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Clinical Cancer Research Vol. 10, 2968-2976, May 1, 2004
© 2004 American Association for Cancer Research

Clinical Trials

Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Paclitaxel in Solid Tumors

Fadlo R. Khuri1, Bonnie S. Glisson2, Edward S. Kim2, Paul Statkevich3, Peter F. Thall2, Michael L. Meyers3, Roy S. Herbst2, Reginald F. Munden2, Craig Tendler3, Yali Zhu3, Sandra Bangert2, Elizabeth Thompson2, Charles Lu2, Xue-Mei Wang2, Dong M. Shin2, Merrill S. Kies2, Vali Papadimitrakopoulou2, Frank V. Fossella2, Paul Kirschmeier3, W. Robert Bishop3 and Waun Ki Hong2

1 Winship Cancer Institute, Emory University, Atlanta, Georgia; 2 The University of Texas M. D. Anderson Cancer Center, Houston, Texas; and 3 Schering-Plough Research Institute, Kenilworth, New Jersey


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Purpose: To establish the maximum tolerated dose of lonafarnib, a novel farnesyltransferase inhibitor, in combination with paclitaxel in patients with solid tumors and to characterize the safety, tolerability, dose-limiting toxicity, and pharmacokinetics of this combination regimen.

Experimental Design: In a Phase I trial, lonafarnib was administered p.o., twice daily (b.i.d.) on continuously scheduled doses of 100 mg, 125 mg, and 150 mg in combination with i.v. paclitaxel at doses of 135 mg/m2 or 175 mg/m2 administered over 3 h on day 8 of every 21-day cycle. Plasma paclitaxel and lonafarnib concentrations were collected at selected time points from each patient.

Results: Twenty-four patients were enrolled; 21 patients were evaluable. The principal grade 3/4 toxicity was diarrhea (5 of 21 patients), which was most likely due to lonafarnib. dose-limiting toxicities included grade 3 hyperbilirubinemia at dose level 3 (100 mg b.i.d. lonafarnib and 175 mg/m2 paclitaxel); grade 4 diarrhea and grade 3 peripheral neuropathy at dose level 3A (125 mg b.i.d. lonafarnib and 175 mg/m2 paclitaxel); and grade 4 neutropenia with fever and grade 4 diarrhea at level 4 (150 mg b.i.d. lonafarnib and 175 mg/m2 paclitaxel). The maximum tolerated dose established by the continual reassessment method was lonafarnib 100 mg b.i.d. and paclitaxel 175 mg/m2. Paclitaxel appeared to have no effect on the pharmacokinetics of lonafarnib. The median duration of therapy was eight cycles, including seven cycles with paclitaxel. Six of 15 previously treated patients had a durable partial response, including 3 patients who had previous taxane therapy. Notably, two of five patients with taxane-resistant metastatic non-small cell lung cancer had partial responses.

Conclusions: When combined with paclitaxel, the recommended dose of lonafarnib for Phase II trials is 100 mg p.o. twice daily with 175 mg/m2 of paclitaxel i.v. every 3 weeks. Additional studies of lonafarnib in combination regimens appear warranted, particularly in patients with non-small cell lung cancer.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Mutations of the ras family of oncogenes that result in unregulated cell proliferation are common in human cancers (1) . The ras mutations have been implicated in the development of colorectal cancer and have been associated with shortened survival in several tumor types, including non-small cell lung cancer (NSCLC; Refs. 2, 3, 4, 5, 6 ). Ras genes encode a protein, p21, that is located on the inner surface of the plasma membrane (1 , 7) . The p21 protein has GTPase activity and participates in signal transduction. Activation of the ras oncoprotein requires prenylation, a process that is catalyzed by farnesyltransferase (8, 9, 10, 11, 12) .

Farnesyltransferase inhibitors (FTIs) are a novel class of compounds that block this critical enzymatic step in the formation of active ras proteins (8, 9, 10, 11, 12, 13) . Lonafarnib (Sarasar; Schering-Plough Corporation, Kenilworth, NJ) is a tricyclic nonpeptidomimetic compound (Fig. 1)Citation that is active against a variety of tumors in vitro and in animal models of cancer (14) . The antitumor activity of lonafarnib and other FTIs is related to the inhibition of farnesylation, although controversy currently surrounds the exact farnesylated proteins that are the key targets of FTIs (15 , 16) . For example, Ashar et al. (17) and Crespo et al. (18) have shown that FTIs have important effects on cell cycle arrest. The data of Crespo et al. suggest a direct effect on spindle formation with resultant prometaphase accumulation of mitotic lung cancer cells. Ashar et al. also showed that CENP-E and CENP-F, two centromeric proteins preferentially expressed in mitotic cells, are direct substrates for FTIs, and that their prenylation is completely inhibited by lonafarnib (19) .



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  		Fig. 1. Structure of lonafarnib {(11R)-4-[2-[4-(3,10-dibromo-8-chloro-6,11-digydro-5H-benzo[5,6] cyclohepta [1,2b]pyridin-11yl)-1-piperazinyl]-2-oxoethyl]-1-piperidinecarboxamide}.

 
Compelling data reported by Moasser et al. supplied the scientific underpinning for our present study (20) . They showed that, in several cell lines initially resistant to paclitaxel, the addition of a FTI enhanced the sensitivity of those cell lines to paclitaxel. Subsequent preclinical studies have demonstrated synergistic effects with lonafarnib plus paclitaxel on a number of human cell lines in vitro (21 , 22) and enhanced activity in vivo (22) . In the NCI-H460 lung cancer xenograft model, inhibition of tumor growth was significantly greater with oral lonafarnib plus i.p. paclitaxel than with either agent alone (86% versus 52% and 61%, respectively; P < 0.05). Tumor growth inhibition on days 7 and 14 were 56 and 65% greater, respectively, with the combination than with paclitaxel alone. In line 69 wap-ras/F transgenic male mice, which develop paclitaxel-resistant mammary tumors at 6–9 weeks of age, oral lonafarnib significantly inhibited tumor growth (P = 0.05) and also sensitized the tumors to paclitaxel treatment, so that the combination of lonafarnib plus paclitaxel was more effective than lonafarnib alone (P = 0.06 for days 7 to 21; Refs. 22 , 23 ). One proposed explanation for the synergistic activity is that treatment with FTI causes cells to accumulate in the G2-M phase of the cell cycle in which paclitaxel is most effective (21 , 24) .

The main objectives of this trial were to establish the maximum tolerated dose (MTD) of lonafarnib, a novel FTI, in combination with paclitaxel in patients with solid tumors and to characterize the safety, tolerability, and dose-limiting toxic effects of this combination in patients with advanced solid malignancies. Furthermore, we particularly wanted to see whether durable responses could be achieved in a variety of taxane-sensitive tumors in patients previously treated with taxanes. Finally, we sought to characterize the pharmacokinetics of multiple-dose lonafarnib after its daily oral administration and of paclitaxel coadministered with daily lonafarnib.


   PATIENTS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We sought to establish the MTD and the dose-limiting toxicity (DLT) of the lonafarnib/paclitaxel combination in adult patients with solid tumors. Previously treated patients and untreated patients were allowed to participate in the study. Eligibility criteria included a Karnofsky performance status of at least 70%, a histologically confirmed malignancy for which no curative treatment was available, measurable disease, and adequate hematological parameters [including a WBC count >= 3,000/mm3, an absolute neutrophil count of 1,500/µl (>= 1.5 x 109/liter), a platelet count >= 100 x 109/liter, and a hemoglobin level >= 10 g/dl]. Furthermore, patients were required to have adequate renal function, with a serum creatinine level <= 1.5 times the upper limit of normal or a measured 12-h creatinine clearance time of >=50 ml/min/1.73 m2. Also mandatory were normal hepatic function (baseline transaminase levels <= 3 times the upper limit of normal, bilirubin <= 2.0 mg/dl, and albumin >= 3.0 g/dl) and no manifestations of a malabsorption syndrome. All patients had to sign a written informed consent approved by the Institutional Review Board at the University of Texas M. D. Anderson Cancer Center. Patients taking agents that might alter the metabolism of lonafarnib via the CYP3A4 hepatic enzymatic system (such as azoles, macrolides, cyclosporin, systemic corticosteroids, estrogens, antiseizure drugs, rifampin, or isoniazid), or who had metastases to the brain were excluded from the study.

Patients received lonafarnib capsules p.o. twice daily (b.i.d.) with food as 50-mg, 75-mg, and 100-mg formulations in combination with paclitaxel administered i.v. every 3 weeks at 135 mg/m2 or 175 mg/m2 over 3 h (Fig. 2)Citation . Premedication consisted of 20 mg i.v. dexamethasone and 8 mg of i.v. ondansetron.



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  		Fig. 2. Study design. Patients begin lonafarnib 1 week before receiving paclitaxel. Reevaluation occurs after every three cycles of treatment. If patients have responsive or stable disease, they proceed on study. If patients have progressive disease, they go off the study protocol. CT, computed tomography; MRI, magnetic resonance imaging.

 
Statistical Methods.
The dose-finding portion of the trial was conducted in a group of patients with a variety of different head and neck and lung cancers. The principal scientific goal was to determine a MTD, defined as the dose level at which the toxicity rate was closest to 20% and less than 33% with at least 33% of patients experiencing dose-limiting toxicities (DLT) at the next higher level. DLT was defined as the following: absolute neutrophil count < 500/µl for longer than 5 days or with fever >= 38.3°C; grade 4 thrombocytopenia (platelets < 25,000/µl) or anemia (Hb < 6.5 g/dl); grade 3–4 nausea/vomiting or grade 3 diarrhea despite optimal antiemetic or antidiarrheal treatment; or any other grade 3 treatment-related nonhematological toxicity; and treatment delay for toxicity lasting >2 weeks.

Associations between pairs of variables were assessed using the Fisher exact test, Kruskal-Wallis test, and Jonkheere-Terpstra test (25) . Regression models of toxicity on the doses of paclitaxel and lonafarnib, and the indicator of prior chemotherapy, were fit using exact logistic regression (26 , 27) . Confidence intervals for probabilities of toxicity at particular dose and prior chemotherapy combinations were computed by repeating the exact logistic regression on 1000 bootstrap samples of the data. All of the computations were carried out using StatXact and SAS Proc Logistic.

Pharmacokinetic Methods.
Plasma lonafarnib and paclitaxel concentrations were determined using validated liquid chromatography with tandem mass spectrometric detection and the high-performance liquid chromatography method, respectively. The lower limits of quantitation were 5.00 and 10.0 ng/ml plasma for lonafarnib and paclitaxel, respectively, and the linear ranges were 5.00–2500 ng/ml and 10.0–2500 ng/ml, respectively. The assay precision (% coefficient of variation) and accuracy (% Bias) were <11% and <10%, respectively, for lonafarnib, and <9% and <6%, respectively, for paclitaxel. Noninterference from the respective coadministered drug was demonstrated for both of the lonafarnib and paclitaxel methods.

Blood samples (~3 ml) for determination of plasma lonafarnib and paclitaxel concentrations were collected on day 1 of Cycle 1. Plasma was separated by centrifugation (4°C, ~3000 rpm for 15 min), then divided into two aliquots, and was stored frozen at –70°C until shipped to the analytical facility.

Individual plasma lonafarnib and paclitaxel concentrations were used for pharmacokinetic analysis using model-independent methods. The maximum plasma concentration (Cmax) and time of maximum plasma concentration (Tmax) were the observed values. The terminal phase rate constant (K) was calculated as the negative of the slope of the log-linear terminal portion of the plasma concentration-versus-time curve using linear regression. The terminal phase half-life, t1/2, was calculated as 0.693/K. The area under the plasma concentration-versus-time curve from time 0 to the time of final quantifiable sample (AUC(tf)) and from time 0 to 12 h (AUC(0–12 h)) was calculated using the linear trapezoidal method. For paclitaxel, the AUC(tf) was extrapolated to infinity when appropriate as follows: AUC({infty}) = AUC(tf) + C(tf)/K, where C(tf) is the estimated concentration determined from linear regression at time tf. Total body clearance, CL/F (lonafarnib) or CL (paclitaxel), was calculated by the following equation: CL/F = Dose/AUC. The apparent volume of distribution, Vd/F (lonafarnib) or Vd (paclitaxel), was calculated as: Vd/F = (Dose/AUC)/K.

For paclitaxel, the volume of distribution at steady state, Vdss, was estimated as total body clearance multiplied by mean residence time (MRT).


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Twenty-four patients with a mean age of 58.3 years were enrolled on this Phase I study at the University of Texas M. D. Anderson Cancer Center, with the enrollment of new patients beginning on June 16, 1999, and continuing through March 30, 2000. Twenty-one patients actually received both paclitaxel and lonafarnib (Table 1)Citation . Patients were predominantly male (67%) and Caucasian (92%), with Karnofsky performance status of 90 to 100 (71%; Table 2Citation ). Slightly more than one-half of the patients had a primary diagnosis of NSCLC.


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  		Table 1 Number of patients and cycles by dose level of paclitaxel and lonafarnib in Phase I trial

 

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  		Table 2 Patient demographics and disease characteristics

 
Toxicities.
Among all of the dose levels, 92% of patients reported at least one toxicity at any grade and 54% of patients reported at least one grade 3/4 treatment-emergent nonhematological adverse event judged to be related to the study drugs. The most common treatment-related treatment-emergent nonhematological adverse events (including all grades) reported were gastrointestinal effects in 92% of patients (diarrhea 92%, nausea 79%, vomiting 50%, constipation 46%, stomatitis 38%, abdominal pain 29%); fatigue (88%), alopecia (83%), peripheral neuropathy (79%), arthralgia (71%), infections and infestations in 50% of patients (folliculitis 38%, oral candidiasis 13%, pneumonia 8%), respiratory system disorders (63%), anorexia (54%), rash (46%), weight decrease (29%); dizziness (25%); fever, blurred vision, liver and biliary system disorders, dehydration, myalgia, dry skin (21% each). All other adverse events occurred in fewer than 20% of patients. Grade 3 and grade 4 nonhematological toxicities by dose level are listed in Table 3Citation .


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  		Table 3 Number of patients with severe (grade 3) or life-threatening (grade 4) nonhematologic toxicities

 
Hematological toxicities occurred in 54% (13 of 24) of patients overall. Seven patients (29%) had grade 3/4 hematological toxicities. Table 4Citation shows that any grade and grade 3/4 anemia occurred in 34% (8 of 24) and 4% (1 of 24) of patients, respectively; any and grade 3/4 leukopenia occurred in 38% (9 of 24) and 21% (5 of 24) patients, respectively; and any and grade 3/4 neutropenia occurred in 17% (4 of 24) and 13% (3 of 24) of patients, respectively. Thrombocytopenia at any level was not observed in this study.


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  		Table 4 Number of patients with hematological toxicities by dose level during the treatment period

 
Both hematological and nonhematological toxic effects were generally mild and were neither more common nor more severe than those expected with paclitaxel. Patients had a median of one prior treatment with 13 of 22 evaluable patients having had prior chemotherapy including 9 who had a prior taxane (Table 2)Citation . Seven of the 9 patients previously treated with a taxane had disease progression on or within 3 months of taxane-based therapy, and 10 of 13 pretreated patients overall had progression of disease on or within 3 months of therapy.

Protocol-Defined DLTs.
Overall, seven patients had DLTs as defined by protocol. No DLTs were seen at dose level 2. One patient at dose level 3 had grade 3 bilirubinemia. When the dose was escalated to level 4 (150 mg b.i.d. lonafarnib and 175 mg/m2 paclitaxel) two of four patients had dose-limiting toxic effects in the first cycle (one grade 4 neutropenic fever, one grade 4 diarrhea). We then introduced dose level 3A (125 mg b.i.d. of lonafarnib, 175 mg/m2 of paclitaxel) to determine whether an intermediate dose level would be tolerated. At this dose, two patients had grade 4 diarrhea in the first cycle. All of the DLTs were reversible on modification or cessation of treatment. On the basis of analysis of all available safety data, it has been determined that lonafarnib 100 mg b.i.d. and paclitaxel 175 mg/m2 is appropriate for further evaluation in patients with NSCLC.

Pharmacokinetics of Lonafarnib.
Nineteen patients had samples collected for pharmacokinetic evaluations. Lonafarnib was slowly absorbed after oral administration with food. Median Tmax ranged from 3 to 8 h (Table 5Citation ; Fig. 3Citation ). Half-life (t1/2) could not be estimated in this study because of the lack of a definitive terminal phase in the plasma concentration-versus-time profiles after b.i.d. oral administration of lonafarnib with food (see Fig. 3Citation ). Mean plasma lonafarnib concentrations at 12 h after the dose were ~34–99% of the corresponding mean Cmax values. The mean total body clearance ranged from 165 to 364 ml/min. The increases in lonafarnib AUC values were dose-related after oral administration of 100 mg, 125 mg, and 150 mg in combination with paclitaxel 175 mg/m2. After administration of lonafarnib 100 mg with paclitaxel 175 mg/m2, the mean lonafarnib Cmax and AUC values were higher than those with paclitaxel 135 mg/m2. However, given the variability of the data and sample size, the distribution of individual Cmax and AUC values encompassed the same range, regardless of paclitaxel dose (Fig. 4)Citation . The Cmax and AUC values obtained in this trial with lonafarnib 100 mg in combination with paclitaxel were similar to those obtained in previous Phase I trials in which lonafarnib 100 mg was administered alone (Table 6Citation ; Refs. 28, 29, 30 ). Thus, these observations suggest that a single dose of either 135 mg/m2 or 175 mg/m2 of paclitaxel did not affect the pharmacokinetics of lonafarnib.


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  		Table 5 Mean (percentage coefficient of variation) pharmacokinetic parameters of lonafarnib

 


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  		Fig. 3. Mean (±1 SD) plasma lonafarnib concentrations after multiple-dose oral administration of lonafarnib in combination with single-dose 3-h i.v. infusion of paclitaxel to patients with solid tumors.

 


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  		Fig. 4. Individual and mean (±1 SD) Cmax (A) and AUC0–12 h values (B) of lonafarnib after multiple-dose oral administration of lonafarnib in combination with single-dose 3-h i.v. infusion of paclitaxel to patients with solid tumors.

 

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  		Table 6 Mean (coefficient of variation) pharmacokinetic parameters of lonafarnib after multiple-dose administration of lonafarnib 100 mg alone (previous Phase I studies) or in combination with paclitaxel (this study)

 
Pharmacokinetics of Paclitaxel.
Plasma paclitaxel concentrations (Cmax and AUC) were similar among the dose groups for paclitaxel 175 mg/m2 with lonafarnib 100 mg, 125 mg, and 150 mg (Table 7Citation ; Figs. 5Citation and 6Citation ). There appear to be no effects on paclitaxel pharmacokinetics at a dose of 175 mg/m2 paclitaxel when the lonafarnib dose is increased from 100 mg to 150 mg. The relationships between dose and paclitaxel Cmax or AUC values were disproportionate after the administration of paclitaxel 135 mg/m2 and 175 mg/m2 in combination with lonafarnib 100 mg; a 30% increase in paclitaxel dose resulted in an increase of ~74% in Cmax and ~87% in AUC. This finding provided additional evidence for the nonlinear disposition for paclitaxel, as noted previously (31) .


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  		Table 7 Mean (percentage coefficient of variation) pharmacokinetic parameters of paclitaxel

 


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  		Fig. 5. Mean plasma paclitaxel concentrations after single-dose 3-h i.v. infusion of paclitaxel in combination with multiple-dose oral administration of lonafarnib to patients with solid tumors.

 


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  		Fig. 6. Individual and mean (±1 SD) Cmax values of paclitaxel after single-dose 3-h i.v. infusion of paclitaxel in combination with multiple-dose oral administration of lonafarnib to patients with solid tumors.

 
Plasma paclitaxel concentrations decreased rapidly immediately after cessation of the 3-h infusion, which was followed by a prolonged terminal phase (see Fig. 5Citation ). The mean terminal elimination t1/2 of paclitaxel ranged from 12 to 19 h when blood samples were collected up to 48 h postdose for the first 17 patients. The mean t1/2 was ~6 h when blood samples were collected up to 24 h postdose for patients 18–24 (see Table 7Citation ). The 6-h half-life was similar to that reported in the literature (31) . The Cmax and AUC values obtained in this study were similar to those previously reported when paclitaxel was given alone as a 3-h i.v. infusion (Table 8Citation ; Ref. 31 ).


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  		Table 8 Mean (coefficient of variation) pharmacokinetic parameters of paclitaxel after 3-h i.v. infusion of paclitaxel 135 mg/m2 or 175 mg/m2 in combination with multiple-dose lonafarnib 100 mg b.i.d., 125 mg b.i.d., or 150 mg b.i.d. (this study) or alone (previously reported study)

 
Clinical Activity.
The median number of treatment cycles on trial was eight, with a median of seven cycles containing paclitaxel. Activity was seen at the four dose levels studied (2, 3, 3A, and 4). Nine responses were durable, which we defined as a response detected at three or six cycles and confirmed at six or eight cycles, with median response duration of 6 months (range, 4–14 months). Most provocatively, we saw meaningful responses in three patients who had received prior taxane-based therapy, including two of five NSCLC patients who met the standard definition of taxane resistance (progression on or within 3 months of taxane therapy). Only 4 of 21 patients had progressive disease by cycle 3, although all 21 patients had manifested disease progression within 3 months of study enrollment.

At the cycle-3 assessment interval, 7 patients demonstrated a partial response, 10 had minor responses or stable disease, and 4 had progressive disease (Table 9)Citation . Six of 7 responses were confirmed after six cycles. When total responses achieved on study were examined, 6 (50%) of the 12 patients with NSCLC achieved a partial response. In the setting of head and neck squamous cell carcinoma, two of the three patients had a partial response, and the one patient with a salivary gland tumor had prolonged disease stabilization and was treated for 30 cycles before disease progression. No significant associations were noted between response after three cycles or after six cycles and the dose of either lonafarnib (P = 0.81, P = 0.70, respectively) or paclitaxel (P = 0.19, P = 0.32, respectively).


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  		Table 9 Clinical activity of lonafarnib in combination with paclitaxel

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Other than the occasionally dose-limiting side effect of diarrhea, lonafarnib did not seem to contribute any significant side effects to those caused by paclitaxel. Patients with previous chemotherapy had a higher risk of toxicity. The substantial overlap of the eight 90% confidence intervals is due in large part to the small sample size (n = 21 evaluable patients). The only discernable trend with dose is an increase in the upper confidence limit with increasing total combined dose. Seven of the eight confidence intervals contain the targeted 30% toxicity rate. More precise estimates of the probability of toxicity would necessitate a larger sample size. The MTDs of lonafarnib and paclitaxel in this trial were lower than the doses recommended for either agent alone. The MTD of lonafarnib alone was determined to be 200 mg b.i.d. DLTs in studies of lonafarnib alone were generally similar to those seen in this trial and included reversible renal insufficiency (elevated creatinine levels), gastrointestinal symptoms (diarrhea, nausea, vomiting, anorexia), and hematological toxicities. Phase I studies of paclitaxel have demonstrated an MTD of 200 mg/m2 for a single continuous infusion i.v. regimen. Myelosuppression and neurotoxicity are the primary DLTs of paclitaxel. Severe allergic reactions and skin rash associated with the vehicle (cremaphor EL) necessitate pretreatment with dexamethasone, diphenhydramine, and cimetidine or ranitidine.

No pharmacokinetic evidence was observed that either paclitaxel or lonafarnib enhanced the metabolism of the other agent. The pharmacokinetic values suggest that areas under the curve of both drugs were achieved in the active range. The target exposure for lonafarnib in clinical studies was to maintain a predose concentration in the range of 1–1.5 µM based on the concentration required to inhibit anchorage-independent growth of a series of human tumor cell lines.

We saw encouraging clinical activity in this Phase I study of combined paclitaxel and lonafarnib, confirming the preclinical activity previously reported for this combination (14 , 20 , 22 , 32, 33, 34) . Several Phase I studies of farnesyltransferase inhibitors have now been published (28, 29, 30 , 35, 36, 37, 38, 39) . Before this study, a total of two responses have been documented (one each with tipifarnib and lonafarnib) in previously treated patients with NSCLC (29 , 36) . The activity manifested with this protocol using fairly moderate doses of lonafarnib and paclitaxel is more substantial. It is particularly heartening because little if any evidence exists to support the efficacy of paclitaxel as a second-line agent when administered as a 3-h infusion on a 3-week cycle (40, 41, 42, 43, 44) .

The extent of disease stabilization that our trial revealed with this regimen was dramatic in an extensively pretreated heterogeneous patient population with progressive disease at the time of study enrollment. Recent evidence suggests that the stabilization of NSCLC may lead to clinically meaningful survival benefits.

In conclusion, this is the first reported clinical study of the combination of a taxane with a farnesyltransferase inhibitor in human solid tumors. Phase II trials of the combination as first-line and second-line therapy of stage III and IV NSCLC are ongoing to confirm or refute our data-driven hypothesis, namely, that lonafarnib may enhance taxane sensitivity and possibly overcome clinical taxane resistance in solid tumors.


   ACKNOWLEDGMENTS
 
We thank Judie Wells for transcription and editing of the manuscript, Julie Starr for her expert editorial assistance, and Delores Curtis and Stephen Maxwell for bioanalytical support.


   FOOTNOTES
 
Grant support: F. Khuri was supported by Schering-Plough Research Institute and DAMD 17-02-1-0706.

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: Fadlo R. Khuri, Winship Cancer Institute, Emory University, 1365 Clifton Road NE, Building C-3094, Atlanta, GA 30322. Phone: (404) 778-4250; Fax: (404) 778-5520; E-mail: fkhuri{at}emory.edu

Received 10/15/03; revised 12/16/03; accepted 1/ 9/04.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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