A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies

Abstract

Background: Synergistic cytotoxicity with high-dose statins and erlotinib has been demonstrated in preclinical models across a number of tumour types. In this phase I study, we evaluated the safety and potential anti-tumour activity of escalating doses of rosuvastatin in combination with the standard clinical dose of erlotinib in heavily pretreated patients with advanced solid tumours.

Methods: This was a single-center, phase I open-label study to determine the safety and recommended phase two dose (RPTD) of rosuvastatin in combination with 150 mg/day standard dose of erlotinib. Using a 3 + 3 study design and 28-day cycle, escalating doses of rosuvastatin from 1 to 8 mg/kg/day × 2 weeks (cycle 1) and 3 weeks (subsequent cycles) given concurrently with erlotinib were evaluated. In order to expand the experience and to gain additional safety and pharmacokinetic data, two expansions cohorts using concurrent or alternating weekly dosing regimens at the RPTD were also evaluated.

Results: All 24 patients enrolled were evaluable for toxicity, and 22 for response. The dose-limiting toxicity (DLT) of reversible muscle toxicity was seen at the 2 mg/kg/day dose level. Maximal tolerated dose (MTD) was determined to be 1 mg/kg/day. Thirty-three percent of patients developed at least 1 ≥ grade 2 muscle toxicity (rhabdomyolysis: 1/24, myalgia: 7/24) resulting in one study-related death. Durable stable disease for more than 170 days was seen in 25 % of patients that received concurrent treatment and were evaluable for response (n = 16). Plasma erlotinib levels on study were unaffected by the addition of rosuvastatin.

Conclusions: The observed disease stabilization rate of 25 % with combination therapy in this heavily pretreated population is encouraging, however, the high levels of muscle toxicities observed limited this combination strategy.

Keywords: Epidermal growth factor receptor; Erlotinib; Pharmacokinetics; Statins; Therapeutics.

Fig. 1

Phase I trial outline. a Schematic of the patient cohorts including patient numbers and treatment regimens evaluated in this study. b Treatment schedules employed in this Phase I study

Fig. 2

Patient responses on study. a Days on study for each evaluable patient segregated into concurrent treatments (Cohorts 1 and 2-dose escalation and Schedule A) and the alternating weekly schedule (Schedule B). b Days on study based on tumour type in the concurrent treatments. c Kaplan-Meir curve evaluating progression free survival in all evaluable patients. d Waterfall plot of the number of days on study of evaluable patients in this study

Fig. 3

Pharmacokinetic analysis of Schedule A patients. a Serum erlotinib levels were determined for these patients at day 6 (erlotinib alone, left panel) and at day 14 (erlotinib + rosuvastatin treatments) every 2 h following drug administration for 24 h. b For the 5 evaluable patients (14–18), area under the curve (AUC) values showed no statistical difference between the two treatments with respect to serum erlotinib exposure. P value determined by T test. c Serum rosuvastatin levels were determined for these patients at day 14 (erlotinib +1 mg/mg/day rosuvastatin treatments) every 2 h following drug administration for 24 h