Combination Paclitaxel and Palbociclib: Results of a Phase I Trial in Advanced Breast Cancer

• Published in: Clinical cancer research 2019-04, Vol.25 (7), p.2072-2079
• Main Authors: Clark, Amy S, McAndrew, Nicholas P, Troxel, Andrea, Feldman, Michael, Lal, Priti, Rosen, Mark, Burrell, Jessica, Redlinger, Colleen, Gallagher, Maryann, Bradbury, Angela R, Domchek, Susan M, Fox, Kevin R, O'Dwyer, Peter J, DeMichele, Angela M
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Breast Neoplasms - diagnosis; Breast Neoplasms - drug therapy; Breast Neoplasms - etiology; Breast Neoplasms - therapy; Drug Administration Schedule; Female; Humans; Middle Aged; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Paclitaxel - administration & dosage; Piperazines - administration & dosage; Pyridines - administration & dosage; Retreatment; Treatment Outcome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-0790

The CDK 4/6 inhibitor palbociclib rapidly and reversibly inhibits the cell cycle. The goal of this study was to exploit the cell cycle through intermittent, alternating dosing with palbociclib/paclitaxel to enhance efficacy. We determined the combination dose-limiting toxicity (DLT) in patients with Rb protein-expressing, advanced breast cancer. This open-label, phase I trial (NCT01320592) enrolled patients to sequential cohorts of palbociclib orally dosed intermittently between days 1 and 19 of a 28-day cycle alternating with weekly paclitaxel. Dose escalation proceeded in a standard 3 + 3 design. Ten additional patients received the combination at the recommended phase II dose (RP2D). Those who reached response plateau ≥6 cycles could continue on palbociclib alone on a 3 week on/1 week off schedule at one dose level above their combination dose. Twenty-seven patients enrolled. Although there was only 1 DLT (grade 3 alanine aminotransferase/aspartate aminotransferase at 125 mg), neutropenia (NTP) requiring dose modification in cycle 1 (C1) resulted in an RP2D of 75 mg palbociclib/80 mg/m paclitaxel. During C1, the most common adverse event was NTP, occurring in 15 patients (55.6%); grade 1 or 2 nausea and peripheral neuropathy were also observed in 8 patients each (29.6%). The clinical benefit rate was 55% at the RP2D; benefit was observed across all receptor subtypes. Alternating sequential palbociclib/paclitaxel in patients with Rb advanced breast cancer is feasible and safe, without evidence of additive toxicity. This represents a new application for CDK 4/6 inhibitors in Rb breast cancer regardless of subtype; efficacy trials are warranted.