A phase I study of single-agent nilotinib or in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors.
OBJECTIVE
To study the safety, tolerability, and pharmacokinetics of the selective tyrosine kinase inhibitor nilotinib as a single agent or in combination with imatinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors.


METHODS
A phase I intercohort dose-escalation trial was done in patients who received either (a) single agent nilotinib 400 mg twice daily or (b) escalating doses of nilotinib (200 mg once daily, 400 mg qd, or 400 mg bid) plus imatinib 400 mg bid (10- and 14-hour interval daily), or (c) nilotinib 400 mg bid plus imatinib 400 mg qd. Safety, pharmacokinetics, and tumor assessments were done.


RESULTS
Oral clearance (CL/F) of nilotinib was similar across the combination groups (mean CL/F, 19.1-25.6 L/h), and lower than in the single-agent cohort (mean CL/F, 35.6 L/h). A linear relationship between nilotinib daily dose and peak concentration was observed in the combination cohorts. Observed adverse events (AE) were mostly nonhematologic. Frequently reported AEs were rash (40%), fatigue (38%), abdominal pain (36%), and nausea (36%). Severe AEs (grade 3 or 4) included abdominal pain (13%) and rash (9%), the latter mainly with the combination. Thirty-eight patients had stable disease and two patients achieved partial response with a median progression-free survival of 134 days for the entire group.


CONCLUSIONS
Nilotinib alone or in combination with imatinib was well tolerated overall and showed clinical activity in imatinib-resistant gastrointestinal stromal tumor patients. This phase I trial identified single-agent nilotinib 400 mg bid or combined with imatinib 400 mg qd as possible phase II doses for further evaluation.
Demetri
George D
GD
Ludwig Center at Dana-Farber/Harvard Cancer Center, Dana-Farber Cancer Institute, Boston, MA 02115, USA. gdemetri@partners.org
Casali
Paolo G
PG
Blay
Jean-Yves
JY
von Mehren
Margaret
M
Morgan
Jeffrey A
JA
Bertulli
Rossella
R
Ray-Coquard
Isabelle
I
Cassier
Philippe
P
Davey
Monica
M
Borghaei
Hossein
H
Pink
Daniel
D
Debiec-Rychter
Maria
M
Cheung
Wing
W
Bailey
Stuart M
SM
Veronese
Maria Luisa
ML
Reichardt
Annette
A
Fumagalli
Elena
E
Reichardt
Peter
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004361:Drug Tolerance; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib