level is 5% for two-sided log-rank tests. Secondary objectives evaluate: Safety–related outcomes, objective response rate, 6–month clinical benefit rate, overall survival, quality of life, and time to first chemotherapy. Exploratory objectives include: Correlation between the intrinsic molecular subtypes and efficacy/safety findings, and identification of new predictive markers. Clinical trial identification NCT03809988. First Posted: January 18, 2019. Legal entity responsible for the study Medica Scientia Innovation Research (MedSIR). Funding Pfizer S.L.U. Disclosure A. Llombart Cussac: Honoraria (institution), Advisory / Consultancy: Roche, GlaxoSmithKline, Novartis, Celgene, Eisai, AstraZeneca; Research grant / Funding (institution): GlaxoSmithKline, Sanofi, Puma Biotechnology; Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Medica Scientia Innovation Research (MedSIR). P. Schmid: Advisory / Consultancy: Pfizer, AstraZeneca, Novartis, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, Puma; Research grant / Funding (institution): AstraZeneca, Genentech, Roche, Oncogenex, Novartis, Astellas; Spouse / Financial dependant, Spouse is consulting for Genentech/Roche: Genentech/Roche. I. Macpherson: Honoraria (self): Celldex, Daiichi Sankyo, Eisai, Genomic Health, Novartis, Pfizer, Roche; Travel / Accommodation / Expenses: Eisai, Roche. J. Gligorov: Advisory / Consultancy: Daichi, EISAI, Genomic Health, Ipsen, Macrogenics, MSD, Novartis, Onxeo, Pfizer, Roche Genentech; Travel / Accommodation / Expenses: EISAI, Genomic Health, MSD, Novartis, Pfizer, Roche Genentech; Non-remunerated activity/ies: Daichi, EISAI, Genomic Health, Immunomedics, Novartis, Pfizer, Roche Genentech. M. Sampayo: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). F. Riva: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). A. Malfettone: Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). J.M. Perez-Garcia: Advisory / Consultancy: Roche, Lilly; Full / Part-time employment: Medica Scientia Innovation Research (MedSIR). J. Cortes: Advisory / Consultancy: Roche, Celgene, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex; Honoraria (institution): Roche, Novartis, Celgene, Eisai, Pfizer, Samsung; Research grant / Funding (institution): Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck SharpD Advisory / Consultancy, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Medica Scientia Innovation Research (MedSIR). All other authors have declared no conflicts of interest. |
