A phase I MMRC clinical trial testing the combination of bortezomib and tipifarnib in relapsed/refractory multiple myeloma

Abstract

8597 Background: Preclinical work from our group has demonstrated that the combination of a farnesyl transferase inhibitor and bortezomib results in enhanced plasma cell apoptosis, and more recently, we have suggested that the mechanism for this synergy is due to inhibition of HDAC6, and inhibition of the proteasome and aggresome pathway. Methods: Patients with relapsed or refractory myeloma were treated with bortezomib at 1.0 or 1.3 mg/m2 on a standard schedule in conjunction with escalating doses of tipifarnib (100–400mg/BID) given on days 2–15 every 21 days. Dose escalation was accomplished using an adaptive phase I design (Escalation With Overdose Control). Results: 22 patients have been enrolled, of which 18 are evaluable, into respective tipifarnib dose levels 100 mg (n=6), 200mg (n=5) and 300mg (n=5) and 400mg (n=2). Median age for the enrolled patients is 59 and median time from myeloma diagnosis was 4.7 years. The average number of prior therapies was 4.5. Among these patients with advanced myeloma and refractory disease, stabilization of disease or better was seen among 8/10 patients with 2 of the 8 achieving an MR. Among the patients achieving clinical benefit, 1 patient had a stable M-protein, but experienced an 80% reduction in circulating plasma cells while on therapy, and another has had a 75% reduction in the free light chain assay. The most common drug related side effect was was Gr2 diarrhea (23.5%). Hematologic toxicities were difficult to ascertain as patients had advanced myeloma and many were entered onto study with platelet counts between 25 and 50. Additional grade 3 toxicities included renal insufficiency (related to PD), pneumonia and altered mental status which were all considered not related to study drug but to progression of disease. There were no Grade 3-5 drug related toxicities. One patient experienced grade 2 peripheral neuropathy who did not have pre existing PN at baseline. Conclusions: The combination of bortezomib and tipifarnib is supported by preclinical rationale and has produced stable disease or better among 10 of 18 patients with refractory myeloma. Optimal dose of tipifarnib and bortezomib have yet to be defined, and additional patients are being enrolled with 1.3mg/m2 of bortezomib, and escalating doses of tipifarnib. [Table: see text]