Phase I multicenter trial of perifosine in combination with sorafenib for patients with advanced cancers including renal cell carcinoma

Abstract

16024 Background: Perifosine (PERI) is an oral alkylphosphocholine with effects on multiple pathways including Akt, MAPK and JNK. Akt is often activated in renal cell carcinoma (RCC) and associated with resistance. To evaluate the single agent activity of PERI, RCC patients (pts) were assessed in a broad phase II trial with 6/9 pts (66%) achieving clinical benefit: 3 PR's, 3 SD ≥ 6 mo's (ASCO 2007 #15622). In vitro PERI is synergistic with MAPK inhibitors. PERI + Sorafenib (SOR) may result in a higher response rate and/or increase in duration of disease control so a phase 1 trial to determine the MTD was initiated. Methods: The trial was designed to accrue 3–6 pts in each of four cohorts. Response by RECIST was a secondary endpoint. PERI was escalated from 50mg qd to 50mg tid and SOR from 400mg qd to 400mg bid. DLT was defined as grade (G) 3 non-hematologic or G4 hematologic toxicity. MTD was the dose below that at which 2/6 pts experienced a DLT. Results: 20 pts were enrolled (12 m/8 f, median age 64 (range 44–87). Median number of prior therapies was 2, (range 1–4). 3 pts were inevaluable due to rapid disease progression. Diagnosis was as follows; RCC (11 pts), sarcoma (5), colorectal (2), hepatocellular (1) and neuroendocrine (1). 17 pts were evaluable for toxicity: No drug related Grade 4 AE's were seen. Suspected DLT of hand-foot syndrome was seen in cohort 4 and additional pts were enrolled. There was no increase in hand-foot syndrome compared to SOR alone. Of interest, 6/9 evaluable RCC pts (67%) had SD >12 wks (median 26 wks, range 12–62+). One hepatocellular pt had SD for 36 wks. After final review, the recommended dose is PERI 50mg bid + SOR 400mg bid. Conclusions: PERI + SOR was well tolerated with no increased hand-foot syndrome compared to SOR alone. 6/9 (67%) RCC pts achieved SD up to 62+ wks. Future studies are currently in development. Cohort 1 N=3 2 N=3 3 N=5 4 N=6 Perifosine Dose (mg) 50 50 100 150 Sorafenib Dose (mg) 400 800 800 800 Adverse Event (AE) Nausea 2 G1 1 G1, 1 G2 3 G1 1 G2 Vomiting 1 G1 2 G1, 1 G2 1 G2 Diarrhea 1 G1, 1 G2 2 G1, 1 G2 2 G1, 2 G2, 1 G3 1 G2 Fatigue 1 G1, 1 G3 1 G1 2 G2 2 G1 Hand-foot Syndrome G2 1 G2 Rash 1 G1 1 G2 1 G1, 1 G2, 1 G3 Hypertension 2 G2 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Keryx Biopharmaceuticals Keryx Biopharmaceuticals Keryx Biopharmaceuticals Keryx Biopharmaceuticals Keryx Biopharmaceuticals