| General information |
| Database: | DB00692 |
| Objective: | The objectives of this study were to identify the recommendedphase II dose (RP2D) and assess safety and tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of PF00562271. |
| Authors: | Infante JR, et al |
| Title: | Safety, pharmacokinetic, and pharmacodynamicphase I doseescalation trial of PF00562271, an inhibitor of focal adhesion kinase, in advanced solid tumors. |
| Journal: | J Clin Oncol. |
| Year: | 2012 |
| PMID: | 22454420 |
| Trial Design |
| Clinical Trial Id: | NCT00666926 |
| Agent: | PF00562271
|
| Target: | Focal adhesion kinase
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | Safety, Pharmacokinetic, and Pharmacodynamic hase I, nonrandomized, escalation study |
| Key Patients Feature: | Key eligibility criteria included advanced solid tumors unresponsive toor for which no effective therapies exist, age 18 years, Eastern CooperativeOncology Group performance status 0 to 2, normal left ventricular ejectionfraction, urinalysis less than 1 blood and 1 protein (or 500 mg/24hours), and adequate bone marrow, liver, and kidney function. Key exclusioncriteria included pregnancy or breastfeeding, GI abnormalities that couldimpair absorption or predispose to hemorrhage, systolic blood pressure lessthan 100 mmHg, and history of arrhythmia, conduction abnormality, QTcmore than 500 ms, cardiomyopathy, or significant cardiac valve abnormalities.Patients with significant cardiac or thromboembolic events within 6 months ofstudy entry were also excluded. Potent CYP 3A4 inhibitors and inducers wereexcluded within 7 and 14 days, respectively. |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | Part 1 was a dose escalation without and with food. Part 2 enrolled specific tumor types in an expansion at the RP2D and also assessed the effect of PF00562271 on singledose midazolam PK in a subgroup of patients. |
| Primary End Point: | MTD, DLTs, PK, tumor response and toxicity |
| Secondary End Point: | NA |
| Patients Number: | 99 |
| Trial Results |
| DLT_MTD: | The 125mg twiceperday fed dose was deemed the maximumtolerated dose (MTD) and RP2D. |
| Objective Response Rate: | Of 14 patients evaluable by [(18)F]fluorodeoxyglucose positron emission tomography in the expansion cohorts, seven metabolic responses were observed. With conventional imaging, 31 patients had stable disease at first restaging scans, and 15 of these remained stable for six or more cycles |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Grade 3 doselimiting toxicities included headache, nausea/vomiting, dehydration, and edema. Nausea was the most frequently observed toxicity (60% of patients, all grades 1 or 2 at RP2D). |
| Conclusions: | The MTD and RP2D of PF00562271 is 125 mg twice per day with food. PF00562271 displayed time and dosedependent nonlinear PK and is likely a potent CYP 3A inhibitor. This firstinclass study supports further investigation of FAK as a promising therapeutic target. |