Multi-institutional phase 2 study of the farnesyltransferase inhibitor tipifarnib (R115777) in patients with relapsed and refractory lymphomas

Abstract

A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib was conducted in 93 adult patients with relapsed or refractory lymphoma. Patients received tipifarnib 300 mg twice daily on days 1-21 of each 28-day cycle. The median number of prior therapies was 5 (range, 1-17). For the aggressive B-cell, indolent B-cell, and T-cell and Hodgkin lymphoma (HL/T) groups, the response rates were 17% (7/42), 7% (1/15), and 31% (11/36), respectively. Of the 19 responders, 7 were diffuse large B-cell non-Hodgkin lymphoma (NHL), 7 T-cell NHL, 1 follicular grade 2, and 4 HL. The median response duration for the 19 responders was 7.2 months (mean, 15.8 months; range, 1.8-62), and 5 patients in the HL/T group are still receiving treatment at 29-64+ months. The grade 3/4 toxicities observed were fatigue and reversible myelosuppression. Correlative studies suggest that Bim and Bcl-2 should be examined as potential predictors of response in future studies. These results indicate that tipifarnib has activity in lymphoma, particularly in heavily pretreated HL/T types, with little activity in follicular NHL. In view of its excellent toxicity profile and novel mechanism of action, further studies in combination with other agents appear warranted. This trial is registered at www.clinicaltrials.gov as #NCT00082888.

Figures

Figure 1

Survival parameters in patients treated with tipifarnib. Kaplan-Meier curves for TTP (A) and OS (B) of 93 patients with relapsed lymphoma treated with tipifarnib. The results are shown by aggressive B cell, indolent B cell, and HL/T (uncommon).

Figure 2

Evaluation of potential markers of drug effect in samples from this trial. (A) CD19+ cells (lanes 1 and 2) and CD3+ cells from 2 normal (Nl) persons were probed with antibodies to RasGRP1 and, as a loading control, histone H1. (B) Example of RasGRP1 blotting in 4 lymphoma samples. β-actin served as a loading control. Nonadjacent lanes from a single blot have been juxtaposed to assemble this panel. (C) Effect of tipifarnib on signaling and Bim expression in situ. Each blot is a separate patient with pre- and post-tipifarnib results. In patients 5 (MCL) and 11 (small lymphocytic lymphoma), circulating tumor cells were examined; in patients 3 and 6 (both large cell), paired lymph node samples were assayed. The HDJ-2 shift after treatment (patients 3 and 5) confirms tipifarnib-induced inhibition of FT. Effects on ERK phosphorylation were variable, with decreases in patients 5 and 6 but an increase in patient 3. Some or all Bim isoforms increased in patients 5, 6, and 11 with a smaller increase in patient 3. (D) Examples of pretreatment Bcl-2 levels.

Figure 3

A 67-year-old man with stage IVA diffuse large B-cell lymphoma. He was treated with rituximab, cyclophosphamide, vincristine and prednisone × 6 with an initial complete response, only to relapse 7 months later. He responded to salvage chemotherapy and received an autologous stem cell transplantation with a 6-month TTP. After failing single-agent rituximab, he joined this study. He responded to tipifarnib 300 mg twice daily. Because of myelosuppression, the dose was reduced to 100 mg twice daily. He maintained remission for 25 months before progressing on therapy. Tumor biopsies before and after tipifarnib demonstrated low bcl-2 protein tumor content at baseline with a marked increase in Bim isoforms and decrease in p-ERK after tipifarnib (patient 6; Figure 2C).