title: A phase I trial to determine the safety of imatinib in combination with vatalanib in patients with advanced malignancies.
abstract: The role of tyrosine kinase inhibitors (TKIs) in the treatment of advanced malignancies is well established. Imatinib and vatalanib are oral TKIs with different mechanisms of action. This trial sought to establish the safety, tolerability, and maximum tolerated dose (MTD) of the two agents in combination. Secondary objectives included determination of potential pharmacologic interactions among vatalanib and imatinib and observation of antitumor activity. Patients with biopsy-proven advanced refractory solid tumors were enrolled in this single-center dose-escalation trial. Patients initially received imatinib and vatalanib once daily following a 14-day run-in period of daily oral vatalanib only, and were observed for a full 28-day treatment cycle prior to dose escalation. An amendment divided the vatalanib dose into two daily doses and gradually escalated the dose over a 2-3 week period. Patients continued combination therapy until disease progression or intolerable toxicity. Forty-five patients were enrolled between September 2004 and November 2007. As of September 2009, a total of 247 cycles of treatment had been administered (range: 1 -44+, median = 2 ). The MTD was determined to be vatalanib 1250 mg daily and imatinib 400 mg daily. Thirty-five patients (78%) were evaluable for response; 2 patients achieved PR, while 14 patients had SD ( 10 had stable disease ≥ 6 cycles). The combination of vatalanib and imatinib was well tolerated. Twice-daily vatalanib dosing improved tolerability and ease of full-dose administration. These results suggest that vatalanib-containing combinations may be active and tolerable, warranting further study.
authors.affiliation: The Sarah Cannon Research Institute, Nashville, Tennessee 37203, USA.
authors.forename: David
authors.initials: D
authors.lastname: Spigel
authors.forename: Suzanne
authors.initials: S
authors.lastname: Jones
authors.forename: John
authors.initials: J
authors.lastname: Hainsworth
authors.forename: Jeff
authors.initials: J
authors.lastname: Infante
authors.forename: F Anthony
authors.initials: FA
authors.lastname: Greco
authors.forename: Dana
authors.initials: D
authors.lastname: Thompson
authors.forename: Habib
authors.initials: H
authors.lastname: Doss
authors.forename: Howard
authors.initials: H
authors.lastname: Burris
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D001706:Biopsy; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D011725:Pyridines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D018570:Risk Assessment; D013714:Tennessee; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001549:Benzamides; D010793:Phthalazines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; C404768:vatalanib; D000068877:Imatinib Mesylate