Feasibility study of intra-patient sorafenib dose-escalation or re-escalation in patients with previously treated advanced solid tumors.
OBJECTIVE
To determine if intra-patient dose escalation of the multi-targeted kinase inhibitor sorafenib is feasible in patients with advanced pretreated solid malignancies.


METHODS
An intra-patient dose escalation scheme starting at 400 mg BID was employed in this prospective trial. Doses were escalated to 600 mg BID for the second cycle and to 800 mg BID for the third cycle in the absence of grade 3+ adverse events. In the event of grade 3+ adverse events during cycle 1, doses were reduced to 400 mg daily through cycle 2. Dose re-escalation for cycle 3 was allowed in the absence of grade 3+ adverse events during cycle 2. Further dose escalation was prohibited. The primary endpoint was the overall percentage of patients tolerating dose escalation to 600 mg BID through cycle 2 or tolerating re-escalation to 400 mg BID through cycle 3.


RESULTS
Fifty eligible patients with various solid tumors and a median of 3 prior therapies were enrolled. Eleven patients (22%) tolerated primary dose escalation or re-escalation. Only 14 patients (28%) completed cycle 1 without dose modification or discontinuing treatment. Seven of 13 patients tolerated primary dose escalation through cycle 2. Four of 5 patients tolerated dose re-escalation through cycle 3. Reasons for escalation failure included tumor progression (42%) and adverse events (26%). Common grade 3+ adverse events included hand-foot skin reaction, hypertension, and hypophosphatemia.


CONCLUSIONS
Intra-patient dose escalation and/or re-escalation of sorafenib were not feasible in pretreated solid tumor patients. Sorafenib dose escalation remains an investigational approach.
Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Cancer Center, Sacramento, CA 95817, USA. thomas.semrad@ucdmc.ucdavis.edu
Thomas J
TJ
Semrad
Courtney
C
Eddings
Chong-Xian
CX
Pan
Derick H
DH
Lau
David
D
Gandara
Laurel
L
Beckett
Primo N
PN
Lara
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects*; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D000077157:Sorafenib
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000077157:Sorafenib