Pharmacokinetic (PK) and phase I study of sorafenib (S) for solid tumors and hematologic malignancies in patients with hepatic or renal dysfunction (HD or RD): CALGB 60301

Abstract

3538 Background: We sought to characterize the PK and determine a tolerable dose of S in patients with HD or RD. Methods: Patients with performance status 0–2 and pathologically proven solid tumors, multiple myeloma, or non-Hodgkin’s lymphoma, for whom standard therapy was exhausted, were assigned to one of 9 cohorts: [1] Bilirubin (B) =ULN and SGOT =ULN and creatinine clearance (CC) =60 ml/min; [2] B > ULN but = 1.5 x ULN and/or SGOT > ULN; [3] CC between 40 and 59 mL/min; [4] B > 1.5 x ULN to = 3 x ULN (any SGOT); [5] CC between 20 and 39 mL/min; [6] B > 3 x ULN to 10 x ULN (any SGOT); [7] CC < 20 mL/min; [8] albumin < 2.5 mg/dL (any B/ SGOT); and [9] hemodialysis. S was administered po as a 400 mg test dose on day 1 with blood sampled before and 1, 2, 3, 4, 6, 24, and 168 hrs afterwards for PK. Total S concentrations were fit to a 2-compartment model and population parameters from previous studies were utilized. On day 8, continuous daily po S started with dose escalation in groups of at least 3 evaluable patients. Dose-limiting toxicity (DLT) by day 29 was defined as: grade 4 neutrophils or platelets; B = 1.5 x baseline in HD and = 2.5 x ULN in RD; CC reduction by > 20 mL/min in RD and >10 mL/min in HD; grade = 3 nausea/vomiting/diarrhea despite optimal supportive care; or any other grade = 3 non-hematologic toxicity. Results: Between 1/05 and 12/06, 146 patients (target 150) were registered but 12 never started therapy. With the exception of cohorts 6 and 7, at least 12 patients per cohort were evaluable. The dose level in each cohort with DLT in less than one third of patients was: [1] 400 mg bid; [2] 400 mg bid; [3] 400 mg bid; [4] 200 mg bid; [5] 200 mg bid; [6] not even 200 mg every third day tolerable; [7] n/a; [8] 200 mg qd; and [9] 200 mg qd. All DLT was non-hematologic: 9 of 12 events in patients with HD were increase in B; other DLT included abdominal pain, rash, fatigue, nausea/vomiting, hand-foot syndrome, congestive heart failure, diarrhea, hemorrhage, and hypertension. PK data are available for 51 patients. Apparent S clearance was: highly variable, median 5.69 (range 1.27 - 19.98) L/hr; not related to age, body weight, or sex; and not different among cohorts. Conclusions: Apparent S clearance does not depend on cohort. We propose the above empiric starting doses by cohort. No significant financial relationships to disclose.