Randomized phase 1 crossover study assessing the bioequivalence of capsule and tablet formulations of dovitinib (TKI258) in patients with advanced solid tumors.
OBJECTIVE
A capsule formulation of the tyrosine kinase inhibitor dovitinib (TKI258) was recently studied in a phase 3 renal cell carcinoma trial; however, tablets are the planned commercial formulation. Therefore, this randomized 2-way crossover study evaluated the bioequivalence of dovitinib tablet and capsule formulations in pretreated patients with advanced solid tumors, excluding breast cancer.


METHODS
In this 2-part study, eligible patients received dovitinib 500 mg once daily on a 5-days-on/2-days-off schedule. During the 2-period bioequivalence phase, patients received their initial formulation (capsule or tablet) for 3 weeks before being switched to the alternative formulation in the second period. Patients could continue to receive dovitinib capsules on the same dosing schedule during the post-bioequivalence phase.


RESULTS
A total of 173 patients were enrolled into the bioequivalence phase of the study (capsule → tablet, n = 88; tablet → capsule, n = 85), and 69 patients had evaluable pharmacokinetics (PK) for both periods. PK analyses showed similar exposure and PK profiles for the dovitinib capsule and tablet formulations and supported bioequivalence [geometric mean ratios: AUClast, 0.95 (90 % CI 0.88-1.01); Cmax, 0.98 (90 % CI 0.91-1.05)]. The most common adverse events, suspected to be study drug related, included diarrhea (60 %), nausea (53 %), fatigue (45 %), and vomiting (43 %). Of 168 patients evaluable for response, 1 achieved a partial response, and stable disease was observed in 32 % of patients.


CONCLUSIONS
Dovitinib capsules and tablets were bioequivalent, with a safety profile similar to that observed in other dovitinib studies of patients with heavily pretreated advanced solid tumors.
Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, 7979 Wurzbach Road, San Antonio, TX, 78229, USA. sarantopoulo@uthscsa.edu.
John
J
Sarantopoulos
Montefiore Medical Center, Bronx, NY, USA.
Sanjay
S
Goel
City of Hope National Medical Center, Duarte, CA, USA.
Vincent
V
Chung
University of California, San Francisco, San Francisco, CA, USA.
Pamela
P
Munster
University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Shubham
S
Pant
Florida Cancer Specialists, Sarasota, FL, USA.|Sarah Cannon Research Institute, Nashville, TN, USA.
Manish R
MR
Patel
Sarah Cannon Research Institute, Nashville, TN, USA.
Jeffrey
J
Infante
The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Hussein
H
Tawbi
Baylor Sammons Cancer Center, Dallas, TX, USA.
Carlos
C
Becerra
University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
Justine
J
Bruce
University of California, Los Angeles, Los Angeles, CA, USA.
Fairooz
F
Kabbinavar
Washington University School of Medicine Siteman Cancer Center, St. Louis, MO, USA.
A Craig
AC
Lockhart
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Eugene
E
Tan
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Shu
S
Yang
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Gary
G
Carlson
Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
Jeffrey W
JW
Scott
University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA.
Sunil
S
Sharma
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D002214:Capsules; D018592:Cross-Over Studies; D003710:Demography; D004339:Drug Compounding; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D015363:Quinolones / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D013607:Tablets; D013810:Therapeutic Equivalency; D016896:Treatment Outcome; D055815:Young Adult
C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002214:Capsules; D047428:Protein Kinase Inhibitors; D015363:Quinolones; D013607:Tablets
Bioequivalence; Capsule; Dovitinib; Pharmacokinetics; TKI258; Tablet