Oral Tipifarnib (R115777) Has Single Agent Anti-Tumor Activity in Patients with Relapsed Aggressive Non-Hodgkin Lymphoma (NHL): Results of a Phase II Trial in the University of Iowa/Mayo Clinic Lymphoma SPORE (CA97274).

Background: Patients (pts) with aggressive NHL who relapse after conventional chemotherapy or stem cell transplant have a poor prognosis. Novel agents are needed for this important subset. Tipifarnib is an orally available methylquinolone derivative that is an inhibitor of the farnesyl transferase enzyme that transfers the farnesyl group from farnesyl pyrophosphate to specific polypeptides including small GTPases of the Ras, Rho-B, and Rheb families, as well as nuclear lamins and kinetochore proteins. Tipifarnib has documented activity in acute leukemia and produces stable disease in relapsed multiple myeloma. The goal of this study was to evaluate the activity of single-agent tipifarnib in patients with relapsed aggressive NHL in the context of a phase II trial.

Methods: Pts with relapsed diffuse large, follicular grade III, or mantle cell lymphoma were eligible for this study. Pts were treated with oral tipifarnib 300 mg twice daily d1–21 q 28 days until progression. Pts were restaged after 2 cycles, 6 cycles, and every 3 cycles thereafter. Tumor was sampled prior to tipifarnib and at day 8 in selected patients with accessible tumors. These paired samples were assayed for accumulation of unprocessed HDJ-2 and prelamin A, two polypeptides that require farnesylation for processing.

Results: Forty-two pts were accrued between March 2004 and June 2006. Thirty-seven pts had diffuse large cell, 1 follicular grade III, and 4 had mantle cell. Of the 38 patients evaluable for response, 7 (18%) had a partial response and 8 (21%) had stable disease. The 7 responders all had diffuse large cell histology. Median progression-free survival (PFS) for all pts was 2 months (range, 0–25+). The PFS of the 7 responders was noteworthy at 4.2, 4.9+, 6.7, 9.6, 14.9+, 21.6+, and 25.1+ months, respectively. The primary toxicity was myelosuppression and 33% of pts required dose reductions. The median dose received in all pts was 300 mg twice daily (mean 275, range, 100–400). The median dose received by the 7 responders was 200 mg twice daily (range, 100–400). The dose of 300 mg twice daily resulted in accumulation of unfarnesylated forms of one or both markers in all pts studied to date.

Conclusion: Oral tipifarnib has antitumor activity as a single agent with an excellent toxicity profile in pts with relapsed/refractory aggressive lymphoma. When given in this dose and schedule, tipifarnib is well-tolerated and can be taken for months without cumulative toxicity. This drug warrants further investigation in combination with conventional chemotherapy and other novel agents for the treatment of this important subset of patients.