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Originally published as JCO Early Release 10.1200/JCO.2005.00.398 on February 14 2005 © 2005 American Society of Clinical Oncology. Phase I Pharmacokinetic and Pharmacodynamic Study of Weekly 1-Hour and 24-Hour Infusion BMS-214662, a Farnesyltransferase Inhibitor, in Patients With Advanced Solid Tumors
From the Departments of Medical Oncology, Pathology, and Radiology, Vall d'Hebron University Hospital, Barcelona, Spain; Bristol-Myers Squibb, Wallingford, CT, Waterloo, Belgium, and Madrid, Spain Address reprint requests to Josep Tabernero, MD, Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron 119-129, Barcelona 08035, Spain; e-mail: jtabernero{at}vhebron.net.
PURPOSE: BMS-214662 is a potent, nonpeptide, small molecule inhibitor of human farnesyltransferase (FT). We have conducted a phase I pharmacokinetic (PK) and pharmacodynamic study of BMS-214662 administered intravenously weekly with 1- and 24-hour infusions. The objectives were to determine the dose-limiting toxicities and the recommended dose (RD), to describe PKs, and to evaluate the relationships between BMS-214662 exposure, FT inhibition, downstream signaling, and induction of apoptosis in tumor samples. PATIENTS AND METHODS: Patients with advanced solid tumors and adequate organ function were eligible. The dose was escalated according to a modified Fibonacci schedule.
RESULTS: BMS-214662 was escalated from 56 to 278 mg/m2 in 37 patients in the 1-hour schedule, and from 84 to 492 mg/m2 in 31 patients in the 24-hour schedule. Dose-limiting toxicities included gastrointestinal and renal events. The RDs were 209 mg/m2 and 275 mg/m2 in the 1- and 24-hour schedules, respectively. Five patients (three with breast, one with gastric, and one with renal cell cancer) had clinical benefit from treatment. BMS-214662 exhibited linear PKs with area under the concentration-time curves at the RDs of 27 and 32 µM x h in the 1- and 24-hour schedules, respectively. The pattern of FT inhibition in peripheral-blood mononuclear cells at the RDs was different in the two schedules: high (> 80%) but short-lived ( CONCLUSION: BMS-214662 can be safely delivered in both the 1-hour and 24-hour infusions at biologically active doses, with the preclinical, PK, and pharmacodynamic profiles favoring the 24-hour schedule.
Ras proteins are critical elements in signaling mediated by receptor tyrosine kinases. The position of these proteins in receptor tyrosine kinase signaling explains their key role in a large number of cellular processes including growth, differentiation, apoptosis, cytoskeletal organization, and membrane trafficking.1-3 After the synthesis of the Pro-Ras protein, a series of post-translational biochemical processes convert this protein to a more hydrophobic one that permits its localization to the cytoplasmic membrane. The first modification of this process is catalyzed by the farnesyltransferase (FT) enzyme, causing the covalent addition of a farnesyl group to the cysteine residue of the C-terminal CAAX sequence of the propeptide. As the first step in this process, farnesylation is the most critical one, and FT blockade causes severe impairment in Ras protein function. Moreover, FT activity in human tumor cells is higher than in normal surrounding cells.4 Therefore, FT has become a relevant target in anticancer drug development.5-11 Initially it was thought that FT inhibitors (FTIs) might selectively decrease the growth of Ras-transformed cells and tumors harboring Ras mutations.12-17 More recent studies have demonstrated that there is no clear correlation between Ras mutations and sensitivity to FTIs.6,18-26 Whereas FTIs effectively inhibit H-ras signaling and transformation, they do not block either the processing or the function of K-ras 4B,27 the isoform of Ras most frequently mutated in human tumors. Indeed, in the presence of FTIs, K-ras can become alternatively prenylated by the FT-related enzyme geranylgeranyltransferase I (GGTI).28,29 Nevertheless, some FTIs can significantly inhibit the growth of tumors containing mutated K-ras4B.30-32 This indicates either that farnesylated proteins other than Ras, like RhoB and the centromere-associated CENP-E and CENP-F, must also play a role in the biologic consequences of FTI treatment,33-36 or that farnesylated and geranylgeranylated Ras function differently, or even that alternative prenylation might also be inhibited by some FTIs. Thus, despite the development of FTIs as drugs targeted to one particular oncoprotein, their actions are complex. Some studies have lightened potential mechanisms of FTIs resistance, in particular, related to K-ras: one is the alternative prenylation of K-ras by GGTI and the other results from K-ras having a higher affinity for FT than H-ras or N-ras, making it more difficult for FTIs to compete with K-ras of FT binding.37 BMS-214662 is a nonpeptide small molecule inhibitor of FT that belongs to a family of compounds distinguished by the presence of an imidazole group attached to the tetrahydrobenzodiazepine nucleus (Fig 1).38 BMS-214662 is a potent in vitro inhibitor of human FT of both H-ras and K-ras, with an IC50 of 1.3 nM and 8.4 nM and an IC90 of 18 and 108 nM, respectively.39 BMS-214662, in contrast with other FTIs, has enhanced cytotoxic effects in preclinical models, resulting in the regression of large, well-established human tumor xenografts in nude mice with either continuous or intermittent dosing schedules.38,40 Another potentially important feature of this compound is that induction of apoptosis occurs both in proliferating and nonproliferating cells. This effect may in part explain the synergistic antitumor activity observed in preclinical models when BMS-214662 is combined with a wide range of cytotoxic drugs.39-42
The objectives of our study were to determine the maximum-tolerated dose (MTD), the dose-limiting toxicities (DLTs), and the recommended dose (RD) of BMS-214662 administered weekly; to further define the pharmacokinetic (PK) profile of this agent; and to determine the relationship between drug exposure and FT inhibition, Ras-mediated signaling, and the induction of apoptosis in both normal and tumor cells. In the first part of the study, we explored a weekly 1-hour infusion. Using this schedule, the toxicity profile was related to maximum plasma concentration (Cmax), and FT inhibition and induction of apoptosis were profound but short lasting. Therefore, we proceeded to evaluate a weekly 24-hour infusion to achieve longer target inhibition.
Patient Population Main inclusion criteria were histologically/cytologically confirmed advanced tumors unresponsive to standard therapy; presence of disease accessible to repetitive biopsies; measurable or assessable disease; age  18 years; life expectancy 12 weeks; Eastern Cooperative Oncology Group performance status of 0 to 2; and adequate bone marrow, hepatic, and renal function. Conditions resulting in exclusion included active infection; uncontrolled or significant pulmonary or cardiovascular disease; brain metastasis; or receiving drugs with known significant P-450 3A4 inhibitory effects at trial entry. All patients gave informed consent, and approval was obtained from the ethics committee at Vall d'Hebron University Hospital and the regulatory authorities. The study followed the Declaration of Helsinki and good clinical practice guidelines.
Treatment and Dose Escalation Criteria
Tolerability and Safety
Response Assessments
Pharmacokinetic Analysis
The concentration of BMS-214662 in plasma was determined by an analytic method involving reversed-phase, high-performance liquid chromatography with ultraviolet detection, as described previously.43 A noncompartmental PK analysis of the plasma samples was calculated using noncompartmental methods by the PKMENU application using the Statistical Analysis System version 6.12 (SAS Institute, Cary, NC). The following PK parameters of BMS-214662 were estimated: empirical time of peak plasma level (tmax), empirical peak plasma level (Cmax), and apparent elimination rate constant (
Pharmacodynamic Assessments FT activity in tumor and surrounding normal tissue samples The inhibition of FT activity in tumor and surrounding normal tissues by BMS-214662 was determined in selected patients. The timing of tumor and normal tissue biopsies was changed as data from previous samples became available, adjusting the timing as required. With the 1-hour infusion, tissue samples were obtained at baseline, 24:00, and 144:00 hours after the first dose of BMS-214662 at the dose levels of 56 to 157 mg/m2; at baseline, 2:00, and 24:00 hours at the dose levels of 209 to 245 mg/m2; and at baseline, 2:00, 6:00, and 24:00 hours at the dose level of 278 mg/m2. In the 24-hour infusion schedule the samples were obtained at baseline, 6:00, 24:00, and 48:00 hours after the first dose at all dose levels. The tissue samples were immediately frozen after the biopsy procedure and were stored at –70 to –80°C. Determination of the FT activity FT activity in extracts of PBMC and normal or tumor tissues was determined by a radioenzyme assay using [3H] farnesyl pyrophosphate and human recombinant H-ras proteins produced in bacteria, as described previously.4,40,43,47 FT activity in each sample was determined as fmol/µg protein/h and reported as a percentage of the activity in the pretreatment sample for each patient. The arithmetic mean of the normalized FT activity was calculated from the determinations made at each time point for the group of patients in each dose level. Signal transduction inhibition and apoptosis in tumor samples MAPK signaling and apoptosis in tumor samples by BMS-214662 were determined in selected patients enrolled in the study. Immunohistochemical analysis of total p42/44 MAPK, phosphorylated p42/44 MAPK at Thr202/Tyr204 (p-MAPK), total Akt, p-Akt at Ser473, p27KIP1 expression, and proliferation marker Ki67 were performed in paraffin-embedded sections from tumor samples, as described previously.48,49 Apoptosis was studied by TUNEL assay49 and by determination of caspase signaling measured as levels of cleaved caspase 3 at Asp175 and cleaved caspase 9 at Asp330 by immunohistochemistry as described previously.50,51 Rabbit polyclonal antitotal p44/42 MAPK #9102, anti-phosphorylated p44/42 (Thr202/Tyr204) MAPK #9101, antitotal Akt #9272, and antiphosphorylated Akt #9277 from Cell Signaling Technology (Beverly, MA); mouse monoclonal anti-p27KIP1 clone SX53G8 and anti-Ki67 clone MIB1 (DakoCytomation, Carpinteria, CA); mouse monoclonal anticleaved caspase 3 at Asp175 #9661 and anticleaved caspase 9 at Asp330 #9501 (Cell Signaling Technology) were used as primary antibodies. Two negative control rabbit polyclonal immunoglobulins (Biogenex, San Ramon, CA; and Santa Cruz Biotech, Santa Cruz, CA) and a negative control mouse monoclonal immunoglobulin (Biogenex) were also used. TUNEL assay 16-dUTP-peroxidase (Roche Diagnostics Gmbh, Mannheim, Germany) was used. Qualitative changes in the expression of markers were assessed in a blinded fashion. For quantitative analysis, the percentage of cells in the tumor tissue that stained with each antibody was scored from representative sections in 10 high-power (x400) microscope fields, and the average percentage of stained cells was calculated in paired samples. Paired pretherapy and on-therapy samples were analyzed using the Wilcoxon rank test by SPSS Data Analysis Program, version 10.0 (SPSS Inc, Chicago, IL). Statistical tests were conducted at the two-sided 0.05 level of significance.
Characteristics of the 37 patients included in the weekly 1-hour infusion schedule and the 31 patients included in the weekly 24-hour infusion schedule are listed in Table 1. The distribution of patients across dose levels is listed in Tables 2 and 3.
Clinical Toxicities Hematologic toxicities were observed more frequently in the 1-hour infusion than in the 24-hour infusion schedule (Table 2). Transient grade 3 to 4 neutropenia and leukocytopenia lasting 24 to 48 hours after the end of BMS-214662 infusion without any clinical significance were observed in 38% and 25% of the patients treated with the 1-hour infusion at doses 209 mg/m2, respectively. One patient treated at the 278 mg/m2 level developed grade 4 thrombocytopenia and disseminated intravascular coagulation in the context of sepsis of gastrointestinal origin. This patient died of multiorgan failure after 10 days in an intensive care unit. In contrast, no grade 3 to 4 hematologic toxicities were observed with the 24-hour infusion schedule up to the 492 mg/m2 dose level except for grade 3 anemia. One patient in the 492 mg/m2 cohort experienced grade 4 thrombocytopenia, neutropenia, and leukocytopenia; these events were considered DLTs.
The profile of nonhematologic toxicity was completely different in the two infusion schedules (Table 2). The most frequent toxicities in the 1-hour infusion schedule were of gastrointestinal origin, including nausea/vomiting and diarrhea. One patient at 209 mg/m2 developed grade 3 nausea/vomiting without any prophylactic premedication. This patient also experienced grade 3 hypotension—considered a DLT—during the vomiting episodes. After this case, antiemetics were administered to all patients on a prophylactic basis. One patient at 245 mg/m2 and two patients at 278 mg/m2 presented grade 3 nausea/vomiting despite the antiemetic prophylaxis, all considered to be dose-limiting. One patient at 245 mg/m2 and three patients at 278 mg/m2 developed grade 3 diarrhea despite early and vigorous oral loperamide treatment and these episodes were considered DLTs. One patient at the 245 mg/m2 dose level developed a fatal grade 4 acute pancreatitis, considered to be possibly related to BMS-214662. Transient grade 3 AST/ALT elevations lasting 24 to 48 hours after the end of BMS-214662 infusion and without any clinical sequelae were observed in 19% of the patients treated at doses In contrast, the most frequent observed severe toxicity with the 24-hour infusion schedule was of renal origin. In the initial dose escalation, toxicity was limited to grade 1 to 2 events up to the 492 mg/m2 dose level, where two of three patients presented DLTs: one patient with reversible grade 3 creatinine elevation and one patient with reversible grade 3 renal failure, grade 3 nausea/vomiting, grade 3 amylase/lipase elevation, grade 3 infection, grade 4 creatinine elevation, grade 4 hepatitis, grade 4 transient neutropenia, and grade 4 hypovolemic shock. Therefore, the 492 mg/m2 dose level was considered a toxic dose and the lower dose level, 370 mg/m2, was expanded to determine the recommended dose. At the 370 mg/m2 dose level, one of four patients presented DLTs with grade 3 vomiting, reversible grade 3 renal failure, and grade 4 creatinine elevation. This renal toxicity was likely due to acute tubular necrosis since the fractional excretion of sodium was higher than 2% and the normalization of the creatinine levels was slow, with two patients requiring transient dialysis. Kidney biopsies were obtained from the two patients treated at 492 and 370 mg/m2, respectively, who experienced reversible renal failure. In both cases, focal acute tubular damage with regeneration signs and thrombotic microangiopathy limited to the interstitial capillaries were observed. Although only one of four patients at the 370 mg/m2 dose level experienced DLTs, recruitment to this dose level was stopped in light of the severe toxicity. Therefore, the number of patients enrolled at the 275 to 278 mg/m2 dose level was expanded. One of a total of 12 patients treated at 275 to 278 mg/m2 developed a reversible grade 2 increase in the serum creatinine and grade 3 nausea/vomiting. In summary, DLTs in the 1-hour infusion schedule (Table 2) occurred at the 209 mg/m2 dose level and higher. The 278 mg/m2 dose level was clearly intolerable, with three DLTs occurring in a total of six patients. The 245 mg/m2 dose level was initially considered to be the MTD. However, the case of fatal pancreatitis observed at this dose level and considered related to BMS-214662 makes the 245 mg/m2 difficult to support for phase II use. Therefore, the 209 mg/m2 dose level, which produced grade 3 nausea/vomiting and hypotension in one of eight patients, and specifically in a patient who had not received antiemetic therapy, is recommended as the dose for further development of BMS-214662 when given as a weekly 1-hour infusion. In the 24-hour infusion schedule, DLTs occurred at the 275 to 278 mg/m2 dose level and higher. The 492 and 370 mg/m2 dose levels were clearly intolerable, with DLTs occurring in two of three and one of four patients, respectively. At the 275 to 278 mg/m2 dose level, one of 12 patients presented DLT. Thus, the dose of BMS-214662 recommended as a weekly 24-hour infusion schedule is 275 mg/m2. The cumulative tolerance of BMS-214662 was globally acceptable (Table 3). In the 1-hour infusion schedule, nine doses out of a total of 287 administered doses were delayed due to toxicity, four in the first 4-week period and five after the initial 4-week period. There were four patients that were dose reduced, one in the first 4-week period and three after the initial 4-week period. In the 24-hour infusion schedule, two doses out of a total of 213 administered doses were delayed due to toxicity, both in the first 4-week period. Four patients needed dose reductions, one in the first 4-week period and three after the initial 4-week period.
Antitumor Activity
Pharmacokinetics
Pharmacodynamics Farnesyltransferase inhibition There was a good correlation between dose and degree of FT inhibition in PBMCs in both infusional schedules. In the 1-hour infusion schedule, the maximum inhibition of FT in PBMCs was observed at the end of the infusion. Greater than 80% inhibition of FT was observed at the 1-hour time point with BMS-214662 doses 118 mg/m2. FT inhibition returned to baseline by the 24-hour time point at all dose-levels (Fig 3A). In contrast, in the 24-hour infusion schedule, FT activity was uniformly inhibited throughout the duration of the infusion, achieving a sustained inhibition of 40% at 275 to 278 mg/m2 and a maximal inhibition of approximately 70% at 370 mg/m2 (Fig 3B). As expected, FT inhibition was more short lasting in the 1-hour infusion (Fig 3C) than in the 24-hour infusion schedule (Fig 3D). There was a good correlation between the BMS-214662 concentration profile and the intensity of FT inhibition in PBMCs in both schedules. The pattern of FT inhibition over time after the exposure of the drug was similar in PBMCs, tumor, and surrounding normal tissue, although there was a trend for a more prolonged inhibition in tumor and surrounding normal tissue than in PBMCs (data not shown).
Effects on signal transduction BMS-214662 did not induce changes in total- and p-MAPK, total- and p-Akt, p27KIP1, and Ki67 in tumor samples. In contrast to this, BMS-214662 induced apoptosis in all but one tumor sample. Apoptosis by TUNEL staining was observed in tumor samples both from patients with signs of antitumor activity and in patients without such activity. Figures 4A through D show the induction of apoptosis in tumor samples obtained from patients in the 1-hour and the 24-hour infusion schedules. Induction of apoptosis—measured by both hematoxylin-eosin and TUNEL stainings—appeared to be related to time after exposure being more prominent at 24- than at 2-hour time points and at the 48-hour than at 24- and 6-hour time points in the 1-hour and 24-hour infusion schedules, respectively. Expression of cleaved caspase 3 and 9 in tumor cells significantly increased after treatment with the two schedules. In the 1-hour infusion schedule, expression of cleaved caspases at 24- and 2-hour time points was significantly increased, being more prominent at the 24-hour time point, whereas in the 24-hour infusion schedule, the expression significantly increased at 48- and 24-hour time points, being more prominent at the 48-hour time point (data not shown). The induction of apoptosis appeared related to dose in the 1-hour infusion schedule and it was observed in all patients with tumor samples at doses 209 mg/m2. However, the induction of apoptosis was not found related to dose in the 24-hour infusion schedule.
In this study, BMS-214662 was developed in a weekly schedule, a dosing regimen more consistent with the preclinical activity of the compound. This phase I study was aimed at identifying the most optimal weekly schedule of BMS-214662 based on the toxicity profile, PK, and PD evaluation of FT inhibition and apoptotic induction in normal and tumor cells. We found that the toxicity profiles of the 1- and 24-hour infusion regimens were completely different. Additionally, the patterns of FT inhibition and apoptotic induction were markedly different with the two regimens. With the 1-hour infusion schedule, DLTs consisted of nausea/vomiting, diarrhea, acute pancreatitis, hypotension, thrombocytopenia and increased serum creatinine. Transient and reversible grade 3 AST/ALT elevations and grade 3 to 4 leukocytopenia/neutropenia lasting 24 to 48 hours after the end of BMS-214662 infusion were also seen, but they did not appear to be of clinical significance. In considering PK and PD studies, FT inhibition completely mirrored the concentrations of BMS-214662 in plasma, with a profound but short-lived FT inhibition in PBMCs and tumor cells.
After completing evaluation of weekly 1-hour infusions, we proceeded to evaluate weekly 24-hour infusions for several reasons. First, the AUC reached with the 1-hour infusion at the RD (27 µM x h) was lower than the AUC predicted in preclinical models to achieve antitumor activity (77 µM x h). To the extent that toxicities might be related to Cmax rather than to AUC, it was anticipated that a higher exposure would be reached with a 24-hour infusion. Second, at the RD with the 1-hour infusion, FT inhibition in tumor cells was nearly complete, but brief (
The 24-hour infusion schedule at the highest dose levels resulted in unexpected renal impairment, likely due to acute tubular necrosis. However, at the RD, this schedule was better tolerated without any significant nausea, vomiting, diarrhea, leukocytopenia, or liver toxicity. The differences in the safety profile with the two schedules suggest that some toxicities are related to Cmax, whereas others are related to global exposure to the drug. It is likely that the liver and hematologic toxicities are related to Cmax since Cmax with 1-hour infusion at 209 to 278 mg/m2 was 18.3 to 19.1 µM, whereas the 24-hour infusion yielded a Cmax of 1.1 to 2.9 µM at 209 to 492 mg/m2 dose levels. In contrast, the renal toxicity is likely related to more prolonged exposure. AUC was 23.5 to 55.7 µM x h at the dose levels 209 to 492 mg/m2 with the 24-hour infusion and 27.2 to 32.6 µM x h at 209 to 278 mg/m2 in the 1-hour infusion. In addition to the most favorable safety profile, the 24-hour infusion is preferred over the 1-hour infusion for several reasons. First, delivery of BMS-214662 in a 24-hour infusion at the RD of 278 mg/m2 allows for clinical drug exposures An important end point of our study was to determine which correlations existed between exposure to the study agent and inhibition of FT in the PBMCs and, of great interest, in the tumor. Although other studies with this43 and other FTIs52,53 had demonstrated a correlation between FTI dose and FT inhibition in PBMCs, and bone marrow cells and buccal mucosa cells, the degree of FT inhibition in the tumor cells with these agents was unknown. Therefore, we evaluated the relationship between the degree of FT inhibition and its timing dependency in the tumor and in selected surrogate tissues. We have demonstrated that there was a good correlation between FT inhibition related to BMS-214662 in PBMCs and normal and tumor tissue samples. As a consequence of this, we suggest that PBMCs can replace tumor tissue to determine the inhibition profile of FT activity related to BMS-214662. In order to characterize target inhibition, we decided to determine the biologic effects of BMS-214662 in the tumor. Based on the preclinical studies suggesting that BMS-214662 had a profound proapoptotic effect, we studied apoptosis induction in tumor samples. We have clinically demonstrated in the serial tumor PD studies that BMS-214662 induced apoptosis but did not inhibit MAPK signaling. Other FTIs have also demonstrated antitumor activity and induction of apoptosis through Ras-independent pathways.20,24,54,55 The degree and duration of apoptosis was higher in the 24-hour infusion than in the 1-hour infusion schedule. Whereas in the 1-hour infusion, there was a clear correlation between dose and degree of apoptosis, we did not find such correlation in the 24-hour infusion schedule. We could not establish any correlation between the degree of observed apoptosis and clinical benefit and/or toxicity. Normal tissues such as PBMCs and skin may be good surrogates for evaluating the exposure of the drug and kinetics of the target inhibition in a clinical model. However, tumor PD studies may better explore the biologic effects of a selected agent than normal surrogate tissues, as tumor cells often respond in a different way to targeted drugs than normal cells, also demonstrated with other compounds in the clinical setting, such as the EGFR inhibitors EMD72000SUP>56 and gefitinib.57,58 Therefore, the antineoplastic PD effect of a selected compound on the human tumor cells in the human host can only be evaluated when tumor biopsies are obtained before and during treatment. We and others support PD studies with tumor biopsies from patients enrolled in clinical trials with new targeted therapies.59,60 These studies can not only evaluate the biologic effect of the drug in the tumor, but they may also identify the genomic and proteomic profile of the population with highest chances to benefit from treatment. BMS-214662 has been administered by other routes and schedules. With the intravenous formulation, BMS-214662 has been administered as 1-hour infusion every 3 weeks,43,61 and once weekly for 4 weeks, followed by 2 weeks of rest.62 BMS-214662 was also formulated in an oral capsule, but the severe gastrointestinal toxicities observed in the clinical setting63 prevented further development with this formulation. Different phase I studies are currently evaluating the synergistic effect of BMS-214662 in combination with cisplatin,64 paclitaxel,65 and both carboplatin and paclitaxel66 in the clinical setting. In summary, this phase I study with weekly 1-hour and 24-hour infusions of BMS-214662 has shown that this agent can be administered with either infusion duration. However, based on the preclinical evaluation, the clinical safety profile and the PK and PD results, with a more sustained FT inhibition and apoptosis induction with a prolonged infusion, we recommend the 24-hour infusion schedule for further development of this agent.
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. Employment: Maurizio Voi, Bristol-Myers Squibb; Michael Cooper, Bristol-Myers Squibb; Anne Van Vreckem, Bristol-Myers Squibb; Veeraswamy Manne, Bristol-Myers Squibb; James A. Manning, Bristol-Myers Squibb; Carmen Garrido, Bristol-Myers Squibb. Consultant/Advisory Role: Jose Baselga, Bristol-Myers Squibb. Stock Ownership: Maurizio Voi, Bristol-Myers Squibb; Veeraswamy Manne, Bristol-Myers Squibb; James A. Manning, Bristol-Myers Squibb. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
We thank Ramon Salazar for critical review of this manuscript.
Presented in part at the 11th NCI-EORTC-AACR Symposium on New Drugs in Cancer Therapy, Amsterdam, Holland, November 7-10, 2000; at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001; and AACR-NCI-EORTC International Conference of Molecular Targets and Cancer Therapeutics, Miami, FL, October 29-November 2, 2001. Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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ABSTRACT
INTRODUCTION
6 hours) in the 1-hour infusion and moderate (> 40%) but long-lived (24 hours) in the 24-hour infusion. BMS-214662 induced apoptosis in tumors but did not inhibit MAPK signaling. 
z), which was calculated by linear regression of the terminal phase of the semilogarithmic plasma levels curve, when this was clearly defined. The elimination half-life (t1/2) was defined as ln2/
