Abstract OT2-6-11: PENELOPE: Phase III study evaluating palbociclib (PD-0332991), a cyclin-dependent kinase (CDK) 4/6 inhibitor in patients with hormone-receptor-positive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy (GBG-78/BIG1-13)
Authors: G von Minckwitz, H Bear, H Bonnefoi, M Colleoni, K Gelmon, M Gnant, S-B Kim, S Loibl, A Makris, M Martin, V Nekljudova, H Rugo, KS Saini, M Toi, M Untch, G Werutsky
Journal: Cancer Research (2013)

Abstract Background: About one third of hormone-receptor (HR)-positive, HER2-normal breast cancer (BC) patients with residual disease after neoadjuvant chemotherapy (NACT) have a substantial risk of relapse. Those patients can be identified using validated clinical-pathologic stage–estrogen/grade (CPS-EG) scoring system. Palbociclib is an oral, highly selective inhibitor of CDK4/6 kinase activity that prevents cellular DNA synthesis by inhibiting cell cycle progression. Luminal tumors have been shown to be sensitive to palbociclib. In a phase 2 study, palbocilcib extended PFS in combination with letrozole as first-line hormonal treatment for advanced BC. In addition, it has shown single agent activity in patients with multiply relapsed hormone positive ABC. Methods: PENELOPE (NCT01864746) is a prospective, international, multicenter, randomized, double-blind, placebo-controlled, phase 3 study aiming to demonstrate that 1 year of adjuvant treatment with palbociclib, in addition to standard anti-hormonal therapy, provides a superior invasive disease-free survival (iDFS) and acceptable safety profile compared to placebo in women with HR-positive/HER2-normal early BC who did not obtain a pathological complete response (pCR) after taxane-containing NACT and are at high risk of relapse (CPS-EG score ≥3). After completion of NACT and adequate surgery and radiotherapy, 800 patients will receive standard adjuvant endocrine treatment (5years) and will be randomized (1:1) to 13 cycles of palbociclib 125mg daily or matching placebo on d1-21 in a 28d cycle. Randomization will be dynamic and patients will be stratified by histological lymph node status at surgery (ypN 0-1 vs ypN2-3), age at first diagnosis (&amp;lt; = 50 vs &amp;gt;50 yrs), Ki-67 (&amp;gt;15% vs &amp;lt; = 15%), pRB and cyclin D immunoreactive scores in residual tumor after NACT (&amp;lt; = 2 vs &amp;gt;2 points), global region of participating site (Eur vs N.America vs RoW). Patients will be followed until any invasive local, regional or distant recurrence, diagnosis of secondary malignancy, unacceptable toxicity, withdrawal of consent or study termination. Primary objective is to compare iDFS for palbociclib vs placebo. Secondary objectives are iDFS excluding second non-breast cancers, overall, distant disease-free and locoregional recurrence-free survival, iDFS per treatment arm in luminal-B tumors, compliance and safety, patient reported outcomes, health economics, correlations between drug exposure and efficacy/safety findings. Further objectives are translational and aim to identify scores/markers for their prognostic value and predictive information on efficacy/safety of palbociclib in this specific setting. Results: Recruitment is planned to start in Oct 2013 at 200-250 sites in 11 countries and continue for 3years. Conclusion: PENELOPE will study whether palbociclib is an effective treatment with a sufficiently favorable safety profile for patients with high risk of recurrence and high CPS-EG score after NACT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-11.