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Journal of Clinical Oncology, Vol 24, No 3 (January 20), 2006: pp. 507-516 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.03.8638 Phase I Trial and Pharmacokinetic Study of the Farnesyltransferase Inhibitor Tipifarnib in Children With Refractory Solid Tumors or Neurofibromatosis Type I and Plexiform NeurofibromasFrom the Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD; Children's Hospital and Medical Center, Cincinnati, Cincinnati, OH; Texas Children's Cancer Center, Houston, TX; and Janssen Research Foundation, Beerse, Belgium. Address reprint requests to Brigitte C. Widemann, MD, Pediatric Oncology Branch, National Cancer Institute, 10 Center Dr, Building 10 CRC, Room 1-5750, MSC 1101, Bethesda, MD 20892; e-mail: widemanb{at}mail.nih.gov
Purpose This pediatric phase I trial of tipifarnib determined the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of tipifarnib in children with refractory solid tumors and neurofibromatosis type 1 (NF1) –related plexiform neurofibromas. Patients and Methods Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at 150 mg/m2/dose (n = 4), with escalations to 200 (n = 12), 275 (n = 12), and 375 (n = 6) mg/m2/dose. The MTD was also evaluated on a chronic continuous dosing schedule (n = 6). Pharmacokinetic sampling was performed for 36 hours after the first dose and peripheral-blood mononuclear cells (PBMCs) were collected at baseline and steady state for determination of farnesyl protein transferase (FTase) activity and HDJ-2 farnesylation. Results Twenty-three solid tumor and 17 NF1 patients were assessable for toxicity. The MTD was 200 mg/m2/dose, and dose-limiting toxicities on cycle 1 were myelosuppression, rash, nausea, vomiting, and diarrhea. The 200 mg/m2/dose was also tolerable on the continuous dosing schedule. Cumulative toxicity was not observed in the 17 NF1 patients who received a median of 10 cycles (range, 1 to 32 cycles). The plasma pharmacokinetics of tipifarnib were highly variable but not age dependent. At steady state on 200 mg/m2/dose, FTase activity was 30% compared with baseline, and farnesylation of HDJ-2 was inhibited in PBMCs. Conclusion Oral tipifarnib is well tolerated in children receiving the drug twice daily for 21 days and a continuous dosing schedule at 200 mg/m2/dose, which is equivalent to the MTD in adults. The pharmacokinetic profile of tipifarnib in children is similar to that in adults, and at the MTD, FTase is inhibited in PBMC in vivo.
The RAS family proteins serve as a switch for signal transduction pathways, including those that regulate cellular proliferation.1 Ras mutations are present in 30% of human cancers, and give rise to growth factor–independent cell proliferation and cell survival.2 RAS pathways can also be upregulated through activating mutations in upstream receptor tyrosine kinases,3 or loss of guanosine triphosphatase–activating proteins, such as neurofibromin, which is mutated or deficient in neurofibromatosis type 1 (NF1).4 Patients with NF1 develop tumors of the nervous system including plexiform neurofibromas, which cause morbidity5 and can undergo transformation to malignant peripheral-nerve sheath tumors.6 Inhibition of Ras activity is thus a rational target for human cancers and NF1-related tumors.7,8 Ras proteins undergo post-translational farnesylation or geranylgeranylation, which is required for activity, and farnesyl protein transferase (FTase) was identified as a therapeutic target to inhibit mutant Ras.9 However, a number of other proteins also require farnesylation for activity, and may play a role in mediating the antitumor effects of FTase inhibitors.10,11 Tipifarnib (R115777; Zarnestra, Johnson & Johnson, Beerse, Belgium), an orally bioavailable, potent, and selective nonpeptidomimetic FTase inhibitor, inhibits cell proliferation in a panel of human tumor cell lines with IC50 values less than 0.1 µmol/L.12 Tipifarnib has undergone phase I,13-20 II,21-23 and III24 trials in adults with refractory cancers, and the maximum-tolerated dose (MTD) of single-agent tipifarnib for 21 days followed by 7 days rest, or continuous dosing with no rest, was 300 mg bid.14,16 Dose-limiting toxicities (DLTs) were myelosuppression and sensory neuropathy. Sensory neuropathy was predominantly observed on the continuous dosing schedule.16,22 This phase I trial determined the MTD of tipifarnib and defined its toxicities, pharmacokinetics, and pharmacodynamics in children with refractory solid tumors or with NF1 and inoperable plexiform neurofibromas.
This trial was sponsored by the Janssen Research Foundation (Beerse, Belgium), coordinated by the Pediatric Oncology Branch of the National Cancer Institute (Bethesda, MD), and included three participating sites: Pediatric Oncology Branch, Children's Hospital of Cincinnati (Cincinnati, OH), and Texas Children's Cancer Center (Houston, TX).
Patient Eligibility
Treatment Regimen and Dose Escalation Tipifarnib was supplied initially as 50- and 100-mg capsules and subsequently as 50- and 100-mg tablets (with comparable bioavailability), and administered orally after a meal every 12 hours for 21 days followed by a 7-day rest period for a 28-day treatment cycle (21-day schedule). Each patient's dose was rounded to the nearest 50 mg using a dosing nomogram in the protocol based on body-surface area. The AM and PM doses had to be identical. The tolerability of the MTD on the 21-day schedule was tested subsequently on a continuous dosing schedule every 12 hours for 28 days with no rest period between treatment cycles (continuous schedule). The starting dose of tipifarnib on the 21-day schedule was 150 mg/m2/dose, which is equivalent to an adult fixed dose of 260 mg, with dose escalations to 200, 275, and 375 mg/m2/dose. A standard phase I dose escalation design with three to six patients per dose level was used. Intrapatient dose escalation was not allowed.
Evaluation During the Study Response was re-evaluated using WHO criteria26 before cycles 2 and 3 for patients with solid tumors, before cycle 3 in patients with NF1, and then after completion of every three additional treatment cycles for all patients.
Definition of MTD and DLT
Hematologic DLT was defined as grade 4 neutropenia (< 500/µL) or grade
Dose Modification for Toxicity
Pharmacokinetic Studies
Plasma tipifarnib concentrations were determined by a validated high-pressure liquid chromatography assay13 at Janssen Research Foundation. Pharmacokinetic parameters for tipifarnib were calculated using noncompartmental methods. Area under the plasma concentration curve to the last quantifiable time point (AUClast) was calculated using the linear trapezoidal method, and then the AUC was extrapolated to infinity (AUCto
Pharmacodynamic Studies
Pharmacodynamic effects of tipifarnib (percentage decrease in absolute neutrophil count from baseline; FTase inhibition) were related to dose and pharmacokinetic parameters using a sigmoid Emax effect model in MLAB (Civilized Software, Bethesda, MD). The model is described by the equation:
Patient Characteristics Thirty-six patients (23 with refractory solid tumors, 13 with NF1) were treated on the 21-day schedule at one of four dose levels, and six patients (two with solid tumors and four with NF1) were treated on the continuous schedule at the dose identified as the MTD on the 21-day schedule. Two of the 36 patients entered on the 21-day schedule were not assessable for toxicity. One patient was removed during cycle 1 for noncompliance, and one patient withdrew from the protocol after two doses of tipifarnib due to non–dose-limiting grade 2 nausea, vomiting, and diarrhea. Characteristics of the 40 assessable patients are listed in Table 2.
Dose Escalation and Toxicities The first two dose levels (150 and 200 mg/m2/dose) were well tolerated. The 275 mg/m2/dose level was expanded initially to six patients after one of the first three patients developed dose-limiting myelosuppression; however, the additional three patients tolerated the 275 mg/m2/dose, and the dose was escalated to 375 mg/m2/dose. At 375 mg/m2/dose, four of six patients experienced a DLT, the MTD was exceeded, and an additional six patients were enrolled at the next lower dose level (275 mg/m2/dose) to study the tolerability within a broader age range of patients. Of 12 patients at the 275 mg/m2/dose, three patients experienced a DLT, which also exceeded MTD. Therefore, the 200 mg/m2/dose level was expanded to 12 patients and only one of the total of 12 patients experienced a DLT. The 200 mg/m2/dose is thus the MTD in patients with solid tumors or NF1 on the 21-day schedule. Six patients were then enrolled at this dose on the continuous schedule and this dose was also tolerable (one of six patients experienced a dose-limiting rash). The DLTs observed on all dose levels during cycle 1 of treatment are listed in Table 3. At the 375 mg/m2 dose level, rash, GI toxicity, and myelosuppression were dose limiting in four of six treated patients; and at the 275 mg/m2 dose level, myelosuppression, fever/infection with neutropenia, and GI toxicity were dose limiting in three of 12 patients.
Although neutropenia and thrombocytopenia were dose limiting in some patients at the higher dose levels, myelosuppression was not a prominent toxicity at the MTD. The median nadir neutrophil count in 18 patients treated with 200 mg/m2/dose on either the 21-day or continuous schedules was 2,940/µL (range, 180 to 7,680/µL), and only one of the 18 patients had a neutrophil nadir below 1,000/µL. All dose-limiting and non–dose-limiting toxicities that were possibly, probably, or definitively related to tipifarnib during the first treatment cycle are listed in Table 4. Myelosuppression, GI toxicity, and rash were the most frequent toxicities, and the frequency and severity of these toxicities appeared to be dose related. Rash was observed in nine patients during the first treatment cycle after a median of 12 days (2 to 26 days) on tipifarnib and was disseminated and pruritic in most patients (Fig 1). In one patient, the rash manifested on day 22 of cycle 1 as an allergic photosensitivity reaction. Other toxicities included fatigue and hypofibrinogenemia. Hepatic dysfunction and sensory neuropathy were observed infrequently and were mild.
Ophthalmologic examinations at baseline and during or at the end of treatment were available for 24 patients. One of these patients showed a slight decrease in visual acuity during cycle 2, but had normal follow-up examinations subsequently. Twenty-eight patients received more than one cycle of tipifarnib. The 17 NF1 patients received a median of 10 cycles (range, one to 32 cycles). Tipifarnib toxicities did not appear to be cumulative in these patients. Three of the 28 patients developed drug-related toxicities on subsequent cycles that were severe enough to necessitate a tipifarnib dose reduction. One patient with an ependymoma (275 mg/m2/dose) developed grade 3 thrombocytopenia and grade 4 neutropenia during the second cycle, but drug was discontinued because of disease progression. A patient with NF1 (200 mg/m2/dose) on the continuous schedule developed grade 4 neutropenia on day 26 of cycle 1. The ANC recovered off tipifarnib, and neutropenia was initially attributed to a viral infection. However, grade 3 neutropenia recurred on cycle 2 after a 40% dose reduction of tipifarnib, and the patient was removed from the study. Dose-limiting, grade 3 hypofibrinogenemia developed in a patient with NF1 (375 mg/m2/dose) during cycle 6. This resolved off tipifarnib, and recurred twice after two dose reductions, which led to discontinuation of tipifarnib after 10 treatment cycles. Other non–dose-limiting toxicities after cycle 1 that were at least possibly related to tipifarnib included grade 1 constipation, rectal spasm, melena, elevated gamma-glutamyl transferase and bilirubin, weight gain, alopecia, exophoria, electrolyte abnormalities, hyperglycemia, hypoproteinemia, bladder spasm, urinary incontinence, arthralgia, and upper respiratory infection; grade 2 anxiety and blurred vision; and grade 3 depression.
Response Evaluation
Pharmacokinetics
Pharmacokinetic parameters derived from the plasma concentrations after the first dose of orally administered tipifarnib are summarized in Table 5. Tipifarnib Cmax and AUCto  increased with increasing dose levels, but did not increase in a manner proportional to the dose (Fig 3) . The median AUCto at the 375 mg/m2/dose level was almost three-fold higher than the AUCto at the 200 mg/m2/dose level.
At the MTD (200 mg/m2/dose), the median steady-state plasma concentration of tipifarnib (AUCto /dosing interval) was 403 ng/mL (820 nmol/L), and the median trough concentration 12 hours after the dose was 32.5 ng/mL (66 nmol/L). However, there was wide interpatient variability for Cmax and AUCto at all dose levels. The coefficient of variation for the AUCto at the 200 mg/m2/dose level was 53%. The median apparent clearance (CL/F) of tipifarnib across all dose levels was 755 mL/min/m2 (range, 223 to 4,310 mL/min/m2), and the median half-life was 4.3 hours (range, 1.6 to 16.7 hours). CL/F was not age dependent. The median CL/F in children younger than 12 years (n = 19) was 750 mL/min/m2 and the CL/F in children 12 to 18 years (n = 23) was 766 mL/min/m2. The median CL/F in children with solid tumors was 680 mL/min/m2 (range, 162 to 4,310 mL/min/m2), and 819 mL/min/m2 (280 to 2,070 mL/min/m2) in children with NF1 (P = .18). The CL/F at the highest dose level (375 mg/m2/dose) is lower (Table 5), but not statistically significantly lower (P = .18), than the CL/F at the other dose levels.
Pharmacodynamics
The degree of neutropenia seemed to be more closely related to the AUCto (Fig 5B) than to the administered dose (normalized to body-surface area; Fig 5A) based on the maximum effect model fitted to the data. The ED50 from the fit of the sigmoid Emax model to the AUCto versus percentage decrease in ANC data was 8,940 ng·h/mL and h was 1.4 (R2 = 0.27; Fig 5B). When the model was fit to the dose per square meters versus percentage decrease in ANC data, the fitted value for the slope was 0, indicating that there was no relationship (Fig 5A).
This phase I trial of tipifarnib in children was unique because the patient population studied included children with refractory solid tumors and with NF1-related plexiform neurofibromas. An advantage of including the NF1 population with the more slowly growing tumors was the ability to gain experience with chronic tipifarnib administration (median cycle number in NF1 = 10), and this trial led directly to an ongoing randomized, placebo-controlled phase II trial in children and young adults with NF1 and progressive plexiform neurofibromas. The MTD and recommended phase II dose of tipifarnib for children with refractory solid tumors or NF1 and plexiform neurofibromas is 200 mg/m2/dose administered twice daily for 21 consecutive days followed by a 7-day break (28-day cycles). This pediatric dose is similar to the MTD in adults (300 mg twice daily, equivalent to approximately 170 mg/m2) with refractory solid tumors on the same 21-day schedule. The toxicity profile of tipifarnib in children was also comparable with that in adults; myelosuppression was the primary DLT in adults.14,16 GI toxicity and rash were other DLTs, which appeared to be dose related in children treated on this trial. Reversible hypofibrinogenemia, a DLT after prolonged administration of tipifarnib on our trial, had not been described previously in adults. The toxicity profile of tipifarnib was similar in children with NF1 and with solid tumors. Even though patients with NF1 had not received prior myelosuppressive treatment, they experienced a similar degree of myelosuppression from tipifarnib compared with the heavily pretreated cancer population. Chronic dosing over many cycles was well tolerated in the NF1 population. Cumulative toxicity was not observed. The MTD (200 mg/m2/dose) on the 21-day schedule was also well tolerated on the continuous schedule. In contrast to adults who experienced dose-limiting neuropathies on this schedule,14,16,22 sensory neuropathy was observed infrequently and was mild on this trial. Four children with NF1 were enrolled onto the continuous schedule, and received 5, 8, 19, and 19 cycles of therapy, respectively, without evidence of cumulative toxicity. The pharmacokinetic profile of tipifarnib in children was characterized by significant variability, but pharmacokinetic parameters at the MTD (200 mg/m2/dose) were similar for children on our trial and adults treated on a phase I trial of tipifarnib. At the 300 mg bid dose level in adults, the Tmax was 2.9 hours compared with 3.0 hours in children treated with 200 mg/m2; the Cmax was 974 ng/mL in adults compared with 909 ng/mL in children; the AUCto 12 hours in adults was 4,670 ng·h/mL compared with 4,330 ng·h/mL in children; and the average Css was 389 ng/mL in adults compared with 403 ng/mL in children.16 Similar to our findings in children, accumulation of drug over the course of therapy was minimal in adults. The accumulation ratio derived from the AUCto 12 hours on days 1 and 28 at 300 mg twice daily was 0.98 compared with the predicted accumulation ratio of 1.09 in our patients. Within the pediatric population on our trial (age 4 to 18 years), there was also no evidence of age dependence in drug disposition.
In part because of the high degree of variability, we were unable to demonstrate a clear dose-proportional increase in the AUC across the four dose levels, despite the relatively large number of patients studied. There was a suggestion at the highest dose level (375 mg/m2/dose) of a disproportionate increase in drug exposure (AUCto
Pharmacodynamic studies in PBMCs confirmed tipifarnib was inhibiting its target in vivo. FTase activity at steady state was reduced to 44% (average), and 35% (median) of baseline activity, and there was no obvious relationship between dose or drug exposure (AUCto In addition to the ongoing phase II trial of tipifarnib in patients with NF1, the development of this agent is also focused on the acute leukemias based on initial observations of responses in the phase I trial of tipifarnib in adults.28 A separate phase I trial of this agent in children with relapsed acute leukemias has also been conducted and will guide the future development of tipifarnib in childhood leukemias.
Althoguh all authors completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Olson MF, Marais R: Ras protein signalling. Semin Immunol 12:63-73, 2000[CrossRef][Medline] 2. Rodenhuis S: Ras and human tumors. Cancer Biol 3:241-247, 1992 3. Stirewalt DL, Meshinchi S, Radich JP: Molecular targets in acute myelogenous leukemia. Blood Rev 17:15-23, 2003[CrossRef][Medline] 4. Cichowski K, Jacks T: NF1 tumor suppressor gene function: Narrowing the GAP. Cell 104:593-604, 2001[CrossRef][Medline] 5. Korf B: Plexiform neurofibromas. Am J Med Genet 89:31-37, 1999[CrossRef][Medline] 6. Evans DG, Baser ME, McGaughran J, et al: Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 39:311-314, 2002 7. Adjei AA: Blocking oncogenic Ras signaling for cancer therapy. J Natl Cancer Inst 93:1062-1074, 2001 8. Weiss B, Bollag G, Shannon K: Hyperactive Ras as a therapeutic target in neurofibromatosis type 1. Am J Med Genet 89:14-22, 1999[Medline] 9. Rowinsky E, Windle J, Von Hoff D: Ras protein farnesyltransferse: A strategic target for anticancer therapeutic development. J Clin Oncol 17:3631-3652, 1999 10. Lancet JE, Karp JE: Farnesyltransferase inhibitors in hematologic malignancies: New horizons in therapy. Blood 102:3880-3889, 2003 11. Santos ES, Rosenblatt JD, Goodman M: Role of farnesyltransferase inhibitors in hematologic malignancies. Expert Rev Anticancer Ther 4:843-856, 2004[CrossRef][Medline] 12. End DW, Smets G, Todd AV, et al: Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 61:131-137, 2001 13. Zujewski J, Horak I, Bol R, et al: Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 18:927-941, 2000 14. Punt CJ, van Maanen L, Bol CJ, et al: Phase I and pharmacokinetic study of the orally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumors. Anticancer Drugs 12:193-197, 2001[CrossRef][Medline] 15. Lara PN Jr, Law LY, Wright JJ, et al: Intermittent dosing of the farnesyl transferase inhibitor tipifarnib (R115777) in advanced malignant solid tumors: A phase I California Cancer Consortium Trial. Anticancer Drugs 16:317-321, 2005[CrossRef][Medline] 16. Crul M, de Klerk GJ, Swart M, et al: Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 20:2726-2735, 2002 17. Sparreboom A, Kehrer DF, Mathijssen RH, et al: Phase I and pharmacokinetic study of irinotecan in combination with R115777, a farnesyl protein transferase inhibitor. Br J Cancer 90:1508-1515, 2004[CrossRef][Medline] 18. Patnaik A, Eckhardt SG, Izbicka E, et al: A phase I, pharmacokinetic, and biological study of the farnesyltransferase inhibitor tipifarnib in combination with gemcitabine in patients with advanced malignancies. Clin Cancer Res 9:4761-4771, 2003 19. Lebowitz PF, Eng-Wong J, Widemann BC, et al: A phase I trial and pharmacokinetic study of tipifarnib, a farnesyltransferase inhibitor, and tamoxifen in metastatic breast cancer. Clin Cancer Res 11:1247-1252, 2005 20. Adjei AA, Croghan GA, Erlichman C, et al: A phase I trial of the farnesyl protein transferase inhibitor R115777 in combination with gemcitabine and cisplatin in patients with advanced cancer. Clin Cancer Res 9:2520-2526, 2003 21. Cohen SJ, Ho L, Ranganathan S, et al: Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol 21:1301-1306, 2003 22. Johnston SR, Ellis PA, Houston S, et al: A phase II study of the farnesyltransferase inhibitor R115777 in patients with advanced breast cancer. Proc Am Soc Clin Oncol 18:83a, 2000 (suppl; abstr 318) 23. Heymach JV, Johnson DH, Khuri FR, et al: Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer. Ann Oncol 15:1187-1193, 2004 24. Rao S, Cunningham D, de Gramont A, et al: Phase III double-blind placebo-controlled study of farnesyl transferase inhibitor R115777 in patients with refractory advanced colorectal cancer. J Clin Oncol 22:3950-3957, 2004 25. End D: Farnesyl protein transferase inhibitors and other therapies targeting the Ras signal transduction pathway. Invest New Drugs 17:241-258, 1999[CrossRef][Medline] 26. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 27. 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 28. Karp JE, Lancet JE, Kaufmann SH, et al: Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: A phase 1 clinical-laboratory correlative trial. Blood 97:3361-3369, 2001 Submitted September 2, 2005; accepted October 18, 2005.
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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
3 thrombocytopenia (< 50,000/µL). Nonhematologic DLT was defined as any grade 
1 toxicity, patients resumed tipifarnib at a 40% lower dose. Patients who experienced a DLT that did not recover to grade 
z) was determined by linear regression of at least three terminal points on the log-transformed concentration-time curve. Time (in hours) to maximum plasma concentration (Tmax) and the observed maximum plasma concentration (Cmax) were taken from the plasma concentration-time profile. The average steady-state concentration (Css) was derived from the AUCto 
) solid tumor patients; (
) neurofibromatosis type 1 patients; (——) the fit of the sigmoid Emax model to the data.
