Phase I study of tipifarnib and sorafenib in patients with biopsiable advanced cancer (NCI protocol 7156)

Abstract

3593 Background: The Ras and Raf kinases are intimately connected.Therefore, inhibiting both Ras (upstream) with a FTase inhibitor (tipifarnib) and B-Raf (downstream) with a Ras inhibitor(sorafenib) may confer synergistic antitumor effect. Moreover, sorafenib has been identified as a RET kinase inhibitor and the combination may also inhibit the RET/Ras/Raf/IKKB/NF-κB pathway. Methods: The trial was a conventional phase I 3+3 dose-escalation design. Each cycle consisted of 28 days of sorafenib and 21 days of tipifarnib.Correlative studies including PKs, optional FNA biopsies and PBMC samples pre and post cycle 1. PD analysis included FTase activity, western blots of downstream signaling of total and phosphorylated MEK1/2, ERK1/2 AKT and STAT3, and RET mutational sequencing of medullary thyroid (MTC) pts. Results: A total of 50 pts have been treated with 20 pts expanded at MTD.The most common drug related toxicities include rash,lymphopenia,& diarrhea.At dose level 4, 2/5 pts entered experienced a DLT of grade 3 rash,therefore the defined MTD is tipifarnib 100mg po BID, sorafenib 400mg qam,200mg qpm.Of the 37 evaluable pts,by RECIST,18 pts(49%) had SD for 4 months or longer.Several pts have had minor responses including papillary thyroid (N=4;20%,13%,19%,16% response)and MTC (N=2;17%,17% response).Two PRs were noted in MTC pts,one confirmed (N=2;44%,35% response). PK analysis showed similar profile for single agent sorafenib, however, tipifarnib plasma concentrations were lower than reported. Measured FTase activity in PBMCs showed little inhibition suggesting sorafenib may intefere with the ability of tipifarnib to inhibit FTase activity. Downstream proteins both total and phosphorylated MEK and ERK showed no changes. However, decrease in P-AKT and P-STAT3 was noted in some FNA samples. RET mutational analysis in 3 MTC pts who had minor response or PR all showed activating RET mutations. Conclusions: The MTD was determined to be tipifarnib at 100mg po BID, sorafenib at 400mg qam,200mg qpm.PK, PD analysis suggests that sorafenib may interfere with both plasma concentrations and FTase activity of tipifarnib. Activity in papillary thyroid and MTC pts warrant further exploration of this combination. No significant financial relationships to disclose.