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Originally published as JCO Early Release 10.1200/JCO.2005.09.005 on February 22 2005

Journal of Clinical Oncology, Vol 23, No 12 (April 20), 2005: pp. 2805-2812
© 2005 American Society of Clinical Oncology.
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Phase I Study of BMS-214662, a Farnesyl Transferase Inhibitor in Patients With Acute Leukemias and High-Risk Myelodysplastic Syndromes

Jorge Cortes, Stefan Faderl, Elihu Estey, Razelle Kurzrock, Deborah Thomas, Miloslav Beran, Guillermo Garcia-Manero, Alessandra Ferrajoli, Francis Giles, Charles Koller, Susan O'Brien, John Wright, Stephen A. Bai, Hagop Kantarjian

From the Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and Bristol-Myers Squibb, Princeton, NJ

Address reprint requests to Jorge Cortes, MD, The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030; e-mail: jcortes{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: To investigate the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of BMS-214662, a farnesyl transferase (FTase) inhibitor, in patients with acute leukemias and high-risk myelodysplastic syndromes (MDS).

PATIENTS AND METHODS: Patients with relapsed or refractory acute leukemias or MDS, or previously untreated but poor candidates for chemotherapy, were included in this phase I study with a 3 + 3 dose escalation design. BMS-214662 was administered as a 1-hour bolus once weekly at doses of 42 to 157 mg/m2. Once the MTD was identified, the schedule was changed to a 24-hour continuous infusion once weekly (starting dose, 300 mg/m2).

RESULTS: Thirty patients were treated at a dose of 42 (n = 1), 56 (n = 3), 84 (n = 3), 118 (n = 13), 157 (n = 6) or 300 mg/m2 (n = 4). DLT occurred in 3 patients at 157 mg/m2, including nausea, vomiting, diarrhea, hypokalemia and cardiovascular problems. No DLT occurred with 24-hour continuous infusion. MTD with a 1-hour infusion was 118 mg/m2, with no MTD identified with the 24-hour infusion. Plasma concentrations of BMS-214662 correlated with the dose. Inhibition of FTase activity of approximately 60% occurred after the infusion with recovery to near baseline after 24 hours. Five patients had evidence of antileukemia activity, including two with complete remission with incomplete platelet recovery, one with hematologic improvement, and two with morphologic leukemia-free state.

CONCLUSION: BMS-214662 is well tolerated at doses of up to 118 mg/m2 as a 1-hour infusion. The toxicity profile and efficacy may be improved with prolonged exposure. Further investigation of this agent in leukemia is warranted.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Farnesyl transferase (FTase) is a cytoplasmic protein that catalyzes a prenylation process characterized by the transfer of a 15-carbon farnesyl group from farnesyl pyrophosphate (FPP) to a cysteine amino acid in the carboxy end of certain proteins.1 The carboxy-terminus region of these proteins is known as the CAAX box. This modification facilitates the attachment of farnesylated proteins to the cell membrane, which is critical for the functional activation of these proteins. Multiple intracellular protein substrates of FTase are known, and they have a variety of functions. These include Ras, involved in cell proliferation and differentiation; RhoB, involved in endocytosis, transcriptional regulation, and apoptosis2,3; CENP-E and -F, involved in cell cycle regulation and centromere binding4; HDJ2, a molecular chaperone; lamin A and B, structural proteins of the nuclear membrane; rhodopsin, a visual protein; and many others.1,5 FTase inhibitors (FTIs) were first developed as a means of inhibiting the Ras family of proteins, which are activated through mutations or other mechanisms in a wide variety of malignancies.6-8

FTIs can be classified into four categories depending on their mechanism of inhibition of the target enzyme.8,9 These include competition with the FPP group using synthetic analogs; competition with the target protein or its CAAX binding site using peptides that mimic this site (ie, peptidomimetics); competition with both FPP and the CAAX box using analogs that combine features of both the FPP analogs and peptidomimetics; and competition with the CAAX box of the protein using nonpeptide analogs, usually small molecules (ie, nonpeptidomimetics).8,9 In preclinical models, FTIs have demonstrated significant antiproliferative, antiangiogenic, and proapoptotic effects in a broad range of tumor cell types.10-13

FTIs were initially investigated in hematologic malignancies because of the role of Ras in malignant transformation.5,7,14 In acute myeloid leukemia, RAS mutations occur in 20% to 40% of patients, whereas in acute lymphoblastic leukemia mutations have been reported in 5% to 20%.7,14 In chronic myelomonocytic leukemia, mutations can occur in 50% to 70% of patients. In addition, Ras can be activated by alternative mechanisms such as Bcr-Abl in chronic myeloid leukemia, and PDGFRß-TEL in chronic myelomonocytic leukemia. However, the prognostic significance of Ras mutations in acute leukemias is controversial.

BMS-214662 is an imidazole-containing nonpeptidomimetic FTI that has demonstrated significant cytotoxicity against several cell lines of diverse histology.15 We conducted a phase I study of BMS-214662 to determine the dose-limiting toxicity and maximum-tolerated dose in patients with refractory or relapsed high-risk myelodysplastic syndromes or acute leukemias.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Eligibility
Patients with any of the following diagnoses were eligible for this study: 1) acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or high risk myelodysplastic syndrome (MDS; defined as refractory anemia with excess of blasts [RAEB] or RAEB in transformation [RAEBT]). Disease was required to meet one of the following conditions: refractory to induction chemotherapy; in relapse with a first remission duration of less than 1 year; in relapse with a first remission duration of more than 1 year, but failed at least one prior salvage attempt; in second or later relapse; previously untreated in elderly patients (older than age 60) who refused or were not eligible for standard induction chemotherapy; or chronic myelogenous leukemia (CML) in blast phase regardless of treatment history. Other eligibility criteria included: ECOG performance status ≤ 2; bilirubin less than 1.5 mg/mL; creatinine ≤ 1.5 mg/mL or creatinine clearance ≥ 60 mL/h; no chemotherapy for at least 4 weeks before enrollment; and recovery from the toxic effects of any prior therapy, although the use of hydroxyurea was permitted up to 24 hours before the start of BMS-214662 if patients had rapidly proliferative disease. Patients with prolonged QTc were excluded. The protocol was reviewed and approved by the institutional review board, and all patients signed and approved informed consent.

Drug Administration
BMS-214662 was provided by the Division of Cancer Treatment and Diagnosis, National Cancer Institute (Bethesda, MD). Vials containing BMS-214662 at a concentration of 20 mg/mL were diluted with 5% dextrose injection, UPS 5% dextrose (D5W) to concentrations between 0.2 mg/mL and 15 mg/mL, as the free base, before intravenous administration. BMS-214662 was administered intravenously over one hour once weekly. The original trial design was with a starting dose of 42 mg/m2 to be administered once weekly for 4 weeks every 6 weeks. After one patient had been treated at this dose, additional information became available from other phase I studies in solid tumors using BMS-214662 weekly without interruptions for over 24 weeks at doses as high as 118 mg/m2 without dose-limiting toxicity. Thus, the schedule was changed to once weekly without interruptions, provided there was no evidence of grade ≥ 3 nonhematologic toxicity or life-threatening infection or hemorrhage, and the starting dose was changed to 56 mg/m2. One cycle was defined as 4 weeks of therapy. After the maximum-tolerated dose (MTD) was identified, the schedule was changed to a 24-hour continuous intravenous infusion administered once weekly. The rationale for the continuous administration was based on both in vitro and in vivo preclinical data that indicated that prolonging the duration of exposure enhanced the therapeutic index of BMS-214662. In addition, a phase I study in patients with solid tumors used the 24-hour infusion with doses escalated to 300 mg/m2 without dose-limiting toxicity. Patients were thus treated with this schedule at a dose of 300 mg/m2. Before an MTD could be established with this schedule, the study had to be ended because of drug availability.

Toxicities were evaluated using the revised National Cancer Institute Common Toxicity Criteria version 2.0. Dose-limiting toxicity (DLT) was defined as any adverse event ≥ grade 3. Specifically, nonhematologic DLT was defined as any grade 3 or 4 toxicity. Nausea and vomiting were considered DLT only if they were not responsive to antiemetic therapy. Hematologic DLT was defined as pancytopenia with a hypocellular bone marrow and no marrow blasts lasting for 6 weeks or more after the start of a course.

Study Design
A minimum of three patients were enrolled at each dose level. If no instances of DLT were observed in three patients treated at a given dose level after the last patient treated had been observed for a minimum of 4 weeks, dose escalation was indicated in the next cohort of patients. If DLT occurred in one of three patients treated at a given dose, three more patients were to be entered at the same dose level. If toxicity ≥ grade 3 developed in two of six patients, this dose was considered to exceed the MTD. MTD was thus defined as the dose resulting in DLT in one or more of six patients. Once the MTD was defined, an expanded cohort of patients was treated at this dose to define toxicity more precisely. Patients who showed no evidence of life-threatening infection or hemorrhage, or nonhematologic toxicity ≥ grade 3 (vomiting included) could receive a second course regardless of initial response. If patients had experienced < grade 2 toxicity with the previous cycle, the dose could be escalated by one dose level. If grade 2 toxicity was observed with the previous cycle, the patient could receive another cycle at the same dose after complete resolution of toxicity. Patients who experienced grade 3 or 4 toxicity and objective response (ie, complete or partial remission, or hematologic improvement), could receive another cycle of therapy with a one dose level–reduction after complete resolution of the adverse effects.

Pretreatment and Follow-Up Studies
Pretreatment evaluation included a history and physical exam; assessment of signs, symptoms, and performance status; CBC, platelet count, differential, and blood chemistry (including creatinine, total bilirubin, alkaline phosphatase, and ALT); and bone marrow aspiration. During the study, CBC, platelet count, and differential were performed two to three times weekly until recovery of counts. Blood chemistry was done weekly, with creatinine, total bilirubin, alkaline phosphatase, and ALT re-evaluated 24 to 48 hours after each dose for the first 4 weeks. Patients who had grade 2 elevations (bilirubin to > 1.5-3.0 x upper limit of normal [ULN], alkaline phosphatase and ALT to > 2.5 to 5 x ULN), had these measures repeated daily until resolution to grade 1, and then every 2 to 4 weeks. Marrow aspiration was performed on day 28 and every 7 to 14 days thereafter as clinically indicated until remission, after which it was planned every one to three courses.

Evaluation of response was performed every 4 weeks. Response criteria were as defined by the International Working Group (IWG) for AML16 and MDS.17 Briefly, complete response (CR) was defined as platelet count > 100 x 109/L, neutrophil count > 1 x 109/L, and a cellular marrow with blasts < 5%. Morphologic CR with incomplete blood count recovery (CRi) was considered when all the criteria for CR were met except for residual neutropenia (< 1 x109 cells/L) or thrombocytopenia (< 100 x 109 cells/L). Morphologic leukemia-free state was defined as < 5% blasts in an assessable sample with at least 200 nucleated cells counted without neutrophils and platelet recovery.16 Hematologic improvement was defined as an increase in platelet count of > 30 x 109 cells/L (if baseline < 100 x109/L), or in absolute neutrophil count (ANC) of at least 100% or > 0.5 x 109 cells/L (if initial ANC < 1.5 x109/L), and/or a hemoglobin improvement of > 2 g/dL (if pretreatment hemoglobin < 11 g/dL).17 Progressive disease was defined as an increase by ≥ 100% of the circulating blast count and to a level > 10 x 109/L. Any disease state not meeting the criteria for any of these three response categories was considered stable disease. Treatment was stopped if any of the following events occurred: disease progression, intercurrent illness that prevented further administration of treatment, unacceptable toxicity, receipt of a bone marrow transplant or other treatment that might prolong survival, or patient withdrawal from the study.

Pharmacokinetics of BMS-214662
The following pharmacokinetic parameters were evaluated in patients having sufficient data to analyze: area under the concentration-time curve (AUCinf), systemic plasma clearance (Cl), apparent volume of distribution at steady state (Vss) and the elimination half-life (t1/2) were calculated using noncompartmental methods by the PKMENU application using the Statistical Analysis System version 6.12 (SAS, Cary, NC).

FTase Inhibition
As a surrogate pharmacodynamic end point of activity of BMS-214662 in patients, the inhibition of constitutive FTase activity in peripheral blood mononuclear cells (PMN) was determined during the first cycle of treatment only. Blood samples were collected into a Benton-Dixon (Franklin Lakes, NJ) CPT Vacutainer tubes before treatment with BMS-214662, at the end of the infusion and at 5 and 23 hours following completion of the infusion. The tubes were centrifuged for 30 minutes at 1,700 x g and 20°C within 15 minutes of collection. The PMNs were transferred to separate polypropylene tubes and washed twice with 10 mL of ice-cold phosphate-buffered saline. Following each washing, cells were separated by centrifugation for 10 minutes. Following the second washing, the PMN pellets were stored at –70 to –80°C. PMN preparations were lysed, and the FTase activity in the cellular extracts determined using exogenous [3H]farnesylpyrophosphate and H-Ras substrates. FTase activity was normalized by cellular protein concentrations.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patient Characteristics
Thirty patients with AML (n = 19), ALL (n = 3), or high-risk MDS (n = 8) were treated (Table 1). Their median age was 53 years (range, 22 to 96 years). Fifteen patients had never achieved a CR, and the median duration of the first CR for the other 14 patients was 22 weeks (range, 4 to 182 weeks). One patient (age 96 years) had never received chemotherapy for AML. Seventeen patients had failed one to five prior salvage attempts with other treatment regimens (median, one prior salvage attempt).


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  		Table 1. Patient Characteristics for 30 Patients Treated With BMS-214662

 
Dose Escalation
One patient was treated at the initial dose schedule of 42 mg/m2 given as a 1-hour infusion weekly for 4 weeks every 6 weeks. After the schedule was changed to weekly without interruption, three patients each were treated at 56 mg/m2 and 84 mg/m2, 13 patients received 118 mg/m2, and six received 157 mg/m2. Four patients were treated at 300 mg/m2 given as a 24-hour continuous infusion. Five patients received more than one cycle of therapy, including three who received two cycles, and one each that received three and four cycles, respectively. Two of these patients had their dose escalated in the second course: one had received 42 mg/m2 on the first cycle and received 56 mg/m2 in the second cycle; the other patient received 300 mg/m2 in the first cycle (24-hour continuous infusion) and 390 mg/m2 in the second cycle. Three other patients received 118 mg/m2 in their first and subsequent cycles, including the two patients receiving more than two cycles.

Toxicity
Patients were considered assessable for toxicity if they received at least three doses of BMS-214662, unless therapy was discontinued because of toxicity. Twenty-five patients were assessable for toxicity. The toxicity for all patients is presented in Table 2. The one patient treated at a dose of 42 mg/m2 had tremors and elevation of creatinine, both grade 1. The most common adverse events were nausea in 15 patients, diarrhea in 10, fatigue in nine, and drug fever in five. No DLT was observed with 1-hour administration at 56, 84, or 118 mg/m2, or with 24-hour continuous infusion at 300 mg/m2.


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  		Table 2. Adverse Events During the First Cycle of Therapy With BMS-214662

 
Three patients treated at a dose of 156 mg/m2 given as a 1-hour infusion experienced DLT. One patient with ALL had grade 3 diarrhea (together with grade 2 nausea), causing dehydration and a syncopal episode after one dose of BMS-214662. The symptoms resolved with medical management, and the patient received one more dose at 118 mg/m2. This was better tolerated, although again causing grade 2 nausea. The patient then decided to receive no further therapy and to seek supportive care only. The second patient developed grade 3 nausea, vomiting and hypokalemia requiring intravenous fluids and electrolyte supplementation after the second dose of BMS-214662. The symptoms resolved rapidly, but the patient was taken off study because of rapidly progressive disease. The third patient developed grade 2 nausea, vomiting, diarrhea and drug fever immediately after the first dose of BMS-214662. This was followed by palpitations; an ECG demonstrated grade 3 prolonged QTc and supraventricular tachycardia. This patient had a history of palpitations and increased heart rate with prior chemotherapy at another institution, but there was no documentation of QTc status then. The rhythm reverted spontaneously to normal sinus, and the patient continued therapy at a reduced dose of 118 mg/m2 without recurrence of the adverse events.

Pharmacokinetics
The results of pharmacokinetic analysis in assessable patients receiving BMS-214662 as a 1-hour infusion are described in Table 3. Of the 30 patients enrolled in the study, adequate pharmacokinetics were available in 12.


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  		Table 3. Pharmacokinetics of Escalating Doses of BMS-214662 Administered As a 1-Hour Infusion

 
The exposure of BMS-214662 was near dose proportional in these patients (Fig 1). The clearance at the three lower doses was slightly higher than that seen in other studies with BMS-214662. The clearance of BMS-214662 at the 118 mg/m2 dose level was, however, as expected. The Vss of BMS-214662 in the two lower dose cohorts was slightly higher than that of the higher two dose cohorts of this study and that seen in other studies. The t1/2 of BMS-214662 was short (ie, < 2 hours), largely due to the relatively small Vss of BMS-214662.



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  		Fig 1. BMS-214662 Plasma concentration-time profiles following a 1-hour infusion of escalating doses—linear scale.

 
Because of the large intersubject variability in the 24-hour infusion study, and to the fact that plasma sampling occurred only up to 24 hours, an adequate pharmacokinetic evaluation was not possible for this cohort. The mean Cmax was 2,681 ng/mL (standard deviation [SD] ± 3,745) reached at the end of the infusion. The AUC (0 to 24 hours) was 25,620 ng/mL·h (SD ± 25,881).

FTase Inhibition
There was significant inhibition of FTase activity with all doses (Fig 2); this was particularly assessable with 118 mg/m2 (five patients). There was a 60% inhibition of FTase activity at the end of infusion. However, in all cases, complete recovery of FTase activity occurred 24 hours after the infusion.



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  		Fig 2. Inhibition of farnesyl transferase in peripheral blood mononuclear cells during therapy with BMS-214662 in (A) patients treated with 1-hour infusion and (B) patients treated with 24-hour continuous infusion.

 
Efficacy
There was clinical evidence of antileukemia activity in five patients (17%) based on the criteria by the IWG.16,17 Two patients achieved a CRi (incomplete platelet recovery). One patient had AML with complex cytogenetic abnormalities, including deletions of chromosomes 5 and 7, and had achieved a CR with prior chemotherapy including high-dose cytarabine (Ara-C) that lasted 14 weeks. On relapse, she became pancytopenic and the bone marrow was hypercellular, with an increase number of blasts (7%) and recurrence of the cytogenetic abnormalities. After the first cycle of BMS-214662, the blast percent in the bone marrow decreased to 4%. After the second cycle, the bone marrow blast percentage was 3% with a sustained neutrophil recovery to > 2 x 109/L and disappearance of peripheral blood blasts. There was no cytogenetic response. The patient then underwent an allogeneic bone marrow transplantation and died of transplant-related complications. The patient was red cell transfusion–independent by the time she started her conditioning regimen. The second patient had failed induction therapy with fludarabine, Ara-C and gemtuzumab ozogamicin. Before start of BMS-214662, he had 14% blasts in the bone marrow and persistence of deletion 20q. After one cycle of therapy with BMS-214662, the blast percentage in the bone marrow decreased to 0%, with recovery of platelet count to 97 x 109/L and neutrophils to 3.0 x 109/L. There was improvement in the cytogenetic analysis, with only one of 20 metaphases showing deletion 20q. The patient received three cycles of BMS-214662. Therapy was discontinued after 5 months because of recurrent thrombocytopenia and recurrence of cytogenetic abnormalities in 40% of the metaphases, although still with only 1% blasts in the bone marrow, and normal neutrophils. The patient was then offered consolidation with standard chemotherapy.

Two other patients had morphologic leukemia-free state by days 21 to 28 from the start of therapy (pretreatment bone marrow blast count, 11% and 15%, respectively) with incomplete recovery of platelets and/or neutrophils. One patient had major hematologic improvement in platelets and neutrophils. This patient had RAEB with 10% blasts and had not responded to prior therapy with interleukin-11 and erythropoietin, and later with 9-nitrocamptothecin. He was pancytopenic with platelets 9 x 109/L and ANC 0.045 x 109/L. There were minimal changes in his peripheral blood counts after the first cycle given at 118 mg/m2, with the platelets stable at approximately 20 x 109/L. After the second cycle (same dose), he showed an increase in platelet count that reached a peak of 113 x 109/L and neutrophils 0.589 x 109/L. These decreased again with the next cycle of therapy, but recovered to a peak of 98 x 109/L and 1.7 x 109/L, respectively. He had no further response after the next cycle and was removed from the study. There was no change in the percentage of bone marrow blasts throughout his therapy. One additional patient had a > 50% decrease in bone marrow blast count (from 73% to 34%), but did not qualify for any response category according to the IWG.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
FTIs are a new class of antineoplastic agents that are undergoing intensive clinical investigation. Within this class, nonpeptidomimetic agents have been most extensively investigated in the clinic. BMS-214662 is a nonpeptidomimetic FTI with significant activity against several tumor lines in preclinical models.15,18,19 BMS-21462 has a potent cytotoxic effect in vitro and in human tumor xenografts of diverse histologic sources.15 This is in contrast to other FTIs, which are mostly cytostatic and produce tumor regression but no cures in animal tumor models,12,13,20,21 although some recent evidence suggests that they also may induce apoptosis in some tumor models.22 Here, we present the results of the first phase I study of this agent in patients with refractory or relapsed acute leukemias or high-risk MDS.

For this trial, we selected initially a bolus administration (1-hour infusion) given once weekly. With this schedule, the MTD was 118 mg/m2 with no ≥ grade 3 toxicity observed among 13 patients treated. Dose limiting toxicities observed at a dose of 156 mg/m2 were gastrointestinal (nausea, vomiting, and/or diarrhea) and cardiac (QTc prolongation). Gastrointestinal toxicity was dose limiting for BMS-214662 in patients with solid tumors, particularly when it was administered orally.23,24 Gastrointestinal toxicity was also dose limiting for other nonpeptidomimetic FTIs, such as lonafarnib, which are administered orally.25,26 QTc prolongation was a concern for FTIs in preclinical models. However, it has been reported rarely with this and other members of this family of drugs.9 The one episode that occurred in this trial (at a dose of 156 mg/m2) was transient and self-limited. A recent phase I study of BMS-214662 in patients with advanced solid tumors used a 1-hour infusion every 21 days. Transient grade 3 transaminitis was observed frequently among patients receiving 200 to 225 mg/m2. We did not identify transaminitis in any of our patients treated with 1-hour infusions at a maximum dose of 156 mg/m2. The MTD identified in our study (118 mg/m2) is lower than the one reported by Ryan et al.27 This is likely the result of a more frequent administration in our trial (ie, once weekly) compared with once every 21 days in that study. Studies with other FTIs have also shown that a more frequent or prolonged course of administration may lead to increased toxicity. Tipifarnib administered twice daily for 4 weeks every 6 weeks was associated with higher toxicity at lower doses28,29 than when given twice daily for 3 weeks every 28 days.30,31

After the MTD was identified, the study was modified to administer BMS-214662 as a continuous infusion over 24 hours. In vitro and in vivo preclinical data indicated that prolonging the duration of exposure enhances the therapeutic index of BMS-214662. Induction of apoptosis in HCT-116 human colon cell lines was not noticeable after 6 hours of exposure to BMS-214662 but it was readily observed after a 24-hour exposure to concentrations as little as 0.37 µmol/L15. A phase I study in patients with advanced solid tumors reported no dose-limiting toxicities at doses up to 209 mg/m2 administered weekly as a continuous infusion, with dose escalation proceeding to 278 mg/m2.32 In the trial reported here, four patients were treated at 300 mg/m2 given as a continuous infusion over 24 hours. This dose is nearly double the dose that resulted in dose-limiting toxicities in three of six patients using the 1-hour infusion in our study. The 24-hour continuous infusion schedule was well tolerated, with no grade 3 toxicity. Unfortunately the study could not be continued because of drug availability. It appears that a continuous infusion schedule may indeed be better tolerated and warrants further exploration.

The plasma pharmacokinetics identified on this study are similar to those previously reported with this agent. The t1/2 is short, approximately 90 minutes, regardless of the dose. The Vss was low and also consistent with previous reports. As expected, the Cmax and the AUC correlate with the dose used. There was significant inhibition of FTase activity at all doses investigated, although with significant variability among patients. The peak effect was seen at the end of the infusion, with nearly 50% of the effect lost after 6 hours, and recovery to baseline activity levels by 24 hours after the infusion in all instances. As mentioned earlier, continuous exposure to BMS-214662 may be more effective.

FTIs have demonstrated significant clinical activity in hematologic malignancies, including AML,25,26,31,33 MDS,34-36 CML,28,37-39 myelofibrosis,28 and multiple myeloma.28,40 In this study, we identified evidence of clinical activity in 20% of patients despite their being heavily pretreated. These included two patients who achieved a CRi and two patients who achieved a morphologic leukemia-free state. These responses were transient, and some of them of minimal clinical significance. It is possible that different schedules may be more effective. More frequent administration of BMS-214662 and continuous infusion schedules may improve the therapeutic index of BMS-214662.15,32 In addition, BMS-214662 has shown synergistic activity in combination with other agents.41 Combinations with cytotoxic agents are being explored in solid tumors24 and should be explored in leukemias. With the available data, it is not clear that there is a clear difference between this and other FTIs in their mechanism of action or clinical potential.

We conclude that BMS-214662 can be administered safely with minimal toxicity at doses of up to 118 mg/m2 when given as a 1-hour bolus infusion. Higher doses can probably be given when administered as a 24-hour continuous infusion. In view of the preclinical data suggesting increased cytotoxicity with prolonged exposure to this agent, this schedule should be investigated further. There was evidence of clinical activity in a population of heavily pretreated patients. Thus, BMS-214662 should be further investigated in hematologic malignancies.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
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: Stephen A. Bai is an employee of 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 the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.


   NOTES
 
Supported in part by grant No. 2057-01 from the Leukemia and Lymphoma Society. J.C. is a Clinical Research Scholar for the Leukemia and Lymphoma Society.

Presented in part at the 43rd annual meeting of the American Society of Hematology, December 2001.

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
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10. Bishop WR, Bond R, Petrin J, et al: Novel tricyclic inhibitors of farnesyl protein transferase: Biochemical characterization and inhibition of Ras modification in transfected Cos cells. J Biol Chem 270:30611-30618, 1995[Abstract/Free Full Text]

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Submitted September 1, 2004; accepted December 16, 2004.




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