Abstract A177: Phase 1, dose-escalation, safety, pharmacokinetic and pharmacodynamic study of single agent PF-03758309, an oral PAK inhibitor, in patients with advanced solid tumors
Autor: | Todd Andrew Blumenkopf, Jorge Gallo, Linda Mileshkin, Jonathan H. Goldman, Sheree Darang, Lee S. Rosen, S. Gail Eckhardt, Diane Wang, Aurora Breazna |
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Rok vydání: | 2011 |
Předmět: | |
Zdroj: | Molecular Cancer Therapeutics. 10:A177-A177 |
ISSN: | 1538-8514 1535-7163 |
DOI: | 10.1158/1535-7163.targ-11-a177 |
Popis: | Background: P21 activated kinase (PAK), a family of serine-threonine kinases, is a downstream effector of the Rho family and functions as a signaling node for various oncogenic pathways. The capability to transform cell cultures and the consistent anti tumor response associated with PAK inhibition in preclinical studies has raised the interest of PAK as a potential target for oncology. PAK consists in 6 isoforms divided into 2 subgroups. PAK isoforms 1 and 4 have been more frequently related to cancer biology. PF309 is a potent ATP-competitive inh of PAK1, 4, 5 and 6. Methods: Adult pts with advanced solid tumors were enrolled in a Ph 1 single agent dose escalation study with a standard 3 + 3 design. Oral PF309 was given on a continuous daily dosing. Tumor response was assessed at baseline and every 8 wks thereafter. AEs were recorded according NCI CTC v3.0. PK assessment was a study objective and PD endpoints (downstream substrates of the PAK pathway, eg: GEFH1, p-PAK4, p-cofilin) were to be explored in pre and post-treatment tumor biopsies as well as in surrogate tissue (hair follicles). Results: 33 pts (17 M and 16 F) were treated with PF309 among 8 dose levels (1 mg QD to 60 mg BID). Median age was 62.0 years (range 24–80) and median ECOG PS was 1. The most frequent tumors were CRC (16 pts), NSCLC (4 pts), breast cancer (2 pts), osteosarcoma (2 pts) and pancreatic cancer (2 pts). Median number of cycles was 3 (range 1 to 10). All subjects experienced treatment emergent AEs; 9 subjects experienced G3–4 AEs, and 2 SAEs were reported from 2 subjects: abdominal pain and hemoptysis (both at 60 mg BID). One patient died while on study due to PD. At the time of this report 2 patients experienced DLTs at 60 mg BID: G3 diarrhea (1 pt), and G2 nausea, vomiting and diarrhea, and G1 abdominal cramping leading to the administration of less than 80% of the planned dose during C1 (1pt). As a result 60 mg BID is the maximum administered dose (MAD). Treatment-related AEs were mainly from the GI tract: G3 diarrhea (1 pt), G1–2 diarrhea (10 pts), G1–2 vomiting (8 pts), G1–2 nausea (8 pts each), abdominal pain (5 pts) and fatigue (3 pts). G1–2 QTcF prolongation was observed in 11 pts (G1 in 6 pts, G2 in 5 pts), 6 of whom had an abnormal pre-treatment QTcF. No QTcF increase > 60 ms above baseline was observed in any patient. G3 lab abnormalities were rarely reported and included hyponatremia, thrombocytopenia, neutropenia and increased bilirubin (1 pt each). The PK data demonstrated that after attainment of Cmax within 5 hours after dosing, PF309 plasma concentrations declined in a multi-exponential manner with an average terminal half-life of 12.4 to 17.8 hs across doses. There was a lack of dose proportionality in the dose range of 10 to 60 mg, likely due to the high inter-patient variability. The inter-patient variability of AUCtau and Cmax at steady-state ranged from 21 to 177% and 45 to 184%, respectively, across doses. So far no tumor responses have been observed. A total of 10 pts have been on study treatment for ≥ 12 weeks. One heavily pretreated pt with CRC and progressive increase of the CEA serum level experienced a decrease in the CEA value from 1343.3 to 625.2 ng/ml, and remained on study for 4 months. Conclusions: GI toxicity is the most relevant toxicity associated with PF309 and 60 mg BID is the MAD. MTD confirmation is ongoing. Clinical development of PF309 is on hold due to PK findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A177. |
Databáze: | OpenAIRE |
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