Abstract P6-13-08: Palbociclib and paclitaxel on an alternating schedule for advanced breast cancer: Results of a phase Ib trial
Authors: Clark AS , O'Dwyer P , Troxel A , Lal P , Feldman M , Gallagher M , Driscoll A , Colameco C , Lewis D , Rosen M , Matro J , Bradbury A , Domchek S , Fox K , DeMichele A 
Published: May 2016

Abstract
Background: Palbociclib (P) is an oral CDK 4/6 inhibitor (CDKi) that was recently FDA approved in combination with endocrine therapy for metastatic breast cancer. We have performed a Phase I trial of P in combination with paclitaxel (T) based on preclinical studies suggesting that P synergizes with T when given on an alternating schedule, enabling cell cycle synchronization in tumor cells. We now present the dose expansion cohort.
Methods: Patients (Pts) enrolled on the trial had Rb-expressing tumors of any estrogen/progesterone/HER2 receptor type, adequate organ function, and ≤3 prior chemotherapy regimens for metastatic breast cancer (mBC). Prior adjuvant or metastatic taxane was allowed. Dose escalation led to expansion at P100mg or 75mg, starting with 3 days of P (run-in) and reduction of P dosing from 5-day to 3-day intervals (days 2-4, 9-11, 16-18 of each 28 day cycle). T at 80mg/m2 was given weekly for 3 cycles; thereafter, T was administered days 1, 8 and 15 of 28 day cycle. Weekly toxicity assessments were performed; RECIST 1.0 response was assessed every 2 cycles as partial response (PR), stable disease (SD) or progressive disease (PD). Pts had the option to discontinue T and continue on P alone (3 on/1 off schedule) if they attained SD after cycle 6.
Results: 27 pts enrolled on study (15- dose escalation, 12- dose expansion). Results are shown in the Table. 21 pts had received prior taxane; pts had received a median of 2 chemotherapy regimens for mBC. DLTs were grade 3 AST/ALT (n=1, at 125 mg) and febrile neutropenia (FN) (n=1, at 100 mg). Uncomplicated grade 3/4 NTP was common and frequently led to dose reduction or dose interruption during the first cycle of therapy. Frequency of NTP did not change with reducing the days of P. Among 24 evaluable patients, 14 (58%), had PR or SD ≥ 6 months across all dose levels. Of 14 pts who responded, 10 (71%) had received prior taxane. 20 pts are off study; 19 for PD, and 2 for toxicity (NTP in cycle 17 and FN in cycle 1); 7 pts remain on study. Prolonged tumor responses were seen.
Conclusions: P and T can be safely combined on an alternating dosing schedule; the optimal combination dose is 75 mg of P and 80mg/m2 of weekly T. The high response rate warrants a randomized trial to determine the incremental benefit over T alone. Additional mechanistic studies are in progress to understand the in vivo effects of the alternating dosing schedule on cell cycle activity and tumor proliferation.
Starting Dose Level P (mg)Number (Total 27)DLTGrade 3/4 NTP (n)Final Dose P mg (n)Dose Interruption (n)Best Response (n)5030050 (1) 50 (1) 50 (1)No (2) Yes (1)PR (1) SD (1) PD (1)7530275 (1) 50 (1) 25 (1)No (1) Yes (2)PR (2) SD (1)100605100 (2) 75 (3) 25 (1)No (1) Yes (5)PR (2) SD (1) PD (3)12531- LFT375 (1) 50 (2)No (0) Yes (3)PR (1) SD (2)75 (Run-In)60175 (5) 50 (1)No (4) Yes (2)PR (1) SD (2) PD (1) N/A (2)*100 (Run-In)61- FN5100 (1) 75 (4) 25(1)No (1) Yes (5)PR (4) SD (1) N/A (1)^*2 pts not yet evaluable. ^1 pt went off study due to FN after cycle 1.
Citation Format: Clark AS, O'Dwyer P, Troxel A, Lal P, Feldman M, Gallagher M, Driscoll A, Colameco C, Lewis D, Rosen M, Matro J, Bradbury A, Domchek S, Fox K, DeMichele A. Palbociclib and paclitaxel on an alternating schedule for advanced breast cancer: Results of a phase Ib trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-08.