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

Purpose: 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 in patients with retinoblastoma (Rb) protein-expressing, advanced breast cancer (ABC). Experimental Design: 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 2 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. Results: Twenty seven patients enrolled. Although there was only 1 DLT (grade 3 ALT/AST at 125 mg), neutropenia requiring dose modification in cycle 1 resulted in an RP2D of 75 mg palbociclib/80mg/m2 paclitaxel. During cycle 1, the most common adverse event was neutropenia, occurring in 15 patients (55.6%); grade 1 or 2 nausea and peripheral neuropathy was also observed in 8 patients each (29.6%). Clinical benefit rate was 55% at the RP2D; benefit was observed across all receptor subtypes. Conclusions: Alternating sequential palbociclib/paclitaxel in patients with Rb+ ABC 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.

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