Abstract CT135: A phase 1b study of palbociclib + nab-paclitaxel in patients (pts) with metastatic adenocarcinoma of the pancreas (PDAC)
Authors: Hidalgo Manuel , Carbonero Rocio Garcia , Lim Kian-Huat , Messersmith Wells , Garrido-Laguna Ignacio , Borazanci Erkut , Lowy Andrew , Rodriguez Laura Medina , Laheru Daniel , Huang Xin , Tammaro Meggan , Martini Jean-François , Kudla Arthur , Kern Kenneth , Macarulla Teresa 
Published: September 2020

Abstract
Palbociclib (P), an oral cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, has shown antitumor activity in preclinical PDAC models. In Avatar PDAC models, P+ nab-paclitaxel (A) was more effective than either agent alone and similar to P+A+gemcitabine. This study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy, and maximum tolerated dose (MTD) of P+A in pts with advanced PDAC. Pts with metastatic PDAC, Karnofsky performance status ≥70 and adequate organ function were eligible. In the dose escalation phase, P was administered orally once daily at doses ranging from 75-125 mg/d for 21 of every 28 days (3/1 schedule). A was administered intravenously at 100-125 mg on days 1, 8 and 15 every 28 days. Additional cohorts were P 75 mg (3/1 schedule or continuously) with A (100- and 125-mg dose, biweekly). The prespecified efficacy target was 12-month survival probability &gt;65% at MTD. In total, 76 pts (median age 61 years [range 39-75], 45% female) received a median of 4 treatment cycles (range 1-21); 44 (57.9%) pts had liver disease and 61 (80.3%) had prior treatment for advanced disease. Four dose-limiting toxicities were observed: grade 3 mucositis (1), grade 4 neutropenia (2), and febrile neutropenia (1). Grade 3/4 adverse events were reported in 67 (88.2%) pts; events reported for ≥5% of pts were neutropenia (61.8%), leukopenia (26.3%), anemia (22.4%), asthenia (9.2%), lymphopenia (7.9%), and peripheral neuropathy (5.3%). PK demonstrated no significant drug-drug interactions. MTD was P 100 mg (3/1 schedule) and A 125 mg (days 1, 8 and 15 every 28 days). Objective response rate and disease control rate in the 23 pts treated at MTD were 13% and 65.2%, respectively. In these pts, median progression-free survival, median overall survival, and survival probability at 12 months were 5.3 months (95% CI: 3.5-9.7), 12.1 months (95% CI: 6.4-14.8), and 50% (95% CI: 29.9%-67.2%), respectively. Thirty of 57 analyzed pts (52.6%) had an on-treatment maximum Ca 19-9 reduction &gt;50% from baseline. In paired skin punch biopsies (26 pts at any dose level, including 13 pts at MTD), pRb decreased during P dosing, increased above baseline during the week off P, and decreased again following P dosing, demonstrating PD modulation of Rb phosphorylation. CDKN2A, RAS, and TP53 mutations were analyzed in plasma DNA; clinical outcome of pts without alterations detected (n=58, 26, and 28, respectively) was superior to those with alterations detected (n=12, 44, and 42 pts, respectively). In conclusion, P+A was tolerated, with side effects as expected based on single agent profiles, and no significant PK interactions. MTD was P 100 mg (3/1 schedule) + A 125 mg (days 1, 8, and 15 every 28 days). PD observations were consistent with CDK4/6 inhibition. The combination regimen did not meet the prespecified efficacy threshold.Pfizer (NCT02501902)
Citation Format: Manuel Hidalgo, Rocio Garcia Carbonero, Kian-Huat Lim, Wells Messersmith, Ignacio Garrido-Laguna, Erkut Borazanci, Andrew Lowy, Laura Medina Rodriguez, Daniel Laheru, Xin Huang, Meggan Tammaro, Jean-François Martini, Arthur Kudla, Kenneth Kern, Teresa Macarulla. A phase 1b study of palbociclib + nab-paclitaxel in patients (pts) with metastatic adenocarcinoma of the pancreas (PDAC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT135.