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

Abstract

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 (DLT) in patients with Rb protein-expressing, advanced breast cancer. Patients and Methods: 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 þ 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. Results: 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 2 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. Conclusions: Alternating sequential palbociclib/ paclitaxel in patients with Rb þ advanced breast cancer is feasible and safe, without evidence of additive toxicity. This represents a new application for CDK 4/6 inhibitors in Rb þ breast cancer regardless of subtype; efficacy trials are warranted.

Assessing the Specificity of Paclitaxel towards the Marker Proteins of Breast Cancer Using In silico Molecular Docking Study

“…Paclitaxel treatment resulted in apoptosis of cancer cells both In vitro and In vivo conditions [35]. The combination of paclitaxel and palbociclib therapy to patients with Rb + advanced breast cancer has been reported to be safe without evidence of toxicity in phase I trial [39]. However, paclitaxel also showed cardiotoxic effects [40] and exert dermatological problems to patients with gynecological organ malignancy [41].…”

<p>Novel Therapeutic Strategies for CDK4/6 Inhibitors in Metastatic Castrate-Resistant Prostate Cancer</p>

“…In preclinical breast cancer models, when the taxane paclitaxel was given concurrently with palbociclib it showed antagonism, but showed synergy when given sequentially via intermittent dosing. 40,41 This finding can be explained by their mechanisms of action. When a CDK4/6i is administered it arrests cells in G1 which prevents cancer cells from eventually entering M phase, thereby, protecting cells from paclitaxel-induced cell death in M phase.…”

“…When given sequentially it is hypothesized that G1 synchronization will occur after CDK4/6i is held, allowing more cells to enter M phase and enable cell death from paclitaxel. 41 A Phase I trial with intermittent dosing in advanced breast cancer was performed and showed safety and tolerability. 41 In PCa, a phase Ib/2 clinical trial is investigating ribociclib with docetaxel and prednisone in mCRPC patients with androgen signaling inhibitor resistance and no prior chemotherapy.…”

“…41 A Phase I trial with intermittent dosing in advanced breast cancer was performed and showed safety and tolerability. 41 In PCa, a phase Ib/2 clinical trial is investigating ribociclib with docetaxel and prednisone in mCRPC patients with androgen signaling inhibitor resistance and no prior chemotherapy. 42 Preliminary results of 14 patients showed PSA decrease by 50% or more in 29% of patients with neutropenia as the most commonly observed adverse event.…”

Triple‑negative breast cancer therapy: Current and future perspectives (Review)

“…The hypothesis was that reversible G 1 arrest of palbociclib could synchronize tumor cells in the cell cycle and following their re-entry later would ensure a higher fraction in mitosis (M) phase when exposed to paclitaxel. In the first combination trial for palbociclib and paclitaxel (NCT01320592) an alternative dosing schedule was feasible and safe, without evidence of additive toxicity in Rb + breast cancer regardless of subtype (75). Phase I follow-up trial (NCT02599363) of ribocilcib and weekly paclitaxel is in progress in patients with Rb + advanced breast cancer.…”