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Clinical Trials |
1 Cancer Research UK Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow, United Kingdom; 2 Department of Medical Oncology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; and 3 Bristol-Myers Squibb Company Inc., Waterloo, Belgium
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Experimental Design: Twenty-nine patients with advanced solid malignancy, refractory to conventional therapy, and with adequate hematological, renal, and hepatic function were treated with escalating doses of BMS-214662 administered as a 1-h infusion, followed after an interval of 30 min by 75 mg/m2 cisplatin administered as a 4-h infusion and repeated every 21 days. Blood and urine samples for pharmacokinetic and pharmacodynamic analyses were collected during the first cycle of treatment only.
Results: Dose-limiting toxicities occurred in 4 of 9 patients enrolled at the 225 mg/m2 BMS-214662 dose cohort, and included elevation of hepatic transaminases, nausea, vomiting, diarrhea, and renal failure. There was no apparent pharmacokinetic interaction between the two drugs at the recommended dose levels, and a dose-dependent inhibition of farnesyltransferase activity was observed, which returned to control levels within 24 h of drug administration. There were no objective responses, but disease stabilization was observed in 15 patients, including 4 patients with stable disease after 6 cycles of treatment.
Conclusions: A dose of 200 mg/m2 of BMS-214662 administered as a 1-h infusion with 75 mg/m2 cisplatin over 4 h is the recommended dose for additional studies.
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Inhibitors of FT were originally regarded as specific and sensitive inhibitors of Ras-mediated cellular proliferation (5 , 7) . However it has become apparent that the critical target of farnesyl transferase inhibitors may not be Ras proteins or may include other polypeptides in addition to Ras (8, 9, 10) . More than 100 proteins have been identified that possess a "CAAX" sequence that can potentially be farnesylated (10) , and up to 20 of these have been shown to undergo farnesylation including rho B, lamins A and B, transducin, and CENP-E and CENP-F. Currently, at least 3 proteins have been identified, inhibition of which may be implicated in the cytotoxic actions of FT inhibitors (FTIs), and these include rho B, which regulates cytoskeleton organization (11) , the centromeric proteins CENP-E and CENP-F, which interact with microtubules (12) , and proteins associated with the phosphoinositide 3-OH kinase AKT pathway (13) . Thus, the molecular targets of FTIs remain unclear, but are likely to include several key proteins and possibly include some or all of the Ras isoforms.
BMS-214662 is an imidazole-containing tetrahydrobenzodiazepine (14) . It is a potent and selective FT inhibitor active in the low nanomolar range in vitro, and with good cytotoxic potency and selectivity against a number of human tumor cell lines including colon, breast, ovarian, prostate, and squamous cell carcinomas (15) . Furthermore BMS-214662 can inhibit FT and H-Ras processing and induce tumor responses in in vivo mouse models (15) . However, no clear correlation was observed between ras mutation status and sensitivity of the tumors to BMS-214662.
The potentially wide therapeutic index of FTIs with low toxicity and relatively low risk of myelosuppression raises the possibility that these agents can be safely combined with conventional cytotoxic agents (16 , 17) . Cisplatin has a broad spectrum of antitumor activity in a variety of solid tumors including testicular, lung, and ovarian cancer (18) . Cisplatin-induced cell death is primarily due to apoptosis (19) , and cisplatin resistance is associated with defects in the induction of apoptosis (20) . Cells transfected with mutant ras genes, in particular RV-H ras, exhibit increased resistance to cisplatin (21, 22, 23) potentially as a result of ras-induced activator protein transcription factor leading to elevated expression of genes known to be involved in conferring cisplatin resistance (24 , 25) . Furthermore, there is some evidence that transfection with H-ras confers increased resistance to cisplatin, whereas transfection with K-ras does not (26) . In vitro evidence suggests that the combination of an FTI with cisplatin is synergistic (27) . FTIs have been associated with increased apoptosis and decreased DNA synthesis in animal tumors, leading to enhanced in vivo efficacy when combined with various cytotoxic agents including cyclophosphamide, 5-fluorouracil, and vincristine (28) . Therefore, the combination of BMS-214662 and cisplatin could potentially be more active than either agent alone.
Consequently, a Phase I study was initiated with BMS-214662 administered i.v. over 1 h in combination with 75 mg/m2 cisplatin administered as a 4-h infusion once every 3 weeks. The dose and schedule of cisplatin is that which is most frequently used in Europe either as a single agent or in combination chemotherapy regimens. The aims of this study were to characterize the toxicities of BMS-214662 when administered as a 1-h i.v. infusion in combination with 75 mg/m2 cisplatin administered as a 4-h infusion both given once every 3 weeks and to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended dose for subsequent Phase II studies. In addition, the pharmacokinetics (PK) profiles of BMS-214662 and cisplatin were determined, and the con-stitutive FT activity in peripheral blood mononuclear cells (PBMCs) was assessed as a surrogate pharmacodynamic (PD) end point.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All of the patients entered into this study had an advanced solid malignancy, verified by histology or cytology, refractory to conventional therapy or for which there was no effective treatment other than single agent cisplatin. Eligible patients were those with a life expectancy of at least 3 months; age >18 years; WHO performance status 0–2; no chemotherapy, immunotherapy, or radiotherapy (involving 
25% of hematopoietic reserves) within 4 weeks of entering the study (6 weeks for nitrosoureas and mitomycin C); no drugs known to be substrates of cytochrome P450–3A4 for 7 days before protocol therapy; adequate hematological (absolute neutrophil count 1.5 x 109/liter, platelets 100 x 109/liter), hepatic (total bilirubin 
1.5 mg/dl, alanine aminotransferase and aspartate aminotransferase 2.5 x upper limit of normal) and renal function (creatinine clearance 60 ml/min as calculated by the Cockcroft and Gault formula). Patients with calculated creatinine clearance <60 ml/min were included if on undergoing an EDTA Cr51 assessment their creatinine clearance was 60 ml/min. Patients with intolerable toxicity to prior cisplatin therapy, >3 prior chemotherapy regimens for metastatic disease, peripheral neuropathy grade 2 (National Cancer Institute Common Toxicity Criteria, version 2.0), symptomatic pulmonary or cardiac disease, recent history of myocardial infarction, cardiac arrhythmia, second or third degree heart block, QTc interval > 450 ms on electrocardiogram, or inability to discontinue therapy with drugs known to prolong the QT interval, were excluded. Patients with cerebral metastases or uncontrolled infection were also excluded.
Treatment Administration.
Pretreatment evaluation included a complete history and clinical examination, full blood count, biochemical profile, creatinine clearance (Cockcroft Gault or EDTA Cr51 determination), urinalysis, chest X-ray, electrocardiogram, and pregnancy test (either serum or urine). Relevant radiological studies to evaluate sites of disease were performed up to 4 weeks before starting chemotherapy.
BMS-214662 was supplied in glass vials as the methanesulfonic acid salt (20 mg/ml as the Free base) and was diluted for use with 5% dextrose for injection, United States Pharmacopoeia, to concentrations between 0.2 mg/ml and 2.5 mg/ml. The dilutions were stable when stored in polyvinylchloride i.v. bags, at room temperature, for up to 24 h. BMS- 214662 was administered through a PVC giving set as a 1-h i.v. infusion followed after an interval of 30 min by cisplatin administered as a 4-h i.v. infusion, both given every 21 days. Cisplatin was administered in 1000 ml of 0.9% saline or 250 ml of 3.0% saline depending on local use. Prehydration (1000–1500 ml of 0.9% saline or 5% dextrose over 3 h) was administered before the BMS-214662 infusion, and patients received posthydration after the cisplatin infusion (1500–3000 ml of 0.9% saline or 5% dextrose over 3–13 h) with appropriate electrolyte supplementation. All of the patients received antiemetic premedication with either granisetron (3 mg) or ondansetron (8 mg) given as a 15 min i.v. infusion in 100 ml of 0.9% saline 30 min before administration of BMS-214662 and also received dexamethasone 8 mg administered as a 15 min i.v. infusion in 100 ml of 0.9% saline after completion of the BMS-214662 infusion and before cisplatin administration. Preclinical studies suggest that BMS-214662 may prolong the QT interval. Consequently, 12-lead electrocardiograms were obtained predose, between 5 and 30 min (to correspond with the time of expected maximum plasma drug concentration), and 24 h after completion of the BMS- 214662 infusion.
On the basis of previous studies of single-agent BMS-214662 administered as a 1-h infusion on a 3-weekly schedule, a starting dose of 126 mg/m2 of BMS-214662 was chosen combined with a fixed dose of cisplatin 75 mg/m2 (29)
. The dose of BMS-214662 was escalated in subsequent cohorts according to a modified Fibonacci schema (Table 1)
, with the dose of cisplatin remaining at 75 mg/m2 in all of the dose cohorts. Patients were able to continue treatment with cisplatin to a maximum of six courses of chemotherapy (or a cumulative dose of 450 mg/m2) and BMS-214662 to a maximum of eight administrations provided there was no evidence of disease progression or unacceptable toxicity.
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DLT was defined as grade 4 neutropenia lasting 5 days or febrile neutropenia (fever 38.5°C with an absolute neutrophil count <1,000/mm3); grade 4 thrombocytopenia (platelets <10,000/mm3) or a bleeding episode requiring platelet transfusion; grade 3 nausea or emesis despite maximal antiemetics; grade 3 nonhematological toxicity with the exception of grade 3 aspartate aminotransferase or alanine aminotransferase elevations, which resolved to baseline within 2 weeks; and a treatment delay of 2 consecutive weeks due to failure of toxicity to resolve to baseline or grade 1.
The MTD was defined as the dose level below that at which >1 of 3 or 2 of 6 patients experienced a DLT. Once the MTD had been defined, an additional 6 patients were recruited at the MTD to gain further experience with this regimen. Dose escalation occurred after all 3 of the patients (or 6 patients in any expanded cohort) had completed at least 1 cycle of treatment. No intrapatient dose escalation was performed.
Dose Delays and Modifications.
Dose delays and modifications were performed on the basis of toxicity. Administration of both agents was delayed for 1 week if drug related toxicity from the previous chemotherapy cycle had not resolved to pretreatment levels or grade 1; if toxicity did not resolve after a delay of 2 weeks study treatment was discontinued. In the event of grade 3–4 nonhematological toxicity, patients could be retreated after reducing the BMS-214662 dose to the dose of the previous cohort. Cisplatin was omitted if an EDTA Cr51 determined that creatinine clearance was <60 ml/min, in which case BMS-214662 could be administered as a single agent at the discretion of the investigator. Similarly, cisplatin administration was discontinued in the event of grade 3 peripheral neuropathy or clinically significant ototoxicity. In addition, patients who developed a hematological DLT could be retreated after reduction of the dose of BMS-214662 to the previous dose level, with no modification of the cisplatin dose. After a dose reduction of either agent, for whatever reason, no dose escalation for subsequent chemotherapy cycles in that patient was allowed, with the exception of recovery of creatinine clearance to 60 ml/min.
Disease Evaluation and Response Assessment.
Tumor assessments were performed by radiological evaluations (computed tomography scan of disease sites) and clinical assessments before starting chemotherapy, and these assessments were repeated after every 2 cycles of treatment. Patients who received at least 2 cycles of treatment were evaluable for response. In addition, patients who developed rapid tumor progression or died of progressive disease before response evaluation were considered evaluable for response. Responses to treatment were defined using the WHO criteria (30)
, and all analyses were carried out on an intention-to-treat basis.
PKs.
Blood and urine samples were collected for PK analysis during the first treatment cycle only. Blood was sampled from a site contralateral to the peripheral vein used for treatment during the first cycle of treatment only. Blood samples for BMS-214662 PK were collected in EDTA Vacutainer tubes before treatment with BMS-214662, 30 min after the start of the infusion, immediately before the end of the 1-h infusion and at 10, 20, and 30 min, and 1, 2, 3, 5, 7, 9, and 23 h after the end of the infusion. Plasma was separated by centrifugation, transferred to appropriately labeled tubes, and transported to Bristol-Myers Squibb (New Brunswick, NJ) for analysis. For measurement of BMS-214662 in human plasma, 0.5-ml aliquots of plasma were transferred to screw-capped vials, and followed by addition of 0.5 ml of 1 M phosphate buffer and 5 ml of 1-chlorobutane. The tubes were capped and mixed thoroughly. After centrifugation, the upper organic phases were transferred to clean tubes, and their contents evaporated under nitrogen. The dried residues were reconstituted in 300 µl of acetonitrile/50-mM ammonium acetate (pH 4.7) and a 100 µl aliquot injected onto the high-performance liquid chromatography. BMS-214662 was separated from endogenous plasma interference using a 4.6 x 150 mm C-18 column with a mobile phase containing acetonitrile/50 mM ammonium acetate (pH 4.7), and BMS-214662 was detected by its UV absorbance at a wavelength of 305 nm.
Blood samples for measurement of cisplatin concentrations were obtained in 4.5 ml heparinized glass tubes taken before infusion; at 2 h after the start of the infusion; at the end of the 4-h cisplatin infusion; and 0.5, 1, 2, 4, and 20 h after the end of the infusion. Immediately after sampling plasma was separated by centrifugation at 3000 x g for 10 min. Next, 500-µl aliquots of the plasma supernatant were added to 1-ml of ice-cold (–20°C) ethanol. After mixing on a vortex-mixer for 10 s, the ethanolic samples were stored until the day of analysis of unbound cisplatin. The remaining plasma was stored for determination of total cisplatin. Urine samples for cisplatin PK analysis were collected before the cisplatin infusion and 0–4, 4–8, 8–12, and 12–24 h after the start of the cisplatin infusion.
For measurement of unbound cisplatin, the ethanolic supernatant was collected by centrifugation of the samples at 23,000 x g for 5 min, which was subsequently transferred to a clean vial. A volume of 600 µl was evaporated to dryness under nitrogen at 60°C, and the residue reconstituted in 200 µl (or 600 µl in the case the concentrations were higher than the highest standard of the calibration curve) water containing 0.2% (v/v) Triton X-100 and 0.06% (w/v) cesium chloride by vigorous mixing. A volume of 20 µl, in duplicate, was eventually injected onto the graphite furnace of the atomic absorption spectrophotometer. For determination of total cisplatin concentrations, a 100-µl volume of plasma was added to 900 µl water containing 0.2% (v/v) Triton X-100 and 0.06% (w/v) cesium chloride. Of this solution, a volume of 20 µl, in duplicate, was injected into the atomic absorption spectrophotometer. Samples were analyzed on a Perkin-Elmer Model 4110 ZL spectrometer with Zeeman-background correction using peak area signal measurements at a wavelength of 265.9 nm and a slid width of 0.7 nm.
The area under the plasma concentration time curve (AUC) of total cisplatin was calculated to the last sampling time point (i.e., 20 h after the end of infusion), by the linear trapezoid method, using the software package Siphar v4.0 (SIMED, Creteil, France). The AUC of unbound cisplatin was calculated to the last sampling time point with detectable drug levels by the linear trapezoid method and extended to infinity. The clearances of total and unbound cisplatin were calculated by dividing the dose administered (expressed in mg/m2 cisplatin) by the observed AUCs. The terminal disposition half-life [T1/2(z)] of unbound cisplatin was calculated as ln2/k, where k is the terminal elimination rate constant (expressed in h–1).
Cisplatin PK parameters are reported as mean values ± SD. Differences in PK parameters of cisplatin between the different dosing groups of BMS-214662 were evaluated statistically using one way of analysis (ANOVA), whereas differences between the two sites were evaluated by two-tailed Student’s t tests, using the software package SPSS for Windows (version 9.0). Probability values of <0.05 were regarded as statistically significant.
The PK parameters AUC, clearance, apparent volume of distribution at steady state, and the T1/2(z) of total BMS-214662 were calculated using noncompartmental methods by the PKMENU application using the Statistical Analysis System (version 6.12; SAS, Cary, NC).
PD.
As a surrogate PD end point of activity of BMS-214662, the inhibition of constitutive FT activity in PBMCs was determined in 22 of the patients during the first cycle of treatment only. Blood samples were collected into Benton-Dixon CPT Vacutainer tubes before treatment with BMS-214662, at the end of the infusion, and at 5 and 23 h after completion of the infusion. The tubes were centrifuged for 30 min at 1700 x g and 20°C within 15 min of collection. The PBMCs were transferred to separate polypropylene tubes and washed twice with 10 ml of ice-cold PBS. After each washing, cells were separated by centrifugation for 10 min. After the second washing, the PBMC pellets were stored at –70 to –80°C. PBMC preparations were lysed, and the FT activity in the cellular extracts determined using exogenous [3H]farnesylpyrophosphate and H-Ras substrates. FT activity was normalized by cellular protein concentrations. FT activity was plotted as a function of time. In addition, FT activity (measured as percentage of FT activity from baseline) was assessed as a function of BMS-214662 plasma concentration using an inhibitory Sigmoid Emax Model (Pharsight Inc.) according to the following relationship: E = Emax [1-(Cn)/Cn + EC50n)], where E is the effect, measured as the percentage of reduction in FT activity from the predose level, Emax is the maximal effect at a concentration (C) of BMS- 214662, EC50 is the plasma concentration of BMS-214662 needed to reduce the maximal effect by 50%, and n is the Hill coefficient of the curve.
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RESULTS |
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. Patient characteristics at baseline are summarized in Table 2
. Tumor types included cancer of the pancreas (6 patients), of unknown primary origin (4)
, head and neck (4)
, colon (3)
, ampulla (2)
, stomach (2)
, and miscellaneous (8)
. Fifteen patients had received at least one previous chemotherapy regimen for advanced disease including 6 patients who had been treated previously with cisplatin or carboplatin. The median number of cycles administered of both BMS-214662 and cisplatin in combination was 2. The dose of BMS-214662 was escalated from 126 mg/m2 to 225 mg/m2 in successive cohorts. Following on from this, an additional 3 patients were entered at the 168 mg/m2 dose level. Finally, 11 patients were treated at the intermediate dose of 200 mg/m2.
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4
5
. DLTs were observed in 4 of 9 patients enrolled at the BMS-214662 225 mg/m2 dose level. This dose cohort was expanded after the treatment of the first cohort of 3 patients rather than escalating the dose of BMS-214662 further, based on preliminary information that was available at that time from studies of BMS-214662 as a single agent. DLTs consisted of transient grade 3 elevation of hepatic transaminases (1 patient), grade 3 nausea (1)
, grade 3 diarrhea with grade 4 hepatic transaminase elevation (1)
with recovery to baseline occurring after 6 days, and grade 3 diarrhea, vomiting, and renal failure (1)
. A dose of 225 mg/m2 of BMS-214662 in combination with 75 mg/m2 cisplatin over 4 h was, therefore, the maximum administered dose. Consequently, an additional 3 patients were entered at the next lower dose level of 168 mg/m2 (for a total of 6 patients at this dose level) with no DLTs being observed. The dose of BMS-214662 was escalated subsequently to an intermediate dose of 200 mg/m2. Two of 11 patients treated at this dose level experienced DLTs with one transient grade 4 hepatic transaminase elevation (resolving to baseline after 4 days) and one transient grade 3 elevation of creatinine (resolving to grade 2 after 24 h). A dose of 200 mg/m2 BMS-214662 administered 3-weekly as a 1-h infusion in combination with 75 mg/m2 cisplatin as a 4-h infusion given 3-weekly was defined as the MTD and the recommended dose for subsequent Phase II studies.
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3 neutropenia with temperature 38.5°C, occurred. There was no apparent cumulative toxicity, and there were no deaths due to drug-related toxicity.
Dose Modifications and Delays.
Chemotherapy was delayed for >3 days in 19 cycles in 12 patients due to inadequate recovery of the neutrophil count in 10 cycles, inadequate recovery of the platelet count in 1 cycle, and for other reasons in 8 cycles (patient request, 3 cycles; delayed recovery of nonhematological toxicities, 3 cycles; and administrative reasons, 2 cycles). Chemotherapy was discontinued due to toxicity in 5 patients. For 3 patients, this was due to a single toxicity: renal failure (1 patient), electrocardiogram change (T-wave inversion;1), and persistent leukopenia and neutropenia for at least 2 weeks (1)
. For the other 2 patients, chemotherapy was discontinued due to multiple toxicities: diarrhea, vomiting, raised creatinine and infection in 1 patient; and sensory neuropathy, nausea, and vomiting in the other. The dose of BMS-214662 was reduced by one dose level from 225 mg/m2 to 168 mg/m2 due to DLT in 2 patients after 1 cycle of treatment. The dose of BMS-214662 was reduced from 200 mg/m2 to 168 mg/m2 in 1 patient after 1 cycle. Cisplatin was discontinued in 2 patients due to decreased creatinine clearance.
Objective Response and Survival.
Twenty-three patients received at least 2 cycles of treatment and were evaluable for assessment of antitumor activity, of which all had measurable or evaluable disease at baseline. Six patients received only 1 cycle of chemotherapy and were withdrawn due to toxicity (2 patients), rapid clinical deterioration in keeping with disease progression (1)
, withdrawal of consent (1)
, and physician decision due to inadequate venous access and recurrent infection (2)
. There were no objective responses. Disease stabilization for at least 2 cycles was observed in 15 patients. Disease stabilization was observed for at least 4 cycles in 7 patients with cancer of the bladder, head and neck, ampulla, esophagus, stomach, mesothelioma, and bronchoalveolar cancer. Four patients with cancer of the bladder, stomach, mesothelioma, and bronchoalveolar cancer had stable disease on completion of 6 cycles of treatment.
PK Analysis.
Blood samples for PK analysis of BMS-214662 were available for 27 patients including 8 of the patients at the recommended dose level of 200 mg/m2 (Table 6)
. Of the 27 patients from whom samples were obtained for PK analysis of cisplatin in plasma and urine, all but 1 were evaluable for total cisplatin PK analysis in plasma, and 23 were evaluable for urine analysis. A total of 16 patients also had samples collected for the analysis of unbound cisplatin, of whom 15 were evaluable. The PK analysis of cisplatin are summarized in Table 7
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. The level of activity generally returned to control levels within 24 h. The percentage of FT activity with increasing BMS-214662 concentration is shown in Fig. 2
. On the basis of fitting the results to the inverse sigmoid model, the estimated Emax value was 89.4%, the EC50 was 127 ng/ml, and the n was 0.24.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The PK studies showed that the clearance of unbound cisplatin seems dependent on the dose of BMS-214662 (P = 0.006, ANOVA), with higher clearance of unbound cisplatin at higher doses of BMS-214662. The mechanism behind this phenomenon might be related to higher protein binding of cisplatin with higher doses of BMS-214662. At the highest dose of BMS- 214662, no interaction with the PK of cisplatin is observed. However, this study was not designed to evaluate the potential interaction of BMS-214662 on the clearance of cisplatin. Nevertheless, the urine excretion of cisplatin is dependent on the dose of BMS-214662 (P = 0.028, ANOVA), with lower excretion at higher doses of BMS-214662, and this would be in agreement with the above hypothesis that there may be an interaction at the level of protein binding, because only the unbound fraction of cisplatin can be excreted by the kidneys (i.e., lower unbound fractions results in lower urinary excretion).
The AUC of BMS-214662 increased in a ratio of 1:1.5:2.1:3.7 in a dose ratio of 1:1.3:1.6:1.8. The greater than proportional increase in the exposure at the highest dose studied (225 mg/m2) may in part be due to the wide variability in the AUC values (45% coefficient of variation). If this study is compared with single agent BMS-214662 PK studies, cisplatin does not appear to have an effect on the disposition of BMS-214662 (31) . In summary, at the recommended dose of BMS-214662, a PK interaction between BMS-214662 and cisplatin is not apparent. However, because the number of patients studied per dose cohort is small, and different hydration schedules were used for cisplatin administration, a relevant interaction cannot be completely excluded.
PD studies demonstrate a precipitous drop in FT activity in the PBMCs after BMS-214662 infusion that appears to be dose dependent, with FT activity returning to control levels within 24 h. The Emax inverse sigmoid model gave an EC50 of 127 ng/ml.
However, with a plasma protein binding of drug of 
99%, this value is similar to the IC50 value for FT in in vitro assays, suggesting that there is a close correlation between the in vitro and in vivo values for FT IC50 with BMS-214662. These PD studies, taken with the short elimination half-life of BMS-214662, would suggest that a single i.v. infusion of this agent may not be the optimal schedule to produce a sustained PD effect. However, it is not clear what is the duration of the biological effect of FT inhibition within tumors, nor what duration of biological effect is required for optimal potential synergy with cisplatin. Studies of single-agent BMS-214662 administered weekly as a 24-h infusion have suggested that schedules of administration of BMS-214662 that provide sustained plasma exposure and FT inhibition may be required for optimal pharmacological activity (32
, 33)
.
An important initial observation with the FTIs was that many of their cellular effects appeared to be cytostatic rather than cytotoxic (34) , and thus potentially antagonizing the effects of classical cytotoxic drugs. In vitro studies with BMS-214662, however, demonstrated that it is one of the most potent of the FTIs in inducing apoptosis, suggesting that it could potentially be combined with classical cytotoxic agents to give an additive or synergistic effect. There were no objective responses observed in this study. However, disease stabilization was observed in 15 patients with 4 patients having disease stabilization on completion of 6 cycles of treatment.
This study defined a dose of 200 mg/m2 BMS-214662 administered as a 1-h infusion in combination with 75 mg/m2 cisplatin over 4 h as the recommended dose. However, the optimal dose and schedule for FTIs in patients with advanced cancer may not be the MTD as determined in Phase I studies using standard clinical toxicity criteria. It is likely that a biological threshold exists such that additionally increasing the dose of drug does not lead to further gain. Consequently, future studies should incorporate metabolic tumor imaging and the measurement of robust surrogate markers of intratumoral FT activity to determine the optimal biologically effective dose and schedule.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: T. R. Jeffrey Evans, Cancer Research UK, Department of Medical Oncology, Beatson Laboratories, Garscube Estate, Switchback Road, Glasgow, G61 1BD, United Kingdom. Phone: 44-141-211-1741; Fax: 44-141-330-4127; E-mail: J.Evans{at}beatson.gla.ac.uk
Received 10/ 1/03; revised 11/20/03; accepted 12/10/03.
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, 126 mg/m2 (n = 3); 
, 168 mg/m2 (n = 5); 
, 200 mg/m2 (n = 7); 
, 225 mg/m2 (n = 7); bars, ±SD.