Clinical Cancer Research 13, 3623-3629, June 15, 2007. Published Online First May 17, 2007;
doi: 10.1158/1078-0432.CCR-07-0158
© 2007 American Association for Cancer Research
Phase I Trial of Weekly Paclitaxel and BMS-214662 in Patients with Advanced Solid Tumors
Howard H. Bailey1,
Dona B. Alberti1,
James P. Thomas1,
Daniel L. Mulkerin1,
Kimberly A. Binger1,
Marco M. Gottardis2,
Robert E. Martell2 and
George Wilding1
Authors' Affiliations: 1 University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin and 2 Oncology Drug Discovery and Oncology Global Clinical Development, Bristol-Myers Squibb, Princeton, New Jersey
Requests for reprints: Howard H. Bailey, University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, K4/650 CSC, 600 Highland Avenue, Madison, WI 53792. Phone: 608-263-8624; Fax: 608-265-8133; E-mail: hhbailey{at}wisc.edu.
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Abstract
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Purpose: To assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacodynamics, and antitumor activity of continuous weekly-administered paclitaxel and BMS-214662, a novel farnesyl transferase inhibitor.
Experimental Design: Patients were treated every week as tolerated with i.v. paclitaxel (fixed dose, 80 mg/m2/wk) administered over 1 h followed by i.v. BMS-214662 (escalating doses, 80–245 mg/m2/wk) over 1 h starting 30 min after completion of paclitaxel.
Results: Twenty-six patients received 94 courses (one course, 21 days) of study treatment. Two patients received five courses of BMS-214662 as a weekly 24-h infusion (209 mg/m2/wk). The most common toxicities were grade 1 to 2 nausea/vomiting and/or diarrhea. DLTs observed at or near the MTD (200 mg/m2/wk) were grade 4 febrile neutropenia with sepsis occurring on day 2 of course 1 (245 mg/m2/wk), reversible grade 3 to 4 serum transaminase increases on day 2, and grade 3 diarrhea (200 and 245 mg/m2/wk). Objective partial responses were observed in patients with pretreated head and neck, ovarian, and hormone-refractory prostate carcinomas, and leiomyosarcoma. The observed pharmacokinetics of paclitaxel and BMS-214662 imply no interaction between the two. Significant inhibition (>80%) of farnesyl transferase activity in peripheral mononuclear cells was observed at the end of BMS-214662 infusion.
Conclusions: Pretreated patients with advanced malignancies can tolerate weekly paclitaxel and BMS-214662 at doses that achieve objective clinical benefit. Due to multiple DLTs occurring at the expanded MTD, the recommended phase 2 dose and schedule is paclitaxel (80 mg/m2 over 1 h) and BMS-214662 (160 mg/m2 over 1 h) administered weekly.
The systemic treatment of malignancies requires either better optimization of current effective agents or development of novel agents. The current study is an example of both approaches.
In the last decade, novel agents have been directed at oncogenes contributing to varying degrees in the etiology of almost all cancers. An example is targeted agents toward Ras. The most common approach has been targeting the required posttranslational modifications of Ras, specifically farnesylation. Inhibiting farnesyl protein transferase blocks the addition of farnesyl (15 carbon) donor to Ras, impairing anchoring to the inner plasma membrane and blocking signal transduction. Development of inhibitors of farnesyl transferase has focused on malignancies with common mutations in Ras, but limited clinical effectiveness and uncertainty about the actual mechanism of antitumor effects of these inhibitors of farnesyl transferase has slowed clinical development.
BMS-214662 is an imidazole-containing tetrahydrobenzodiazepine, non-thiol, non-peptide small-molecule competitive inhibitor of farnesyl transferase (1). Similar to other inhibitors of farnesyl transferase, it is highly specific for farnesyl transferase compared with geranylgeranyl protein transferase and was a potent growth inhibitor of K-Ras– and N-Ras–transformed cell lines (IC50, <1 µmol/L). Also similar to other inhibitors of farnesyl transferase, BMS-214662 also exhibited anticancer effects against cell lines with and without Ras mutations. Unlike other inhibitors of farnesyl transferase, BMS-214662 in preclinical testing exhibited potent cytotoxicity in vivo and an extensive ability to induce apoptosis even at brief low micromolar concentrations (2). Preclinical testing also observed significant in vitro effectiveness against ovarian, colon, breast, prostate, and squamous carcinomas, and leukemias and schedule independent but cumulatively dose-dependent antitumor effects in vivo (2).
An initial phase I study of BMS-214662 administered i.v. over 1 h every 3 weeks observed primarily reversible elevations in hepatic transaminases, nausea, vomiting, and diarrhea over seven dose levels (36-225 mg/m2; ref. 3). Farnesyl transferase inhibition in peripheral mononuclear cells mirrored plasma concentrations of BMS-214662, which is cleared relatively quickly (mean half-life, 1.5 hours; ref. 3). In an effort to increase the duration of farnesyl transferase inhibition, different schedules of BMS-214662 have also been explored. Preliminary results from a phase I study of BMS-214662 administered weekly observed the maximum tolerated dose (MTD) to be comparable with the once every 3-week schedule, 
200 to 225 mg/m2 (4).
Recent studies have examined the potential of combining inhibitors of farnesyl transferase and other classes of anticancer agents. Studies of various inhibitors of farnesyl transferase have shown synergy in combination with classic cytotoxics (5), tyrosine kinase inhibitors (6), and hormonal agents (7). Of note, preclinical studies have shown a significant, sequence-dependent synergy between antimicrotubular agents, such as paclitaxel, and inhibitors of farnesyl transferase (8, 9). The mechanism of the observed preclinical synergy is uncertain, but for BMS-214662 specifically, it may involve its observed preferential cytotoxicity to nonproliferating tumor cells (10, 11). A phase I study of BMS-214662 and cisplatin administered every 3 weeks observed similar toxicity and MTD of BMS-214662 (200 mg/m2) compared with the single-agent studies (12). These data coupled with the clinical interest in weekly paclitaxel support the testing of weekly paclitaxel and BMS-214662 and provide the rationale for our phase I dose escalation study of weekly paclitaxel and BMS-214662.
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Materials and Methods
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Patient selection. Individuals with advanced and/or metastatic solid tumor (measurable or evaluable) for whom no standard effective therapy was available and who gave informed consent according to institutional and Food and Drug Administration guidelines were eligible, provided that the following criteria were met: adequate bone marrow (absolute neutrophil count, 
1,500 cells/mm3; platelet count, 100,000 cells/mm3); adequate hepatic function (total bilirubin, 
1.5 mg/dL; alanine aminotransferase, 1.5 x the institutional upper limit of normal); and adequate renal function defined as a calculated (Cockcroft-Gault formula) or measured creatinine clearance 50 mL/min. Patients were ineligible under the following conditions: <18 years old; life expectancy <3 months; Eastern Cooperative Oncology Group performance status >1; chemotherapy (6 weeks for nitrosourea, mitomycin C, and carboplatin), radiotherapy, immunotherapy, or hormonal therapy <4 weeks from study entry; lack of adequate birth control or of a negative pregnancy test if a fertile female; any ongoing significant pulmonary or cardiac disease or history of significant cardiac arrhythmia; evidence of prolonged QTc interval on electrocardiogram or taking medications known to prolong the QTc interval; a history of receiving more than three prior cytotoxic chemotherapy regimens or irradiation to >30% of bone marrow containing skeleton; ongoing peripheral neuropathy > grade 1; a prior history of grade 3 cremaphor or taxane hypersensitivity reaction; and inability to discontinue within 7 days of study entry medications known to be substrates of cytochrome P450-3A4 or potentially nephrotoxic medications.
Treatment plan. Pretreatment evaluations done within 14 days (except X-rays and computed tomography scans within 28 days) of starting study therapy included a history and physical exam, complete blood count, serum chemistry panel, electrocardiogram, urinalysis, and serum pregnancy test for fertile women. After initiating study treatment, electrocardiograms were repeated at the end of the infusion and 24-h postinfusion for days 1 and 2 of cycle 1 only. If QTc prolongation (either QTc >500 msec and/or an increase of 60 msec from baseline) was observed, electrocardiograms were repeated hourly until resolution. Complete blood count and renal and hepatic serum chemistries were repeated 24-h postinfusion of the first dose and weekly thereafter. The history and physical exam, complete blood count, and serum chemistry panel were repeated before each cycle. Radiologic assessment of tumor was done every two cycles.
Paclitaxel was supplied by Bristol-Myers Squibb Co. as a semisynthetic product supplied in vials containing 30 mg product. Before administration, it was diluted in 250 mL D5W. It was administered at the calculated dose with in-line filtration using polyolefin containers and tubing over 1 hour. The following premedications were given 30 to 60 min before the paclitaxel infusion: 20 mg i.v. dexamethasone, 50 mg i.v. hydroxyzine, and 50 mg i.v. ranitidine. After cycle 1, the scheduled dexamethasone premedication was stopped. One patient continued getting dexamethasone for nausea and vomiting, one patient continued dexamethasone for chills (without fever), and one patient continued use for flushing.
BMS-214662 was supplied by Bristol-Myers Squibb in glass vials containing 250 mg drug (20 mg/mL at the free base). Before administration, it was diluted with D5W to concentrations between 0.2 and 15 mg/mL of the free base within polyvinyl chloride bag (diluted solution stable for 24 h at room temperature). BMS-214662 was administered, starting 30 min after completion of the paclitaxel infusion, as a 1-h infusion through polyvinyl chloride tubing via a standard volumetric infusion pump. During the performance of the study, two patients received BMS-214662 as a 24-h infusion weekly (209 mg/m2). Before each administration of BMS-214662, patients received either 32 mg ondansetron or 1 mg granisetron i.v.
The starting dose of paclitaxel was fixed at 80 mg/m2/wk and is below the MTD in pretreated cancer patients (13). The starting dose of 80 mg/m2/wk BMS-214662 was selected due to its association with minimal inhibition of farnesyl transferase and little to no associated toxicity in prior clinical testing. Dose levels of BMS-214662 numbered 0 to 5 were as follows: 80, 120, 160, 200, 225, and 245 mg/m2/dose, all administered over 1 hour. Before expanding the MTD level, two subjects were treated at 209 mg/m2/dose over 24 h. One cycle of treatment was considered 21 days. Weekly treatment was continuous unless toxicity, clinical decisions, or patient compliance led to treatment delays, which allowed 2 weeks before removal from study. Removal from study would occur for patient request, progressive disease, lack of toxicity resolvement to grade 1, repeat incidence of dose-limiting toxicity (DLT) in spite of two dose reductions, and significant clinical deterioration as deemed by the treating physician or Study Chair.
DLT was evaluated by National Cancer Institute Common Toxicity Criteria 2.0 and defined as the following toxicities attributable to paclitaxel and/or BMS-214662: grade 4 neutropenia with duration >5 days; febrile neutropenia; platelet count <25,000 cells/mm3 or platelet count <50,000 cells/mm3 associated with bleeding that required platelet transfusion; grade 2 peripheral neuropathy; grade 3 nonhematologic toxicity (exceptions: hypersensitivity reactions, grade 3 injection site reactions, grade 3 arthralgia/myalgias, grade 3-4 asthenia/fatigue, grade 3-4 nausea/vomiting without optimal antiemetic therapy, grade 3 increase in alanine aminotransferase that resolve to grade 1 before next treatment, and reversible grade 3 diarrhea without loperamide use); toxicity-induced treatment delays of more than 1 week; QTc prolongations to >500 msec during the 24-h period postdosing; and any clinically significant arrhythmia occurring during the 24-h period postdosing.
To receive a treatment for a given week with paclitaxel and BMS-214662, the neutrophil count needed to be 750 cells/mm3, the platelet count 50,000 cells/mm3, and nonhematologic drug-related toxicity (excluding alopecia, injection site reactions, asthenia, and fatigue) needed to be resolved to baseline levels or to grade 1 toxicity. The occurrence of dose-limiting hematologic toxicity resulted in a treatment delay until toxicity resolvement to grade 1 and 25% dose reduction in paclitaxel. Dose-limiting nonhematologic toxicity also resulted in a treatment delay (except grade 2 peripheral neuropathy that did not require a treatment delay) until resolvement to grade 1 and a 25% decrease in paclitaxel and one dose level reduction in BMS-214662.
The MTD was defined as the dose level below that at which >1 of 3 or 2 of 6 patients experienced a DLT during cycle 1. Once the MTD was defined, an additional six to nine patients would be recruited to the MTD level to gain further experience with this regimen and better recommend the phase 2 dose. Dose escalation occurred after all three patients (or six patients in an expanded cohort) had completed at least one cycle of treatment. No intrapatient dose escalation was done.
Disease evaluation was done by radiologic assessment or physical exam prestudy and after two cycles of treatment and every two cycles thereafter. Disease response, whether complete response (complete disappearance of all clinical evidence of cancer, including normalization of serum markers) or partial response (50% decrease in sum of bidimensional measurements and 30% decrease in sum of unidimensional measurements), required two consecutive assessments at least 4 weeks apart. Progressive disease was defined as a 25% increase in the sum of the products of all bidimensionally measurable lesions, 20% increase in the sum of all unidimensionally measurable lesions, appearance of any new lesions, or reappearance of any lesion that had disappeared during treatment.
Blood samples for pharmacokinetics (5 mL) were collected (in tripotassium EDTA Vacutainer tubes) on day 1 for cycle 1 only at the following times relative to the start of paclitaxel infusion (hours:minutes): predose, 00:30, 00:58, 1:15, 1:30, 2:00, 2:28, 2:45, 3:00, 3:30, 4:30, 5:30, 7:30, and 24:00. For the two patients treated with 24-h BMS-214662, the following sampling schedule was used: predose, 00:58, 1:30, 2:30, 3:30, 5:30, 7:30, 24:30, 26:00, 26:30, 27:00, 29:00, 31:00, and 33:00. Plasma was separated by centrifugation, transferred to labeled tubes, and transported to Bristol-Myers Squibb for analysis. Measurement of BMS-214662 in plasma was done via high-performance liquid chromatography as described previously (12). Paclitaxel pharmacokinetic variables were determined with noncompartmental methods by the PKMENU application using the Statistical Analysis System (version 6.12; SAS).
Blood samples (8 mL) to assess the ability of BMS-214662 to inhibit constitutive farnesyl transferase activity in peripheral blood mononuclear cells were collected (in Becton Dickinson CPT Vacutainers®) during day 1 of cycle 1 only at the following time points relative to the start of paclitaxel infusion: predose, 00:58, 2:28, 7:30, and 24:00. For the two patients treated with 24-h BMS-214662, the following sample schedule was used: predose, 00:58, 7:30, and 24:30. Following blood collection, the tubes were inverted several times and centrifuged (room temperature) for 30 min at 1,700 x g and transferred to separate polypropylene tubes and washed twice with 10 mL ice-cold PBS and centrifuged (1,700 x g for 10 min) after each washing. The peripheral blood mononuclear cell pellet was stored at –80° until shipping to Bristol-Myers Squibb. Peripheral blood mononuclear cell preparations were lysed, and the farnesyl transferase activity in the cellular extracts was determined using exogenous [3H]farnesyl pyrophosphate and H-Ras substrates. Farnesyl transferase activity was normalized by cellular protein concentrations (3).
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Results
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A total of 94 courses were administered to 26 patients. One patient at level 3 (200 mg BMS-214662) was unevaluable for course 1 (due to missed dose), but toxicity results from that patient's two courses are included in later tables (see Table 1
). The majority of patients were pretreated (two or more prior chemotherapy regimens) and represented many malignancy types. See Table 2
for patient characteristics.
The combination of weekly 1-h BMS-214662 and 1-h paclitaxel (fixed at 80 mg/m2) resulted in the same predominate toxicities observed in other dose escalation studies of BMS-214662, primarily acute and subacute gastrointestinal toxicity (see Table 3
). The most commonly observed toxicity was grade 1 to 2 nausea/vomiting and grade 1 to 2 diarrhea. The nausea and vomiting occurred within the first 24 h after administration of BMS-214662, despite the use of 5-HT antagonists and other antiemetics. Delayed nausea/vomiting (>24 h after administration) also occurred and was modestly alleviated by various antiemetics. Grade 3 nausea/vomiting was observed in two patients (one each at levels 2 and 3). Grade 1 to 2 diarrhea was also commonly observed. It rarely occurred acutely after drug administration but more commonly worsened over numerous days or after 2 or 3 weekly drug administrations. Dysmotility agents (e.g. loperamide), started after the onset of loose stools, did seem to lessen the severity of the diarrhea. Grade 3 diarrhea was observed during course 1 in two patients at level 3 and one patient at level 5. A patient had grade 3 diarrhea with course 3 at level 2.
DLTs initially occurred in two patients with advanced pancreatic cancer treated at level 5 (245 mg/m2 BMS-214662). Both patients developed acute (<24 h after drug administration) grade 4 neutropenia during course 1 with one patient also having a grade 3 elevation in serum transaminases. Within 48 h of drug administration, both patients exhibited signs of febrile, neutropenic bacteremia/sepsis with resultant blood cultures positive for gram-negative rods. The patients recovered with intensive care and monitoring and the neutrophil counts and serum transaminases returned to near normal values over 4 to 8 days. Neither patient received any further treatment on study. A third patient with advanced adrenal carcinoma received two courses at level 5 with the most significant toxicity being grade 1 diarrhea.
Based on toxicity data from other dose escalation studies of 1-h BMS-214662 (unacceptable toxicity at doses > 200 mg/m2 over 1 h) and the small difference in dose between dose levels 3 and 4 (10%), neither dose level 3 or 4 was expanded. Rather, the six patients treated at levels 3 (200 mg/m2) and 4 (225 mg/m2) were consistent with the protocol design of observing DLT during course 1 in less than two of six patients treated at the MTD. Before expanding the MTD dose (level 3) to better characterize the recommended phase 2 dose and schedule, two patients were entered at dose level 3a (209 mg/m2 administered over 24 h rather than 1 h) and received five courses without DLT. On expansion of level 3, four of five additional patients experienced DLTs during course 1 (one patient with grade 3 neutropenia on day 2 followed by grade 3 diarrhea by day 18, another patient with grade 3 diarrhea, and two patients with reversible grade 3 elevations in serum aspartate aminotransferase on day 2). No other acute elevations in transaminases, other than the aforementioned DLTs, were observed. Numerous patients (one patient at levels 3, 3a, 4, and 5; two patients at level 2) inconsistently experienced fevers and/or chills lasting a few hours after receiving BMS-214662 that were not associated with dose-limiting events. Grade 1 fatigue, possibly related to treatment, was also commonly observed. Renal insufficiency, other than associated with sepsis, was not observed.
One patient with advanced colon cancer entered at level 3a (received scheduled treatment on days 1 and 8) died on day 15 of course 1 of an autopsy-confirmed pulmonary embolus. No other patients died on-study. Toxicities primarily associated with weekly paclitaxel (peripheral neuropathy, alopecia, and neutropenia) occurring after day 2 were mild (grade 1-2) and uncommon. Paclitaxel infusion-related allergic reactions were observed in a patient at level 3 (grade 3, course 1, day 1; no further treatment on study after day 1) and another patient at level 3a (grade 2, course 1, day 1; day 8 administered without allergic reaction).
Extensive cardiac monitoring (pre-BMS-214662 and post-BMS-214662 infusions) starting with level 3 did not reveal evidence for significant cardiac rhythm disturbance or QTc prolongation.
Multiple patients had objective and subjective evidence of benefit and are detailed as follows: (a) Two patients at level 0, a patient with advanced head and neck carcinoma and prior exposure to paclitaxel and cisplatin had an initial partial response after course 2 and eventually had progressive disease after eight courses. (b) A patient with hormone-refractory prostate cancer and prior mitoxantrone noted improvement in bony pain and a prior steadily increasing serum prostate-specific antigen and alkaline phosphatase decreased slightly and stabilized until both values started to increase along with increased bony pain during and after course 9. (c) A patient with hormone-refractory prostate cancer and no prior chemotherapy treated at level 1 noted improvement in bony pain and a steady decline in serum prostate-specific antigen (on-study 182, nadir value 118 after course 6) and alkaline phosphatase (on-study 162, nadir 116) but was removed after course 11 due to recurring bony pain and increasing prostate-specific antigen. (d) Two patients at level 2 with pretreated ovarian cancer exhibited signs of benefit, one patient had demonstrable improvement in measurable disease (not meeting criteria for partial response) and a decrease in serum CA-125 (on-study 449, nadir 102) until evidence for progression (radiographic and increased CA-125) of disease after course 8; the other patient had complete resolution of evaluable disease by computed tomography scanning and normalization of serum CA-125 (on-study 558) until evidence for progression (radiographic and increased CA-125) of disease was noted after course 6; (e) Two patients at level 3, one patient with advanced leiomyosarcoma and prior treatment with doxorubicin and cyclophosphamide was observed to have resolution of pain and a partial response by computed tomography after course 2, the patient declined further treatment after course 3 due to grade 1-2 fatigue and alopecia. A patient with advanced endometrial carcinoma and prior treatment with paclitaxel and carboplatin had marked improvement in malignant ascites after course 1 but had evidence of clinical worsening after course 3 (due to a DLT occurring on day 2 of course 1, all further treatment was with BMS-214662 at 160 mg/m2 and paclitaxel at 60 mg/m2).
The pharmacokinetics of BMS-214662 administered as a 1-h infusion are very similar to prior published data of BMS-214662 administered as a 1-h infusion alone (3) and with cisplatin (12) or carboplatin and paclitaxel (see Fig. 1
; ref. 14). Exposure to BMS-214662 increased in a near proportional fashion with dose, between the 80 to 225 mg/m2 dose (see Table 4
). Plasma clearance and half-life did not vary with dose, with half-lives ranging from 1.3 to 1.7 h. The volume of distribution at steady-state approximated total body water and also did not seem related to dose. The pharmacokinetics of paclitaxel (see Table 5
) administered as a 1-h infusion also approximate prior reported data (15) and do not seem to correlate with increasing doses of BMS-214662, suggesting no pharmacokinetic interaction between paclitaxel and BMS-214662.
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Fig. 1. Mean plasma concentrations of escalating doses of BMS-214662 in combination with paclitaxel (80 mg/m2) in patients with advanced solid tumors.
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Table 4. Pharmacokinetics of escalating doses of BMS-214662 administered as a 1-h infusion to cancer patients following a 1-h infusion of paclitaxel (80 mg/m2)
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Table 5. Pharmacokinetics of 80 mg/m2 doses of paclitaxel administered as a 1-h infusion to cancer patients before a 1-h infusion of escalating doses of BMS-214662
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Determination of constitutive farnesyl transferase activity in peripheral blood mononuclear cells from patients during course 1 also observed results very similar to prior published results (3, 12). Maximal inhibition of peripheral blood mononuclear cells farnesyl transferase activity was observed at the end of the BMS-214662 infusion correlating with its Cmax. Maximal inhibition from predose activity ranged from 67% to 86% among the treatment cohorts. With the exception of dose level 5 (245 mg/m2), farnesyl transferase activity returned to baseline levels by 7.5 to 24 h (see Fig. 2
).
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Fig. 2. Effect of BMS-214662 on the mean farnesyl transferase activity in peripheral blood mononuclear cell.
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Discussion
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The combination of weekly paclitaxel and BMS-214662 was well tolerated at a paclitaxel dose of 80 mg/m2 and at doses up to 160 mg/m2 BMS-214662 administered over 1 h starting 1 h after paclitaxel. The actual MTD from our study was a BMS-214662 dose of 200 mg/m2 administered over 1 h because a dose of 245 mg/m2 had unacceptable first dose toxicity in two of three patients and six of six patients treated at 200 or 225 mg/m2 did not have unacceptable toxicity during their first course. However, when the 200 mg/m2 dose level was expanded to further characterize the potential recommended phase 2 dose, four of five additional patients experienced unacceptable toxicity. When examining all eight evaluable patients at the 200 mg/m2 dose level, half experienced DLT with course 1. The predominate DLTs were secondary to BMS-214662 and were either an acute (starting within 24 h of receiving BMS-214662) syndrome of a sudden leukopenia/neutropenia and elevation in serum transaminases or gastrointestinal toxicity (both acute nausea/vomiting and diarrhea occurring days after drug infusion). These have been the DLTs or commonly observed toxicities in other phase I dose escalation studies of BMS-214662 (3, 12, 14, 16, 17). Unlike some of the prior studies, renal insufficiency was not observed. Whereas one patient (level 3, 200 mg/m2) with the acute neutropenia/transaminitis seemed to suffer no ill effects from this, two patients at level 5 (245 mg/m2) exhibited signs of the functional significance of their neutropenia when they rapidly developed gram-negative bacteremia/sepsis. The possible etiology of these rapid onset but reversible abnormalities is conjecture (e.g., sequestration of leukocytes in the reticuloendothelial system). Gastrointestinal toxicity was the most common toxicity observed and the main limiting toxicity at level 3 (200 mg/m 2). It consisted of acute nausea/vomiting, which was partially ameliorated by scheduled antiemetics, and delayed nausea/vomiting, which was minimally ameliorated by antiemetics, as well as relatively common grade 1 to 2 diarrhea and occasional grade 3 diarrhea. It is possible with more aggressive antidiarrheal medications that the occurrences of grade 2 and 3 diarrhea could be lessened to the degree to allow higher BMS-214662 doses; however, the nausea/vomiting and the concerns over the other DLTs diminish the clinical viability of this. Toxicities likely from weekly paclitaxel were mild and infrequent. Despite the amount of prior treatment, grade 3 or 4 neutropenia or grade 2 neuropathy attributable to paclitaxel was rarely observed.
Consistent with the known clinical effectiveness of weekly paclitaxel, multiple patients seemed to derive clinical benefit in terms of both objective tumor shrinkage or stabilization and subjective improvement in tumor-related symptoms. In terms of the combination, it is encouraging that many of the patients with observed benefit were often pretreated, including prior every 3-week paclitaxel and platinum. Most noteworthy were the following: a near complete response in a pretreated patient with ovarian cancer and partial responses in a patient with prior anthracycline-refractory leiomyosarcoma and a patient with prior chemotherapy-treated prostate cancer. Although it is possible that the above patients would have benefited from weekly paclitaxel alone, the nature of the observations is consistent with the preclinical evidence supporting a synergistic interaction between paclitaxel and BMS-214662.
The pharmacokinetic data support the lack of any pharmacokinetic interaction between paclitaxel and BMS-214662 and the data for each agent closely approximates prior published single-agent pharmacokinetic data. Part of the rationale for briefly trying a 24-h administration schedule of BMS-214662 during this trial was to better approximate the concentration/exposure times of the preclinical studies and to hopefully allow higher dose escalations. Although the 24-h infusion schedule (209 mg/m2) had acceptable toxicity in two patients treated during this trial, a different trial did not observe any advantage in terms of toxicity compared with the 1-h infusion, which led to the decision to only pursue the 1-h infusion (18).
Assessment farnesyl transferase activity in peripheral blood mononuclear cells also was very similar to prior clinical trials in terms of the degree and pattern of farnesyl transferase inhibition by BMS-214662. Whereas the degree of maximal inhibition was similar across dose levels (66-86%), the return to near baseline farnesyl transferase activity was markedly different between the highest dose level (245 mg/m2) and all lower levels. This was most marked at 7.5- and 24-h post-initiation of paclitaxel where farnesyl transferase activity seemed to remain well below baseline levels for dose level 5 but returned to normal or near normal levels for all other doses. The persistent inhibition at 7.5 h could be explained by persistent BMS-214662 concentrations near 1,000 ng/mL for dose level 5, whereas other levels had mean concentrations well below this. However, no apparent meaningful difference in mean drug concentrations between dose levels was observed at 24 h because all dose levels had mean drug concentrations between 10 and 100 ng/mL. The persistent farnesyl transferase inhibition observed at dose level 5 may also be spurious. As expected, farnesyl transferase activity in peripheral blood mononuclear cells did not seem effected by paclitaxel.
Based on the clinical activity observed in this study, the combination of weekly paclitaxel and BMS-214662 certainly seems worthy of further study. The most expeditious next step would be a randomized comparison trial of weekly paclitaxel with and without BMS-214662 in patients with advanced disease. The patient population could either be taxane naive or taxane refractory (every 3-week schedule) and any one of the many taxane-responsive tumor types could be the disease target. The recommended combination dose and schedule based on our data would be 80 mg/m2 paclitaxel over 1 h followed by 160 mg/m2 BMS-214662 infused over 1 h.
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Acknowledgments
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We thank Mary Gillitzer, RN, and the University of Wisconsin General Clinical Research Centers staff for their rigorous performance of drug administration and pharmacokinetic sampling and Bristol-Myers Squibb staff for their assay performance.
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Footnotes
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Grant support: General Clinical Research Centers grant MO1RR03186.
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.
Received 1/19/07;
revised 3/ 7/07;
accepted 3/23/07.
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Abstract
Materials and Methods
