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© 2001 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of the Oral Farnesyl Transferase Inhibitor SCH 66336 Given Twice Daily to Patients With Advanced Solid TumorsFrom the Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), Rotterdam; Department of Ophthalmology, University Hospital, Rotterdam; and NDDO Oncology, Amsterdam, the Netherlands; Institut Jules Bordet and European Organization for Research and Treatment of Cancer Early Clinical Studies Group, Brussels, Belgium; and Schering-Plough Research Institute, Kenilworth, NJ. Address reprint requests to Ferry A.L.M. Eskens, MD, Department of Medical Oncology, University Hospital Rotterdam, PO Box 2040, 3000 CA Rotterdam, the Netherlands; email: eskens{at}oncd.azr.nl
PURPOSE: A single-agent dose-escalating phase I and pharmacokinetic study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile, maximum-tolerated dose, and recommended dose for phase II studies. Plasma and urine pharmacokinetics were determined. PATIENTS AND METHODS: SCH 66336 was given orally bid without interruption to patients with histologically or cytologically confirmed solid tumors. Routine antiemetics were not prescribed. RESULTS: Twenty-four patients were enrolled onto the study. Dose levels studied were 25, 50, 100, 200, 400, and 300 mg bid. Pharmacokinetic sampling was performed on days 1 and 15. At 400 mg bid, the dose-limiting toxicity (DLT) consisted of grade 4 vomiting, grade 4 neutropenia and thrombocytopenia, and the combination of grade 3 anorexia and diarrhea with reversible grade 3 plasma creatinine elevation. After dose reduction, at 300 mg bid, the DLTs consisted of grade 4 neutropenia, grade 3 neurocortical toxicity, and the combination of grade 3 fatigue with grade 2 nausea and diarrhea. The recommended dose for phase II studies is 200 mg bid, which was found feasible for prolonged periods of time. Pharmacokinetic analysis showed a greater than dose-proportional increase in drug exposure and peak plasma concentrations, with increased parameters at day 15 compared with day 1, indicating some accumulation on multiple dosing. Plasma half-life ranged from 4 to 11 hours and seemed to increase with increasing doses. Steady-state plasma concentrations were attained at days 7 through 14. A large volume of distribution at steady-state indicated extensive distribution outside the plasma compartment. CONCLUSION: SCH 66336 can be administered safely using a continuous oral bid dosing regimen. The recommended dose for phase II studies using this regimen is 200 mg bid.
IN MAMMALIAN CELLS, three functional ras genes are found. K-ras, N-ras, and H-ras genes encode for K-Ras, N-Ras, and H-Ras proteins, respectively. Ras is synthesized as a soluble and biologically inactive protein that undergoes several posttranslational modifications before being localized to the inner surface of the plasma membrane, where it exerts its activity as transducer of various extracellular growth-promoting stimuli. An essential step in the posttranslational processing of Ras is farnesylation, the addition of a farnesyl or C15 isoprenoid moiety from farnesyl diphosphate to the cysteine residue at the C-terminal side of Ras. Farnesyl transferase is the crucial enzyme in this process.1-10 Mutations in one or more ras genes are frequently found in various human tumor types in variable incidence.3,8,10 Mutated ras oncogenes encode for oncoproteins that are synthesized in a way completely comparable to the synthesis of normal Ras. However, Ras oncoproteins are insensitive to the inhibitory activity of GTPase activating protein. As a result, cells harboring these Ras oncoproteins will show autonomous proliferation and malignant transformation. As farnesylation of Ras oncoproteins is the essential enzymatic step in the process of posttranslational activation, inhibiting this step could theoretically result in the inhibition of this autonomous and malignant growth and proliferation. Thus, specific inhibitors of farnesyl transferase could possibly lead the way toward a specifically targeted treatment of ras oncogene–dependent tumor. Recently, however, evidence has emerged that the antiproliferative effects of farnesyl transferase inhibitors do not depend solely on inhibition of Ras and that the gain of alternate prenylated (geranylgeranylated) forms of the Rho protein Rho-B mediate cell growth inhibition.11 Besides, when inhibiting farnesylation, it has to be taken into account that this process is not restricted to Ras, as other cellular proteins also have to be farnesylated before exerting their activity.3 Several specific inhibitors of farnesyl transferase have been developed. SCH 66336 ((11R) 4[2[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6] cyclohepta [1,2b]pyridin-11yl)-1-pyperazinyl]-2-oxoethyl]-1-piperidinecarboxamide) ( Fig 1) is a tricyclic nonpeptidyl, nonsulphydryl farnesyl transferase inhibitor. In vitro, it blocks farnesylation of H-Ras by purified human farnesyl protein transferase with an 50% inhibitory concentration (IC50) of 1.9 nmol/L and farnesylation of K-Ras-4B with an IC50 of 5.2 nmol/L. SCH 66336 blocks anchorage-independent growth of K-Ras–transformed rodent fibroblasts with an IC50 of 0.4 µmol/L and blocks the transformed growth properties (eg, anchorage-independent growth) of rodent fibroblasts that have been transformed with mutant ras and human tumor cell lines containing mutated ras.12,13 It does not inhibit geranylgeranyl protein transferase 1 in concentrations up to 50 µmol/L. Anchorage-independent growth of various mutated K-ras–containing human tumor cell lines, such as HTB 177 lung carcinoma, A549 lung carcinoma, HCT 116 colon carcinoma, and HPAF II and MiaPaCa pancreatic carcinoma, is inhibited by SCH 66336 at concentrations of 0.5 µmol/L, whereas the growth of the DLD-1 colon carcinoma cell line is inhibited at 3 µmol/L. Interestingly, several human tumor cell lines that do not contain ras mutations, such as HTB 173 and HTB 175 lung carcinoma and MCF-7 breast carcinoma, are also sensitive to the growth-inhibitory effects of SCH 66336. This might be explained in part by the action of oncogenes or autocrine factors that lie upstream in the Ras signal transduction pathway. In in vivo studies, SCH 66336 showed growth-inhibitory effects in human tumor xenografts, including DLD-1 and HCT 16 colon carcinoma, A549 and HTB 177 lung carcinoma, AsPc-1, HPAF-II, HS 700T and MiaPaCa pancreas carcinoma, and DU 145 prostate carcinoma. Additionally, in a WAP-H-ras transgenic mouse model developing tumors of the mammary and salivary gland, dose-dependent tumor regressions have been recorded.14 Preclinical chronic oral toxicity studies revealed dose-dependent myelosuppression, weight loss, diarrhea, and vomiting in rats and monkeys (Schering-Plough Research Institute, Kenilworth, NJ, data on file).
This phase I and pharmacokinetic study represents the first administration of SCH 66336 in patients with advanced solid tumors using a continuous twice daily oral dosing regimen.
Eligibility Criteria Patients with a cytologically or histologically confirmed diagnosis of a solid tumor refractory to standard treatment or for whom no standard therapy was available were eligible for this study. Patients with primary CNS neoplasm, known brain or leptomeningeal metastases, or known bone marrow involvement were excluded. Further eligibility criteria included the following: age  18 years; World Health Organization performance status of  2; life expectancy of 12 weeks; no anticancer therapy in the previous 4 weeks (6 weeks for nitrosoureas or mitomycin); no prior bone marrow or stem-cell transplantation; no known human immunodeficiency virus positivity or AIDS-related illness; adequate function of bone marrow (hemoglobin 6.2 mmol/L, absolute neutrophil count 1.5 x 109/L, platelet count 100 x 109/L), liver (bilirubin 25 µmol/L; AST and ALT within 2.5 times the normal upper limit), and kidney (serum creatinine 140 µmol/L); ability to take oral medication; and no more than two prior combination chemotherapy regimens or one prior combination regimen plus two single-agent regimens. Local ethics boards approved the protocol and informed-consent brochures. All patients gave written informed consent at study entry.
Pretreatment Assessment and Follow-Up Studies
Drug and Drug Administration
Dosage and Dose Escalation
Dose escalation was performed according to a schedule of dose doublings. At each dose level, a minimum of three patients had to have 28 days of treatment before escalation was allowed. Once DLT was seen in one patient at a given dose level, at least six patients had to be treated at that dose level before further dose escalation was allowed. DLT was defined as any
Pharmacokinetic Studies For each patient, the area under the plasma concentration-versus-time curve (AUC) was calculated by the trapezoidal rule and extrapolated to infinity by linear regression analysis. The apparent total-body clearance/F (F denotes the oral bioavailability fraction) was calculated as dose/AUC. The apparent volume of distribution at steady state (Vd,ss/F) was calculated by a noncompartmental method based on the statistical moment theory.17 The terminal disposition half-life was calculated by dividing 0.693 by the fitted rate constant for drug elimination from the central compartment, estimated by linear regression analysis of the final data points of the log-linear concentration-time plot.
Statistical Analysis
Twenty-four patients (14 men and 10 women) with a median age of 56 years (range, 28 to 77 years) were enrolled onto the study. Patient characteristics are listed in Table 1. The median duration of treatment was 40 days (range, 5 to 280 days; mean, 63.4 days). Dose levels studied were 25 (n = 4), 50 (n = 5), 100 (n = 3), 200 (n = 6), 400 (n = 3), and 300 (n = 3) mg bid.
Hematologic Toxicity Hematologic toxicities observed in this trial are listed in Table 2. Transient grade 1 neutropenia reversible without treatment interruption was seen in the fourth week and in the fourth month of treatment in one patient at 50 mg bid and in the first week and the second month of treatment in one patient at 100 mg bid. At 400 mg bid, grade 4 neutropenia lasting from day 14 to 28 was seen in one patient. Granulocyte colony-stimulating factor was administered from day 26 to 29. This patient also developed transient grade 4 thrombocytopenia after withdrawal of the study drug. At 300 mg bid, grade 4 neutropenia lasting from day 17 to 35 was seen in one patient. No granulocyte colony-stimulating factor was administered. Transient grade 1 thrombocytopenia was recorded in the third week of treatment in one patient at 25 mg and 300 mg bid, respectively. One patient at 300 mg bid developed grade 2 thrombocytopenia lasting 5 days after treatment had been stopped because of other toxicities. One patient at 400 mg bid developed grade 3 anemia 6 days after treatment had been stopped.
Nonhematologic Toxicity Major nonhematologic side effects observed in this trial are listed in Table 3. Toxicity was mainly gastrointestinal and consisted of watery diarrhea, nausea, vomiting, and anorexia. In patients with diarrhea, loperamide administered on an as-needed basis resulted in prompt relief of symptoms. At lower doses, vomiting was usually mild and required no specific treatment. Anorexia occurred mainly at the highest dose levels, was mild, and required no specific therapy. Other toxicities consisted of grade 1 or 2 elevation of liver enzymes and reversible grade 1 or 2 elevated plasma creatinine levels recorded at all dose levels studied. In one patient at 400 mg bid, grade 3 anorexia and diarrhea, together with grade 2 nausea and grade 1 vomiting, resulted in grade 3 creatinine due to dehydration, defining DLT. Grade 1 weight loss was recorded in three patients at 200 mg bid and one patient each at 300 and 400 mg bid. Almost all patients who experienced weight loss had various concurrent gastrointestinal toxicities. Transient grade 2 fever was recorded in one patient at 300 mg bid who also developed transient grade 2 oral mucositis after SCH 66336 administration was interrupted because of other side effects. Atrial flutter/fibrillation was recorded in the third month of therapy in a single patient at 100 mg bid. This patient had a prior history of atrial fibrillation. Asymptomatic sinus bradycardia (55 beats/min) was recorded in the third week of treatment in one patient at 300 mg bid. A 24-hour Holter monitoring following the day of onset revealed numerous episodes of bradycardia. Nineteen days after discontinuation of the study drug because of other toxicities, 24-hour Holter monitoring showed no further episodes of bradycardia. Serial ECGs showed no relevant changes in any of the patients. Ophthalmologic examinations revealed no retinal changes.
DLT Since in the first three patients at 200 mg bid no toxicity greater than grade 1 was recorded, the dose was doubled to 400 mg bid. At this dose, DLT was seen in three consecutive patients. It consisted of grade 4 vomiting in the first week of treatment in one patient, grade 4 neutropenia lasting 14 days that coincided with grade 4 thrombocytopenia lasting 5 days which occurred after 2 weeks of treatment in a second patient, and the combination of grade 3 diarrhea, grade 3 anorexia, grade 2 nausea, and grade 1 vomiting leading to reversible grade 3 elevation of plasma creatinine that occurred after the first week in a third patient. Three additional patients were then treated at the next lower dose level of 200 mg bid, but as no additional DLTs were recorded, it was decided to escalate the dose to 300 mg bid. At this dose, DLT was again observed in three consecutive patients, consisting of grade 4 neutropenia lasting 10 days and occurring after 3 weeks of treatment, reversible grade 3 neurocortical toxicity consisting of disorientation and confusion in the first week of treatment, and the combination of grade 3 fatigue with grade 2 nausea and grade 2 diarrhea occurring in the third week of treatment. No patient at 400 mg bid or 300 mg bid was able to complete 28 days of treatment. The recommended dose for phase II trials was set at 200 mg bid. The six patients treated at this dose level received the drug for a median of 57 days (range, 52 to 280 days).
Pharmacokinetics
Response No partial or complete responses were seen. One patient with pseudomyxoma peritonei had stable disease for 9+ months, whereas one patient with metastatic follicular thyroid carcinoma had stable disease for 7 months with ongoing treatment.
We performed a phase I and pharmacokinetic study to explore safety, tolerability, maximum-tolerated dose, and pharmacokinetics of the oral farnesyl transferase inhibitor SCH 66336. In this study using continuous oral bid administration, side effects attributable to the study drug were hematologic and nonhematologic, whereas DLTs included neutropenia, thrombocytopenia, various gastrointestinal side effects, and neurocortical toxicity with reversible disorientation and confusion. The hematologic toxicity of SCH 66336 in the current study consisted of dose-dependent, uncomplicated, and reversible neutropenia and thrombocytopenia occurring mainly at the two highest, nontolerable dose levels tested. At the dose level recommended for phase II studies, 200 mg bid, myelosuppression did not occur, even in the patient who was on treatment for up to 9+ months. This parallels the experience in three other studies using different dosing regimens of SCH 66336 in which hematologic toxicity was absent at these dose levels.18-20 One of these studies also used a continuous treatment schedule.20 This finding is in contrast to results obtained with other farnesyl transferase inhibitors. In two published reports on L-778,123, a peptidomimetic farnesyl transferase inhibitor given intravenously, myelosuppression comprised one of the DLTs and also occurred at dose levels recommended for further activity testing.21,22 Out of three phase I studies23-25 that have been reported on the farnesyl transferase inhibitor R115777, myelosuppression comprised DLT in two,23,24 whereas in the third study, which used a 5 days on, 9 days off schedule, only minimal hematopoietic toxicity was observed.25 In the only published phase I study with the novel farnesyl transferase inhibitor BMS-214662, exploring an intermittent treatment schedule, no myelosuppression was recorded.26 Clearly, for farnesyl transferase inhibitors, myelosuppression is a class effect, with marked differences depending on agent and schedule of administration. The nonhematologic side effects of SCH 66336 in our current study were predominantly gastrointestinal and consisted of mild dose-dependent, noncumulative, and reversible diarrhea, vomiting, anorexia, and nausea. When diarrhea occurred at the recommended dose for phase II studies, treatment with loperamide always resulted in prompt and complete relief. Patients were advised to use loperamide on an on-demand basis, which always proved to be sufficient. At the recommended dose for phase II studies, vomiting was also usually mild and short-lasting and required no specific treatment. Anorexia and nausea occurred at virtually all dose levels and usually were mild. Gastrointestinal side effects were recorded in all studies of SCH 66336 and comprised DLT in all treatment schedules analyzed. This may suggest that gastrointestinal toxicity is not cumulative. Presumably partly related to these various gastrointestinal side effects, mild weight loss was noted in almost all patients. However, patients without gastrointestinal toxicity also experienced some weight loss that occurred mainly within the first 2 weeks of treatment. Remarkably, no additional weight loss was seen with ongoing treatment. Nongastrointestinal side effects were diverse, infrequent, and usually mild. At the lower dose levels, noncumulative and reversible grade 1 creatinine increases were seen, but coinciding urine analysis never revealed any abnormality; therefore, we cannot rule out mild dehydration caused by various gastrointestinal side effects as the principal cause of these creatinine increases. In the patient at the nontolerable dose level 400 mg bid in whom grade 3 creatinine was recorded, urine analysis revealed no abnormalities and interruption of SCH 66336 dosing and intravenous rehydration resulted in a rapid and complete normalization of creatinine levels. In the present study, two episodes of reversible atrial rhythm abnormalities (atrial fibrillation in a patient with previous cardiac history and asymptomatic sinus bradycardia) occurred, but serial ECGs did not show consistent changes in all other patients. This is in sharp contrast with the data from studies with L-778,123, in which prolongation of the Q-T time constituted DLT.21,22 In the current study, one episode of grade 3 rapidly reversible neurocortical toxicity consisting of disorientation and confusion was recorded, but no other episodes of either neurocortical toxicity or peripheral neuropathy were recorded in any of the other studies with SCH 66336. Reversible peripheral neurosensory and motor as well as central neurocortical toxicity have been described with oral R115777.23-25 No neuropathy was recorded with BMS-214662.26 When considering which treatment schedule of SCH 66336 should preferably be used in future clinical trials, one should note that preclinical data demonstrate that SCH 66336 is a reversible competitive inhibitor of farnesyl transferase, and the biochemical effects are rapidly reversed on withdrawal of the compound. Because the compound thus is a competitive inhibitor, the schedule most likely to result in continuous inhibition of farnesyl transferase would be the continuous schedule. This schedule achieves the highest total dose and the longest exposure time. When summarizing the results of the recorded toxicity profiles of the farnesyl transferase inhibitors that are currently being tested in clinical studies (SCH 66336, R115777 and L-778,123, and BMS-214662), one can conclude that myelosuppression is a common feature, whereas nonhematologic toxicities differ in essential ways. Table 5 lists the results of the clinical studies with farnesyltransferase inhibitors presented to date.
This present study clearly demonstrates a dose dependency in SCH 66336 plasma pharmacokinetics in cancer patients, which contrasts with previous findings from preclinical dose-response studies. In the rat, peak plasma levels reached values of 3, 10, and 30 µmol/L at oral doses of 10, 30, and 100 mg/kg, respectively.27 In cancer patients, both the apparent clearance and the apparent Vd,ss/F demonstrated a more than four- to 10-fold decrease at a dose of 400 mg, compared with 25 mg. The most likely explanation is an increase in F with multiple dose administration resulting in an apparent decrease in Vd and an apparent decrease in total-body clearance/F. The opposing effects of these two processes on drug elimination leaves the apparent terminal disposition half-life almost dose-independent, except at the two highest dose levels. In addition, at repeated dosing, ie, when comparing the mean drug exposure and peak plasma concentrations of the various dose levels tested at day 15 with those of day 1, substantial increases were found that were greater than predicted based on accumulation processes alone. Clearly, this may have important clinical ramifications; if clinical outcomes are related to drug exposure, then a simple percentage increase in dose will have a much greater impact on total drug exposure than would be expected with a behavior based on linear pharmacokinetics. Trough plasma concentrations drawn around day 14 to 16 do not show trends suggesting that steady-state was reached. Most importantly, at the recommended dose for further clinical studies applying continuous dosing regimens with SCH 66336, trough plasma concentrations were shown to exceed 1.5 µmol/L, which is above concentrations required in vitro to induce significant growth inhibition in colony assays against various primary human tumor specimens.28 The general principles of dose dependency in pharmacokinetics have recently been reviewed.29 The dose-dependent pharmacokinetic behavior of SCH 66336 in cancer patients most likely involves multiple nonlinear (absorption) mechanisms, including saturation of metabolic processes responsible for presystemic biotransformation (eg, the cytochrome P450 system) or saturation of outward-directed drug-carrier systems that mediate transmembrane drug flux, such as MDR1 P-glycoprotein. Saturation of presystemic metabolism or degradation in the gut lumen, the intestinal mucosae, or the liver after oral administration of drugs in humans is relatively common and has been well described for the calcium antagonist verapamil30 and also for fluorouracil.31 However, the phenomenon of a dose-dependent decrease in extravascular binding (Vd,ss/F) as seen here with SCH 66336 is highly unusual, although it has been reported to occur with 3-hour infusions of paclitaxel, presumably as a result of extensive binding to microtubules or micellar encapsulation in its formulation vehicle.32 Further analysis of the absorption and disposition of SCH 66336 in individual cancer patients, with respect to the current findings, should be of great importance for our ability to better understand the role of the various biologic factors that may influence the compound’s pharmacokinetic behavior and pharmacologic actions, and effects of other drug administered concomitantly. In conclusion, this phase I and pharmacologic study with continuous oral bid SCH 66336 has shown that this farnesyl transferase inhibitor can be safely administered using a continuous oral bid dosing schedule. The recommended dose for phase II studies using this treatment schedule is 200 mg bid.
1. Gibbs JB: Ras C-terminal processing enzymes: New drug targets? Cell 65: 1-4, 1991[Medline] 2. Lowy DR, Willumsen BM: Function and regulation of Ras. Annu Rev Biochem 62: 851-891, 1993[Medline] 3. Khosravi-Far R, Der CJ: The Ras signal transduction pathway. Cancer Metastasis Rev 13: 67-89, 1994[Medline] 4. Gibbs JB, Oliff A, Kohl NE: Farnesyltransferase inhibitors: Ras research yields a potential cancer therapeutic. Cell 77: 175-178, 1994[Medline] 5. Gibbs JB, Kohl NE, Koblan KS, et al: Farnesyltransferase inhibitors and anti Ras therapy. Breast Cancer Res Treat 38: 75-83, 1996[Medline] 6. Omer CA, Kohl NE: CA1A2X-competitive inhibitors of farnesyltransferase as anti-cancer agents. Trends Pharmacol Sci 18: 437-444, 1997[Medline] 7. Gibbs JB, Ollif A: The potential of farnesyltransferase inhibitors as cancer chemotherapeutics. Annu Rev Pharmacol Toxicol 37: 143-166, 1997[Medline]
8.
Rowinsky EK, Windle JJ, Von Hoff DD: Ras protein farnesyl transferase: A strategic target for anticancer therapeutic development. J Clin Oncol 17: 3631-3652, 1999 9. Oliff A: Farnesyl transferase inhibitors: Targeting the molecular basis of cancer. Biochim Biophys Acta 1423: C19-C30, 1999[Medline]
10.
Bos JL: ras oncogenes in human cancer: A review. Cancer Res 49: 4682-4689, 1989 11. Prendergast JC: Targeting farnesyltransferase: Is Ras relevant? ASCO Educational Book Spring:22-28, 1999 12. Liu M, Lee S, Yaremko B, et al: SCH 66336, an orally bioavailable tricyclic farnesyl protein transferase inhibitor, demonstrates broad and potent in-vivo antitumor activity. Proc Am Assoc Cancer Res 39: 270, 1998 (abstr 1843) 13. Izbicka E, Lawrence R, Davidson K, et al: Activity of a farnesyl transferase inhibitor (SCH 66336) against a broad range of tumors taken directly from patients. Proc Am Assoc Cancer Res 40: 524, 1999 (abstr 3454)
14.
Liu M, Bryant MS, Chen J, et al: Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase in human tumor xenograft models and wap-ras transgenic mice. Cancer Res 58: 4947-4956, 1998 15. World Health Organization: WHO handbook for reporting results of cancer treatment. Geneva, Switzerland, World Health Organization, 1979 (Offset Publication No. 40) 16. Kim H, Likhari P, Lin CC, et al: High-performance liquid chromatographic analysis of the antitumor agent SCH 66336 in cynomolgus monkey plasma and evaluation of its chiral inversion in animals. J Chromatogr B Biomed Sci Appl 728: 133-141, 1999[Medline] 17. Gibaldi M, Perrier D: Noncompartmental analysis based on statistical moment theory, in Pharmacokinetics (ed 2). New York, NY, and Basel, Switzerland, Marcel Dekker, 1982, pp 409-417
18.
Adjei AA, Erlichman Ch, Davis JN, et al: A phase I trial of the farnesyl protein transferase (FPT) inhibitor SCH 66336: Evidence for biological and clinical activity. Cancer Res 60: 1871-1877, 2000 19. Hurwitz HI, Colvin OM, Petros WP, et al: Phase I and pharmacokinetic study of SCH 66336, a novel FPTI, using a 2-week on, 2-week off schedule. Proc Am Soc Clin Oncol 18: 156a, 1999 (abstr 599) 20. Awada A, Eskens FALM, Piccart MJ, et al: A clinical, pharmacodynamic and pharmacokinetic phase I study of SCH 66336 (SCH), an oral inhibitor of the enzyme farnesyl transferase, given once daily in patients with solid tumors. Clin Cancer Res 5: 3733s, 1999 (suppl, abstr 20) 21. Britten CD, Rowinsky E, Yao S-L, et al: The farnesyl protein transferase (FPTase) inhibitor L-778,123 in patients with solid cancers. Proc Am Soc Clin Oncol 18: 155a, 1999 (abstr 597) 22. Rubin E, Abbruzzese JL, Morrison BW, et al: Phase I trial of the farnesyl protein transferase inhibitor L-778,123 on a 14 or 28-day schedule. Proc Am Soc Clin Oncol 19: 178a, 2000 (abstr 689) 23. Schellens J, De Klerk G, Swart M, et al: Phase I and pharmacologic study with the novel farnesyl transferase inhibitor (FTI) R115777. Proc Am Soc Clin Oncol 19: 184a, 2000 (abstr 715) 24. Hudes G, Schol J, Baab A, et al: Phase I clinical and pharmacokinetic trial of the farnesyl transferase inhibitor R115777 on a 21-day dosing schedule. Proc Am Soc Clin Oncol 18: 156a 1999 (abstr 601)
25.
Zujewski J, Horak ID, Bol CJ, et al: Phase I and pharmacokinetic study of farnesyl transferase inhibitor R115777 in advanced cancer. J Clin Oncol 18: 927-941, 2000 26. Ryan DP, Eder JP, Supko JG, et al: Phase I clinical trial of the farnesyltransferase (FT) inhibitor BMS-214662 in patients with advanced solid tumors. Proc Am Soc Clin Oncol 19: 185a, 2000 (abstr 720) 27. Bryant MS, Liu M, Wang S, et al: Pharmacokinetics of a potent orally bioavailable inhibitor of farnesyl protein transferase in the mouse, rat and cynomolgus monkey. Proc Am Assoc Cancer Res 39: 177, 1998 (abstr)
28.
Petit T, Izbicka E, Lawrence RA, et al: Activity of SCH 66336, a tricyclic farnesyltransferase inhibitor, against human tumor colony-forming units. Ann Oncol 10: 449-453, 1999 29. Lin JH: Dose-dependent pharmacokinetics: Experimental observations and theoretical considerations. Biopharm Drug Dispos 15: 1-31, 1994[Medline] 30. Freedman SB, Richmond DR, Ashley JJ, et al: Verapamil kinetics in normal subjects and patients with coronary artery spasm. Clin Pharmacol Ther 30: 644-652, 1981[Medline]
31.
Wagner JG, Gyves JW, Stetson CL, et al: Steady-state nonlinear pharmacokinetics of 5-fluorouracil during hepatic arterial and intravenous infusions in cancer patients. Cancer Res 46: 1499-1506, 1986 32. Kearns CM, Gianni L, Egorin MJ: Paclitaxel pharmacokinetics and pharmacodynamics. Semin Oncol 22: 16-23, 1995 (suppl 6)[Medline] Submitted April 27, 2000; accepted October 4, 2000.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, 50 mg (•), 100 mg (
), 200 mg (
), or 400 mg (
). Mean values (symbols) and SE (bar) are shown for all patients treated on day 1 at the indicated SCH 66336 dose level.
