Phase I study of pemetrexed with sorafenib in advanced solid tumors

Abstract

Purpose: To determine if combination treatment with pemetrexed and sorafenib is safe and tolerable in patients with advanced solid tumors.

Results: Thirty-seven patients were enrolled and 36 patients were treated (24 in cohort A; 12 in cohort B). The cohort A dose schedule resulted in problematic cumulative toxicity, while the cohort B dose schedule was found to be more tolerable. The maximum tolerated dose (MTD) was pemetrexed 750 mg/m2 every 14 days with oral sorafenib 400 mg given twice daily on days 1-5. Because dosing delays and modifications were associated with the MTD, the recommended phase II dose was declared to be pemetrexed 500 mg/m2 every 14 days with oral sorafenib 400 mg given twice daily on days 1-5. Thirty-three patients were evaluated for antitumor activity. One complete response and 4 partial responses were observed (15% overall response rate). Stable disease was seen in 15 patients (45%). Four patients had a continued response at 6 months, including 2 of 5 patients with triple-negative breast cancer.

Experimental design: A phase I trial employing a standard 3 + 3 design was conducted in patients with advanced solid tumors. Cohort A involved a novel dose escalation schema exploring doses of pemetrexed every 14 days with continuous sorafenib. Cohort B involved a modified schedule of sorafenib dosing on days 1-5 of each 14-day pemetrexed cycle. Radiographic assessments were conducted every 8 weeks.

Conclusions: Pemetrexed and intermittent sorafenib therapy is a safe and tolerable combination for patients, with promising activity seen in patients with breast cancer.

Keywords: clinical trial; pemetrexed; solid tumors; sorafenib.

Figure 1. Treatment duration and tumor size change from baseline for patients with a best response of stable disease (SD), partial response (PR), or complete response (CR)

(A), each bar represents the treatment duration of an individual patient. The tumor type and cohort for each patient is given on the y-axis. (B), each bar represents the maximum change in tumor size in comparison to baseline for an individual patient. The tumor type and cohort for each patient is given on the x-axis.

Figure 2. Clinical vignettes

(A), diagnosis: hormone receptor positive breast cancer; previous treatment: 6 lines of systemic therapy; best response: PR; duration of therapy: 12 months. (B), diagnosis: initially ER+, Her-2- breast cancer, with subsequent development of triple-negative metastatic disease; previous treatment: 5 lines of systemic therapy; best response: PR; duration of therapy: 12 months. (C), diagnosis: triple-negative breast cancer; previous treatment: 7 lines of systemic therapy; best response: PR; duration of therapy: 9 months.