Phase I Dose Escalation, Pharmacokinetic, And Biomarker Study Of Imatinib Mesylate Plus Capecitabine In Advanced Solid Tumor Malignancies.

3093 Background: Preclinical data have suggested at least additive antitumor effects when imatinib (I) and 5-FU are combined. The goals of this study were to determine the maximal tolerated dose for the combination of I and capecitabine (C) in solid tumor patients (pts), as well as to describe non-dose limiting toxicities (non-DLT), pharmacokinetics (PK), and pharmacodynamics (PDGFR inhibition in granulation tissue). Methods: 24 pts (12 M, 12 F) with solid tumor malignancies received C plus I using a 21 day (d) cycle. C was dosed BID for 14/21 d. I was dosed QD x 21d. Results: 24 of 24 pts were fully evaluable for toxicity and efficacy. 6 pts were treated at dose level 1 (C 1000 mg/m2 BID, I 300 mg QD). The only dose limiting toxicity (DLT) at dose level 1 was grade (gr) 3 diarrhea in 1 patient; however 5 of 6 pts required dose reductions in a subsequent cycle. Therefore, the next 18 pts were treated at dose level -1 (C 750 mg/m2 BID and I 300 mg QD). One DLT (gr 3 fatigue) was seen at dose level -1. Non-DLT gr ¾ toxicities at any point at dose level -1 were gr 4 anemia (n=1) and gr 3 lymphopenia (n=6). Toxicities requiring dose reductions at any point on dose level -1 occurred in 7/18 patients. Gr ½ toxicities found in > 10% of all patients at any point in the trial were anemia (46%), leukopenia (17%), neutropenia (21%), lymphopenia (29%), thrombocytopenia (29%), nausea (71%), anorexia (41%), edema (42%), diarrhea (38%), hand foot syndrome (33%), vomiting (33%), headache (25%), insomnia (25%), skin rash (25%), constipation (21%), stomatitis (17%), lightheadedness (13%), fatigue (13%), numbness/tingling (13%), taste change (13%), and elevated transaminases (13%). 1 pt with carcinoid tumor had a partial response. 1 pt with non-small cell lung cancer had a minor response, and 5/21 pts had stable disease as their best response. 1 pt had stable disease for 8 months and another pt was stable for 6 months. Conculsions: On a 21 d cycle, the recommended phase 2 dose of C plus I is C 750 mg/m2 BID for 14 d, and I 300 mg QD. [Table: see text]