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Originally published as JCO Early Release 10.1200/JCO.2005.04.9114 on June 12 2006 © 2006 American Society of Clinical Oncology. Targeted Inhibition of Farnesyltransferase in Locally Advanced Breast Cancer: A Phase I and II Trial of Tipifarnib Plus Dose-Dense Doxorubicin and Cyclophosphamide
From the New York Phase II Consortium, including the Albert Einstein Cancer Center, Montefiore Medical Center, Bronx; Weill Cornell Medical Center; Columbia Presbyterian Medical Center, New York, NY; Breast Oncology Program and Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL; and the Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD Address reprint requests to Joseph A. Sparano, MD, Montefiore Medical Center-Weiler Division, Department of Oncology, 2 S, Room 47-48, 1825 Eastchester Rd, Bronx, NY 10461; e-mail: jsparano{at}montefiore.org
PURPOSE: To determine the recommended phase II dose (RPTD) of the farnesyltransferase (FTase) inhibitor tipifarnib when combined with doxorubicin and cyclophosphamide (AC) in patients with advanced breast cancer, the pathologic complete response (pCR) rate after preoperative treatment with four cycles of the combination in locally advanced breast cancer (LABC), and the effect of tipifarnib on primary tumor FTase enzyme activity in vivo. PATIENTS AND METHODS: Thirty-two patients with metastatic breast cancer (n = 11) or LABC (n = 21) received AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) administered intravenously on day 1 plus tipifarnib (100, 200, or 300 mg bid for 6 to 14 days) without (n = 2) or with (n = 30) granulocyte colony-stimulating factor (G-CSF) for up to four cycles. Patients with LABC underwent surgery after up to four cycles of the combination. RESULTS: When combined with AC every 2 weeks plus G-CSF, the RPTD of tipifarnib was 200 mg bid administered on days 2 to 7. Seven (33%) of 21 patients (95% CI, 15% to 55%) with LABC treated with up to four cycles of the combination at the RPTD had a pCR in the breast at surgery. The five patients had serial biopsies that demonstrated at least 50% FTase enzyme inhibition in the primary tumor (median, 100%; range, 55% to 100%) after tipifarnib. CONCLUSION: Tipifarnib may be safely combined with dose-dense AC using a dose and schedule that significantly inhibits FTase enzyme activity in human breast cancer in vivo and may enhance the pCR rate after four cycles of preoperative dose-dense AC.
Ras proteins belong to the low molecular weight guanosine nucleotide–binding GTPases (G protein) superfamily that plays a critical role in cell growth and regulation.1 Oncogenic mutations of the three known human ras genes are found in 30% of all human cancers; these mutations lead to hyperactivation of Ras protein, which becomes constitutively activated. Although the frequency of ras mutations in breast cancer is low (< 2%),2,3 hyperactivation of Ras protein and its downstream effectors is common as a result of either overexpression of upstream components, such as epidermal growth factor receptor and HER2/neu,4,5 or estrogen-dependent aberrant pathways.6 Ras protein overexpression in breast cancer (not associated with ras mutations) has been associated with poor prognosis,7 and RhoC overexpression (a downstream effector of Ras) is associated with regional and/or distant metastases8 and with inflammatory carcinoma.9 Post-translational modification at the carboxyl terminus of Ras, with the 15-carbon lipid farnesyl, is essential for mediation of its downstream effects.10,11 This covalent modification is mediated by farnesyltransferase (FTase), a heterodimeric zinc metalloenzyme. FTase inhibitors (FTIs) causing accumulations in the G2/M phase or G1 phase11-14 induce apoptosis of a variety of tumor cell lines,15 inhibit angiogenesis,16 inhibit growth of MCF-7 human breast cancer xenografts (which have wild-type Ras),17 induce tumor regression in breast cancer transgenic mouse models,18,19 and revert the RhoC GTPase-induced inflammatory breast cancer phenotype.9 Increased Ras/Raf-1/MEK/MARK activity has been implicated in the doxorubicin-resistant MCF-7 cell line,20 paclitaxel-resistant cells,21 and the expression of the P-glycoprotein extrusion pump,22 and FTIs have the potential to reverse these effects. Johnston et al23 reported a 10% objective response rate and a 25% clinical benefit rate for tipifarnib, an orally available FTI (formerly R115777; Zarnestra; Johnson & Johnson, PRD, LLC, Raritan, NJ and Tibotec Therapeutics, Raritan, NJ), in patients with metastatic breast cancer. In addition, other trials have demonstrated the safety of combining tipifarnib with several cytotoxic agents.24 On the basis of these considerations, we initiated a phase I trial of tipifarnib plus doxorubicin and cyclophosphamide (AC) in patients with advanced breast cancer. We herein report the results of the phase I portion of this trial (in patients with metastatic disease) and the results of the first stage of the phase II portion of the trial in patients with locally advanced breast cancer (LABC).
Patient Selection Patients were required to have histologically or cytologically confirmed adenocarcinoma of the breast and to have either nonregional stage IV disease (for the phase I portion of the trial) or locally advanced disease (stage IIB to IIIC) after the recommended phase II dose was identified. Other requirements included at least one bidimensional and/or unidimensional measurable indicator lesion, age  18 years, Eastern Cooperative Oncology Group performance status  1, and normal organ and marrow function (leukocytes 3,000/µL, absolute neutrophil count 1,500/µL, platelets 100,000/µL, serum creatinine and total bilirubin within institutional normal limits, AST and/or ALT 2.5-fold above the institutional upper limit of normal, and left ventricular ejection fraction [LVEF] within normal institutional limits). The protocol was reviewed by the local institutional review board at each participating institution, and all patients provided written informed consent.
Chemotherapy
Tipifarnib Dose and Schedule
Surgery and Additional Therapy
Protocol-Required Studies, Response Criteria, and Toxicity Grading
Statistical Methods for the Phase II Component of the Trial
Optional Tumor Biopsy and FTase Enzyme Analysis
Patient Characteristics Thirty-three patients consented and were registered, but one patient withdrew consent before beginning therapy, leaving 32 assessable patients. Eleven patients enrolled onto the dose-escalation phase I component of the study had confirmed or presumed metastatic disease, and the remaining 21 patients with LABC were enrolled onto the phase II portion of the trial. The characteristics of the 32 assessable patients are listed in Table 1.
Results of Dose Escalation The results of the dose escalation are listed in Table 2. At dose level 1, AC was administered every 3 weeks on day 1 without G-CSF, and tipifarnib was administered at 100 mg bid on days 1 to 14. One of two patients experienced DLT at this dose level, which was characterized by grade 4 febrile neutropenia followed by a severe oral herpes simplex infection that occurred after neutrophil recovery. Because of a study demonstrating the benefit of adjuvant dose-dense AC administered every 2 weeks plus G-CSF28 and the toxicity observed at the first dose level, the study was amended to administer AC at the same dose every 2 weeks rather than every 3 weeks, to reduce the duration of tipifarnib administration from 14 to 7 days, and to add G-CSF from days 2 to 13. Of the next six patients treated with tipifarnib 300 mg bid (dose level 2), two experienced DLT, including febrile neutropenia also associated with oral herpes simplex infection (n = 1) and grade 3 nausea/vomiting (n = 1). Four patients then received tipifarnib 200 mg bid on days 1 to 7 (dose level 3), including the first three patients who had metastatic disease and one patient with LABC (when it was thought that this dose level would be the RPTD). Although no patients at this dose level had cycle 1 DLT, the absolute neutrophil counts for these four patients on day 8 were 1,230/µL, 109/µL, 144/µL, and 384/µL; therefore, the protocol was amended to continue with the same tipifarnib dose (200 mg bid) but reduce the duration of tipifarnib from 7 to 6 days (days 2 through 7), thereby eliminating concurrent administration of AC and tipifarnib on the same day (dose level 4). None of the initial three patients with LABC treated at dose level 4 had a cycle 1 DLT, and none of the remaining 17 patients who were accrued at this dose level experienced a cycle 1 DLT. Also, the incidence of severe neutropenia was lower; the nadir neutrophil count was less than 500/µL in nine (45%) of 20 patients treated at this dose level during the first cycle. Therefore, dose level 4 was defined as the RPTD.
Treatment Information at the RPTD A total of 76 cycles of AC plus tipifarnib was administered to the 21 patients with LABC treated in the phase II portion of the trial, including 20 patients at dose level 4 (the RPTD) and one patient at dose level 3. Seventeen (81%) of 21 patients received all four cycles of the combination. Four patients (19%) received less than four cycles of the combination, including one patient who received one cycle (patient 25), two patients who received two cycles (patients 20 and 21), and one patient who received three cycles (patient 22). Reasons for discontinuing the combination included persistent neutropenia and thrombocytopenia in one patient (patient 25) and GI adverse effects of nausea, vomiting, and/or dyspepsia in the other three patients. The dose of AC was reduced in one patient (5%) as a result of toxicity. Of 55 second or subsequent cycles of therapy administered to 20 patients who received at least two treatment cycles, all cycles were administered on schedule in 17 patients (85%); three treatment cycles were delayed 1 week or more in three patients (15%) as a result of adverse events, including grade 2 skin infection, grade 2 stomatitis, and persistent sinus tachycardia in one patient each.
Overall Toxicity
With regard to other serious, unusual, or treatment-limiting toxicities observed in both the phase I and II portions of the study, four patients (13%) had GI adverse effects (eg, nausea, vomiting, dyspepsia, or gastritis) that prompted discontinuation of tipifarnib or met the criteria for DLT. In addition, five patients (16%) developed oral herpes simplex infections (n = 4) or disseminated varicella zoster (after the fourth cycle of therapy; n = 1). One patient with metastatic disease treated at dose level 3 died after the fourth cycle of therapy; she developed febrile neutropenia, culture-negative sepsis, and pneumonia requiring mechanical ventilation, which was complicated by hemiparesis, and subsequently, the patient died. Computed tomography of the brain demonstrated multiple brain lesions consistent with metastases. She also had a decrease in the LVEF to 20% (from 63% at baseline) during this episode. A second patient was found to have a decrease in LVEF to 20% (grade 3 LVEF dysfunction) after presenting with dyspnea 3 months after completing therapy; she improved with medical therapy and is alive at 6 months. Four other patients (13%) had an absolute decline of LVEF of between 10% and 20%, but their LVEF was still above normal. No other patients had a decrease in LVEF below normal. Therefore, a total of two patients (6%) developed congestive cardiomyopathy that was possibly attributed to therapy; both of these patients received four cycles of the AC plus tipifarnib combination (cumulative doxorubicin dose of 240 mg/m2).
Clinical and Pathologic Response to Treatment
Effect of Tipifarnib Plus AC on FTase Enzyme Activities Breast tumor FTase enzyme activity was reduced by 55%, 91%, 100%, 100%, and 100% in the five patients evaluated (Fig 1 and Table 4). All patients who underwent biopsy had taken tipifarnib 200 mg bid for at least 6 days.
We performed a phase I trial of the FTI tipifarnib in combination with dose-dense AC chemotherapy plus G-CSF in patients with advanced breast cancer. The RPTD of tipifarnib was 200 mg bid for 6 days (ie, on days 2 through 7), which is a dose that is lower than when tipifarnib is administered alone using a similar schedule.29 Neutropenia and vomiting were dose limiting at higher doses of tipifarnib or at lower doses administered for longer periods (up to 14 days). Tipifarnib significantly inhibited FTase in primary breast cancer in all five patients evaluated. Although previous studies have demonstrated that FTIs such as tipifarnib inhibit FTase activity in leukemic cells,30 this is the first demonstration to our knowledge that FTIs inhibit the target enzyme in solid tumors in humans. In addition, we observed a breast pCR in seven (33%) of 21 patients with LABC treated preoperatively with up to four cycles of the AC plus tipifarnib combination, which exceeds the 15% pCR rate that we had defined a priori for proceeding to the second stage of the phase II trial and also exceeds the 25% pCR rate we had defined a priori as sufficiently promising on completion of the phase II trial. We sought to identify a dose of tipifarnib that would not compromise our ability to administer AC at full dose and on schedule, as well as a dose that demonstrated biologic efficacy. Previous studies indicated that the 200-mg dose significantly increases unfarnesylated proteins in surrogate tissues such as peripheral-blood mononuclear cells (eg, HDJ-2 and lamin-A).17,31 More importantly, we found that this tipifarnib dose significantly inhibits FTase enzyme activity in the primary tumor. Additional patients are currently being evaluated to confirm these findings and to identify whether any pretreatment tumor characteristics or post-treatment downstream effects induced by FTase inhibition are predictive of response. The safety profile of the AC plus tipifarnib combination is generally consistent with that observed for dose-dense AC alone, although the addition of tipifarnib is associated with more severe neutropenia and may increase the risk of viral infections and other complications such as cardiac toxicity; the safety profile of the combination is being monitored carefully in this ongoing phase II trial. Previous studies have demonstrated that approximately 10% of patients with operable breast cancer may have a pCR in the breast after four cycles of neoadjuvant AC administered every 3 weeks and that breast pCR is associated with significantly improved outcome.32 The primary objective of our phase II trial was to determine whether adding tipifarnib to neoadjuvant AC improved breast pCR rate to approximately 25% or higher, which is an increase that is comparable to that achieved by giving four cycles of docetaxel sequentially after four cycles of AC.33 In addition, the breast pCR rate for patients with estrogen receptor–and/or progesterone receptor–positive tumors is typically even lower (approximately 5%).33 It is intriguing that a breast pCR occurred in five (42%) of 12 estrogen receptor–positive or borderline positive tumors, suggesting particular benefit in estrogen receptor–positive disease. Accrual is continuing in the second stage of our phase II trial to confirm this finding.
The authors indicated no potential conflicts of interest.
Supported by the US Department of Health and Human Service Contract No. N01 CM-17103 (Scott Wadler, MD) and Grant No. RO1CA98473 (S.M.S.). Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004; and the 27th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Crespo NC, Ohkanda J, Yen TJ, et al: The farnesyltransferase inhibitor, FTI-2153, blocks bipolar spindle formation and chromosome alignment and causes prometaphase accumulation during mitosis of human lung cancer cells. J Biol Chem 276:16161-16167, 2001 12. Crespo NC, Delarue F, Ohkanda J, et al: The farnesyltransferase inhibitor, FTI-2153, inhibits bipolar spindle formation during mitosis independently of transformation and Ras and p53 mutation status. Cell Death Differ 9:702-709, 2002[CrossRef][Medline] 13. Ashar HR, James L, Gray K, et al: The farnesyl transferase inhibitor SCH 66336 induces a G(2) –> M or G(1) pause in sensitive human tumor cell lines. Exp Cell Res 262:17-27, 2001[CrossRef][Medline] 14. Sepp-Lorenzino L, Rosen N: A farnesyl-protein transferase inhibitor induces p21 expression and G1 block in p53 wild type tumor cells. J Biol Chem 273:20243-20251, 1998 15. 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Eisenhauer EA, O'Dwyer PJ, Christian M, et al: Phase I clinical trial design in cancer drug development. J Clin Oncol 18:684-692, 2000 26. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 27. Kurzrock R, Kantarjian HM, Cortes JE, et al: Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: Clinical and biologic activities in the phase 1 setting. Blood 102:4527-4534, 2003 28. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003 29. Zujewski J, Horak ID, Bol CJ, et al: Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 18:927-941, 2000 30. Zimmerman TM, Harlin H, Odenike OM, et al: Dose-ranging pharmacodynamic study of tipifarnib (R115777) in patients with relapsed and refractory hematologic malignancies. J Clin Oncol 22:4816-4822, 2004 31. Haas N, Peereboom D, Ranganathan S, et al: Phase II trial of R115777, an inhibitor of farnesyltransferase, in patients with hormone refractory prostate cancer. Proc Am Soc Clin Oncol 21:68a, 2002 (abstr 271) 32. Fisher B, Brown A, Mamounas E, et al: Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol 15:2483-2493, 1997 33. Bear HD, Anderson S, Brown A, et al: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol 21:4165-4174, 2003 Submitted November 14, 2005; accepted January 30, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
