A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors.
VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies.



Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state.



Forty-six patients were treated across nine dose levels (12.5-750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d.



VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.
Sarah Cannon Research Institute, 250 25th Avenue North, Suite 200, Nashville, TN, 37203, USA. suzanne.jones@scresearch.net.
Suzanne F
SF
Jones
Princess Margaret Cancer Centre, Toronto, ON, Canada.
Lillian L
LL
Siu
Sarah Cannon Research Institute, 250 25th Avenue North, Suite 200, Nashville, TN, 37203, USA.
Johanna C
JC
Bendell
Brigham and Women's Hospital, Boston, MA, USA.
James M
JM
Cleary
Princess Margaret Cancer Centre, Toronto, ON, Canada.
Albiruni R A
AR
Razak
Sarah Cannon Research Institute, 250 25th Avenue North, Suite 200, Nashville, TN, 37203, USA.
Jeffrey R
JR
Infante
Beth Israel Deaconess Medical Center, Boston, MA, USA.
Shuchi S
SS
Pandya
Princess Margaret Cancer Centre, Toronto, ON, Canada.
Philippe L
PL
Bedard
Pfizer Oncology, Groton, CT, USA.
Kristen J
KJ
Pierce
Pfizer Oncology, La Jolla, CA, USA.
Brett
B
Houk
Pfizer Oncology, Groton, CT, USA.
W Gregory
WG
Roberts
Pfizer Oncology, La Jolla, CA, USA.
S Martin
SM
Shreeve
Dana-Farber Cancer Institute, Boston, MA, USA.
Geoffrey I
GI
Shapiro
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001549:Benzamides; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009930:Organic Chemicals / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011719:Pyrazines; D013449:Sulfonamides
D000970:Antineoplastic Agents; D001549:Benzamides; D009930:Organic Chemicals; D011719:Pyrazines; D013449:Sulfonamides; C584510:defactinib
Defactinib; Dose-escalation study; Focal adhesion kinase; Proline-rich tyrosine kinase-2; VS-6063