Combining Farnesyl Transferase Inhibitors With Cytotoxic Therapy In Breast Cancer And Other Diseases

Sparano et al. (39) performed a phase I trial of tipifarnib plus doxorubicin and cyclophosphamide (AC) in patients with metastatic breast cancer, followed by a phase II trial of four cycles of the tipifarnib-AC combination as preoperative therapy in patients with locally advanced breast cancer. The primary endpoint for the phase II trial was pathological complete response (pCR) in the breast at the time of definitive surgery; pCR has been used as a surrogate marker for identifying active combinations because it has been shown to predict improved disease-free survival in several prospective trials in patients with operable breast cancer (80,81) and retrospective studies in patients with locally advanced breast cancer (82). The objective of the study was to determine whether the addition of tipifarnib to standard AC chemotherapy would increase the breast pCR rate to at least 25%, a result comparable to administering sequential docetaxel following AC for a total of eight cycles (81). Eleven with metastatic breast cancer received AC [doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2)] given intravenously on day 1 every three weeks (N = 2) or two weeks (N = 9) plus tipifarnib (100, 200, or 300 mg BID for 6-14 days). After excessive toxicity consisting of grade 4 febrile neu-tropenia was seen at the first dose level using AC every three weeks plus tipifarnib (100 mg BID) on days 1 to 14, the trial was modified to reduce the duration of tipifarnib administration (days 2-7), add filgrastim, and shorten the interval between AC cycles from every three to every two weeks. Providing further rationale for shortening the interval between AC cycles, dose-dense administration of sequential AC-paclitaxel every two weeks was shown to be more effective than the same regimen given every three weeks as adjuvant therapy (83). The recommended phase II dose of tipifarnib was 200 mg BID given on days 2 to 7 when combined with AC; dose-limiting toxicities were febrile neutropenia and grade 3 nausea and vomiting when tipifarnib was given at higher doses (300 mg BID) using the same schedule. Twenty-one patients with locally advanced breast cancer subsequently received dose-dense AC plus filgrastim and tipifarnib (200 mg BID on days 2-7) for up to four cycles, of whom seven patients (33%; 95% CI, 15-55%) had a breast pCR at surgery, and five patients (24%; 95% CI, 8-47%) had a pCR in the breast and lymph nodes. This exceeded the 10% pCR rate expected for AC treatment alone in this patient population, and met the prespecified endpoint for continuation accrual to a total of 50 patients in the second stage of the phase II trial (accrual has completed). In addition, five of 12 ER-positive cases (42%) and two of nine ER/PR-negative cases (22%) had a breast pCR. Previous studies have consistently demonstrated a lower breast pCR rate in patients with ER-positive disease (6%) compared with ER-negative disease (14%) (81), suggesting that adding tipifar-nib to standard chemotherapy may be particularly effective in augmenting response to treatment in patients with ER-positive disease. Five patients had paired tumor biopsies performed before treatment and after the last tipifarnib dose during the first cycle of therapy. All patients demonstrated at least 50% (median 100%, range 55-100%) inhibition of FTase enzyme activity in the primary breast tumors in vivo, only one of whom had a breast pCR (who demonstrated 91% FTase inhibition). Additional studies are planned to confirm the effectiveness of preoperative tipifarnib combined with standard chemotherapy, particularly in patients with ER-positive disease. Nevertheless, the study provides proof of principle for inhibition of the target enzyme in humans treated with an oral FTI in a solid tumor, and suggests that integration of an FTI with standard therapy may improve the breast pCR rate. Should the clinical activity be confirmed, this may provide sufficient rationale for conducting a large-scale adjuvant trial comparing adjuvant chemotherapy with or without an FTI. However, it remains unclear what breast pCR rate should be established as a threshold for carrying forward with a larger, more definitive phase III adjuvant trial, and whether the trial should be restricted to populations that typically derive less benefit from adjuvant chemotherapy and more potentially benefit from the addition of tipifarnib (e.g., ERpositive disease).

Three other trials combining FTIs with other chemotherapy agents in patients with metastatic breast cancer are currently ongoing. In one trial (E1103), tipifarnib (300 mg BID) is being combined with capecitabine (1000 mg/m2 BID) given for 14 of every 21-day schedule in patients who have had prior anthracycline therapy and progressive disease during taxane therapy (84). A second trial is a phase I-II trial evaluating the combination of tipifarnib (given BID for 14 days) with gemcitabine (given on days 1 and 18 every 21 days) in patients with metastatic breast cancer (85). A phase II trial evaluating the combination of lonafarnib with trastuzumab and paclitaxel in HER2/neu-positive metastatic breast cancer is also ongoing (86).

A phase III trial has been reported comparing gemcitabine given in combination with tipifarnib (200 mg twice a day continuously) or a placebo in 688 patients with untreated, locally advanced or metastatic pancreatic carcinoma, a disease that is associated with Ras mutations in about 90% of cases. There was no difference in median progression-free survival (112 days vs. 109 days, stratified log-rank p = 0.72) or overall survival (193 days vs. 182 days, p = 0.75) of providing unequivocal evidence that this is not a useful treatment strategy for this disease (87). Other ongoing studies include a randomized phase II trial of carboplatin/paclitaxel alone or in combination with lonafarnib in advanced ovarian carcinoma (88), and a phase III trial comparing lonafarnib versus placebo in patients with myelodysplastic syndrome (89). A phase III trial comparing carboplatin/paclitaxel used alone or in combination with lonafarnib in nonsmall cell lung cancer has completed accrual.

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