Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer

J. V. Heymach1, D. H. Johnson2, F. R. Khuri3, H. Safran4, L. L. Schlabach5, F. Yunus6, R. F. DeVore, III2, P. M. De Porre7, H. M. Richards7, X. Jia7, S. Zhang7 and B. E. Johnson1,*

1 Dana Farber Cancer Institute and Massachusetts General Hospital, Boston, MA; 2 Vanderbilt-Ingram Cancer Center, Nashville, TN; 3 MD Anderson Cancer Center, Houston, TX; 4 Brown University, Providence, RI; 5 Erlanger Medical Center, Chattanooga, TN; 6 University of Tennessee Cancer Institute, Memphis, TN; 7 Johnson and Johnson Pharmaceutical Research and Development, Titusville, NJ, USA and Beerse, Belgium

* Correspondence to: Dr B. E. Johnson, Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Dana 1234, 44 Binney St, Boston, MA 02115, USA. Tel: +1-617-632-4790; Fax: +1-617-632-5786; Email: bejohnson{at}partners.org


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: R115777 (tipifarnib, ZarnestraTM) is a farnesyl transferase inhibitor that blocks the farnesylation of proteins involved in signal transduction pathways critical for cell proliferation and survival. This multicenter phase II study was conducted to determine the efficacy, tolerability and pharmacokinetics of R115777 in patients with relapsed small-cell lung cancer (SCLC).

Patients and methods: Patients who had a partial or complete response to their initial chemotherapy regimen, followed by at least 3 months off treatment before relapse (sensitive relapse) were eligible. R115777 was administered in 3-week cycles at a dose of 400 mg orally twice daily for 14 consecutive days followed by 7 days off treatment.

Results: Twenty-two patients were enrolled. The median progression-free survival was 1.4 months and median overall survival was 6.8 months. Non-hematological toxicities were predominantly grade 1–2 and included nausea (64%) and fatigue (60%). Grade 3–4 granulocytopenia and thrombocytopenia occurred in 27% and 23% of patients, respectively. Febrile neutropenia was not observed. Pharmacokinetic studies demonstrated peak plasma concentrations of R115777 2.6–4.5 h after oral dosing and no significant drug accumulation. The trial was terminated because no objective responses were observed in 20 patients evaluable for response.

Conclusions: R115777 showed no significant antitumor activity as a single agent in sensitive-relapse SCLC.

Key words: farnesyl transferase inhibitor, R115777, Ras, small-cell lung cancer, tipifarnib


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The aberrant activation of specific intracellular pathways regulating cell proliferation, differentiation and survival is thought to be one of the critical steps in the development of human cancers. Investigations into these pathways have led to the identification of a number of potential targets for therapeutic intervention. Among these, members of the ras oncogene family (N-ras, H-ras and K-ras) have attracted considerable attention because activating mutations of these genes are frequently observed in human cancers. K-ras mutations are present in ~20% of adult malignancies, with higher frequencies in pancreatic adenocarcinoma (90%), colorectal carcinoma (50%), and non-small-cell lung cancer (NSCLC; 30%) [1Go, 2Go]. Therefore, agents that can prevent the aberrant signaling of the mutated Ras proteins have been investigated as potential anticancer agents.

Many proteins, including Ras, undergo the covalent addition of a farnesyl or geranylgeranyl group (prenylation) to become functional in signal transduction and other pathways. An initial step in this process involves farnesylation by the enzyme farnesyl protein transferase (FPT). A number of FPT inhibitors (FTIs) have been developed to target this pathway. The first FTI to enter clinical testing was R115777 (tipifarnib), an oral, nonpeptidomimetic FTI which competitively inhibits the farnesylation of lamin B and K-rasB peptide substrates in vitro with an IC50 of 0.86 nM and 7.9 nM, respectively [3Go]. R115777 inhibited the growth of 75% of the human tumor cell lines tested in vitro, including those of melanoma, rhabdomyosarcoma, pancreatic adenocarcinoma and NSCLC origin. This included 82% (27 out of 33) of cell lines bearing the wild-type ras gene and 65% (13 out of 20) bearing ras mutations [3Go]. R115777 also inhibited the growth of xenograft models of melanoma, colon and pancreatic cancer bearing either mutant H-ras, K-ras or wild-type ras genes by 76–90% [3Go].

The antitumor activity of FTIs was initially thought to be mediated through the inhibition of aberrant Ras signaling, although recent studies suggest that their activity may be mediated by effects on multiple other proteins including RhoB [4Go], members of the phosphatidylinositol 3'kinase (PI3'K)/AKT pathway [5Go], and the centromere-associated proteins CENP-E and CENP-F [6Go]. Consistent with these observations, small-cell lung carcinoma (SCLC) cells have demonstrated sensitivity to FTIs in preclinical studies despite the lack of known ras mutations [7Go–9Go]. For example, the in vitro growth of three out of three human SCLC lines (H345, H716 and H510A) was inhibited by peptidomimetic FTI L-744 832 [10Go]. The growth of NCI-H446 SCLC tumors in athymic nude mice was delayed by 72% with treatment with R115777 (Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium). These studies suggested that FTIs may have antitumor activity against SCLC.

To further investigate FTIs for the treatment of SCLC, we have conducted this phase II trial of R115777 in patients with SCLC who have relapsed after an initial response to therapy. The goals of the study were to determine the clinical activity and tolerability of R115777 administered on a schedule of 400 mg twice daily (BID) for 14 of 21 days, and to investigate the impact of treatment on the quality of life of the study population. This schedule was chosen in an effort to maximize drug exposure while avoiding the dose-limiting myelosuppression that typically occurs in susceptible patients ~10–14 days after administration of doses above 300 mg BID [11Go, 12Go]. For patients that did not show evidence of myelosuppression during the first cycle, a dose escalation to 500 mg BID for 14 of 21 days was permitted at the beginning of cycle two.

R115777 has been administered in phase I–III clinical trials using continuous or intermittent dosing schedules. The continuous dosing caused dose-limiting toxicities (DLTs) of myelosuppression and peripheral neurotoxicity at doses above 300 mg BID [11Go, 12Go]. At doses over 600 mg BID given for 21 consecutive days of every 4-week cycle, DLTs have included central neurotoxicity, including confusion, ataxia and visual disturbances [11Go, 13Go, 14Go]. Most frequent toxicities included myelosuppression, fatigue, nausea and anorexia [11Go–13Go].

Small-cell lung cancer is responsible for about 15% of lung cancers [15Go]. It is typically sensitive to combination chemotherapy as the initial therapy with response rates of up to 80% in limited stage patients [16Go]. Unfortunately, the vast majority of patients eventually relapse, at which point SCLC is significantly less responsive to chemotherapy. Topotecan has been approved by the Food and Drug Administration for the treatment of relapsed SCLC. Despite treatment of patients with relapsed SCLC with active agents such as topotecan, the median survival after relapse is typically <7 months and the 5-year survival is ~1% [17Go–19Go]. These agents are also associated with significant side-effects, with the majority of patients experiencing grade 3–4 hematological toxicity [17Go–19Go]. Therefore, there is clearly a need for more effective and less toxic agents for the treatment of patients with relapsed SCLC.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient eligibility and selection
Patients were eligible if they had initial pathological or cytological evidence of SCLC. The patients needed to have had a complete or partial response to their initial treatment and a 3-month chemotherapy-free interval after the completion of their initial therapy (sensitive relapse) [17Go]. A pathological or cytological confirmation of relapse was required for patients whose sole relapse site was within a previous radiation port. The maximum number of cycles of prior chemotherapy that could have been administered was eight and the maximum duration was 6 months. Subjects treated with two or more prior chemotherapy regimens were not eligible. The patients needed to wait at least 2 weeks since their last dose of irradiation and have no option for potentially curative therapy available. Other eligibility criteria included bidimensionally measurable disease with at least one lesion ≥2 cm, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and age ≥18 years. For women of childbearing potential, a negative pregnancy test was required prior to enrolment and the use of birth control was required while participating in the trial. All subjects were required to have adequate bone marrow function, defined by an absolute neutrophil count >1500/µl and a platelet count >100 000/µl, as well as bilirubin within normal limits, alanine aminotransferase and aspartate aminotransferase <2.5 times the upper limit of normal (<5 times the upper limit of normal if documented liver metastases were present), and serum creatinine below 2.5 mg/dl. Subjects with mixed small-cell/non-small-cell histology, extensive liver metastases replacing >50% of liver parenchyma, uncontrolled brain metastases, prior extensive radiation therapy to >25% of bone marrow reserve, or other coexisting medical conditions likely to interfere with study participation were not eligible.

The study was approved by the Institutional Review Boards at each participating center and was conducted in accordance with Institutional Review Board regulations. All patients provided written, informed consent.

Treatment plan and study design
The trial was designed as a two-stage, single-arm, open-label, fixed-dose phase II trial of R115777. The initial stage called for 22 patients to be enrolled and observed for response to treatment; the trial would be terminated if fewer than three patients had a partial or complete response to treatment. The trial was terminated at this initial phase. The primary objective was to determine the overall objective response rate and duration of response to treatment with R115777. Secondary objectives were to estimate the time to progression, overall survival and safety in patients with relapsed SCLC. The quality of life and lung cancer related symptoms were assessed at screening and day 15 of each cycle using the Q-tility scale and FACT-L (Functional Assessment of Cancer Therapy-Lung) Version 4, which incorporates five functional scales related to general health and lung cancer (physical, social/family, emotional and functional well-being as well as lung cancer symptoms). Possible scores range from 0 (asymptomatic) to 136 (fully symptomatic).

R115777 was given orally at a dose of 400 mg BID for 14 days followed by a 7-day rest period (21-day cycle) until disease progression or unacceptable toxicity. For patients with no evidence of hematological toxicity grade ≥3, or non-hematological toxicity grade ≥2, a dose escalation to 500 mg BID using the same schedule was permitted at the beginning of cycle two. Toxicities were scored according to the National Cancer Institute (NCI) common toxicity criteria version 2.0. Treatment was temporarily held for grade ≥2 neurological or renal toxicity, or grade 3–4 hematological or non-hematological toxicity if they were deemed to be drug-related. When the toxicity diminished to grade 1 or resolved, treatment was reduced by 100 mg BID. A second dose reduction was permitted. For subjects developing grade ≥2 neurological or renal toxicity, or grade 3–4 hematological or non-hematological toxicity despite two reductions, treatment was discontinued permanently.

Patient evaluation
Pretreatment evaluation included a complete medical history and physical examination, electrocardiogram, clinical laboratory studies, and a pregnancy test for women of childbearing potential. In addition, because de novo cataract formation was observed in one chronic toxicity study in rats, but not in dogs or other studies, an ophthalmic examination with slit lamp biomicroscopy was performed before starting treatment, after completing cycle 1, and at every other cycle thereafter. Tumor assessment at baseline included computerized tomography of the head, chest and abdomen as well as any other sites of known or suspected disease. Patients were evaluated for response to therapy every two cycles unless otherwise clinically indicated. Responses were classified as complete response (CR), partial response (PR), progressive disease (PD) or stable disease (SD) using the World Health Organization response criteria [20Go].

Pharmacokinetics
A sparse sampling procedure was followed to characterize the pharmacokinetics of R115777. On treatment day 1, one venous blood sample was collected between 1 and 3 h after drug intake. On treatment day 8, two venous blood samples were collected at times separated by at least 1 h. All venous blood samples were collected in heparinized tubes, centrifuged (2500 r.p.m. at 1000 g for 10 min), and separated plasma was stored at –20°C prior to transportation to Johnson and Johnson Pharmaceutical Research and Development (Beerse, Belgium) for determination of plasma R115777 concentration by a validated liquid chromatography with tandem mass spectrometry method (lower limit of quantification of <2 ng/ml) [13Go].

 A Bayesian estimation of pharmacokinetic (PK) parameters of R115777 was implemented in NONMEM software (GloboMax LCC, Hanover, MD, USA) using the POSTHOC option. The results of a previous population PK analysis of R115777 using data from six phase I trials were used to describe the time course of R115777 plasma concentration. The PK model is a three-compartment disposition model, with first-order elimination from a central compartment and sequential zero order–first order absorption process and lag time. Area under the curve (AUC) values were calculated from the individual Bayesian estimation of clearance and absolute bioavailability, and normalized for dosing of 400 mg BID [21Go].


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Twenty-two patients were treated on the study from June 1999 to November 2000: 11 men (50%) and 11 women with a median age of 62 years (Table 1). All patients had previously been treated with systemic chemotherapy, consisting of etoposide plus either cisplatin or carboplatin in 18, or a three-drug regimen which included etoposide plus cisplatin or carboplatin plus either paclitaxel or topotecan in four patients. Thirteen patients were previously treated with chest radiotherapy, eight were treated with cranial irradiation and one was treated for bone metastasis in spine and femur. Six patients had an ECOG performance status of 0 and 16 (73%) had a performance status of 1.


View this table:
[in this window]
[in a new window]
 
Table 1. Patient characteristics

 
Treatment duration
The median period of time enrolled on the study was 35 days (range 2–142). Sixteen patients were discontinued for progressive disease and six due to drug-related adverse events described below. Nineteen patients (87%) received less than or equal to two cycles of therapy, while two patients received four cycles and one received seven cycles. One patient died on day 7 from respiratory failure secondary to tumor progression with lymphangitic spread after receiving 3 days of R115777.

Efficacy
Twenty out of 22 patients were evaluable for response to therapy because two patients had their R115777 discontinued during the first cycle for drug-related toxicity and were therefore not evaluable. No objective tumor responses were observed. One patient did have stable disease for 4.7 months. The median time to disease progression was 1.4 months. The trial was terminated at the end of the first stage as designed, because of the absence of objective tumor responses. Five patients died within 30 days after discontinuation from the trial, in addition to the aforementioned patient who died on day 7 from disease progression. These deaths were attributed to disease-related hypoxemia (two patients) and disease progression (three patients). All 22 patients enrolled in the study have died. The median overall survival for all 22 patients was 6.8 months (range 0.2–46.9 months), with 1-year and 2-year survival rates of 23% and 14%, respectively (Figure 1).



View larger version (12K):
[in this window]
[in a new window]
 
Figure 1. Kaplan–Meier curve for overall survival.

 
Quality of life parameters were evaluated using the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale. A six-point change in FACT-L has been shown to be clinically meaningful [22Go]. For 15 evaluable patients who completed the survey at baseline and at the end of study, the score at the end of the study (72.42) was not significantly different from baseline (70.42). Likewise, for the Q-tility index, which addresses different items related to quality of life, scores were unchanged (data not shown).

Pharmacokinetics
Pharmacokinetic (PK) analysis of R115777 was performed on the basis of 47 plasma samples obtained from 19 patients. The time course of R115777 plasma concentration following first and repeated doses is shown in Figure 2 for the administration of the 400 mg BID regimen. The circles in the figure represent the observed plasma concentration, and the lines represent the median and the 90% prediction interval, calculated by simulation from the population PK model used to obtain the individual Bayesian estimates of the PK parameters. A descriptive summary of the R115777 PK parameters and their variability is shown in Table 2. Between and within patients, variability in PK of R115777 was high. After repeated doses, the mean plasma concentration of R115777, defined as the mean AUC over 24 h divided by 24 h, was 724 ng/ml (range 350–1536 ng/ml). This value (1480 nM) is above the range of IC50 concentrations at which antiproliferative activity was observed in vitro (~1–100 nM) for the majority of human cancer cell lines evaluated [3Go].



View larger version (18K):
[in this window]
[in a new window]
 
Figure 2. Pharmacokinetic analysis of R115777. Time course of R115777 plasma concentrations after the first (A) and repeat doses (B) of R115777 400 mg twice daily. Open circles represent observed plasma concentration. The median values (solid line) and 90% prediction interval (gray line) are shown.

 

View this table:
[in this window]
[in a new window]
 
Table 2. Pharmacokinetic parameters of R115777 in SCLC patients

 
Tolerability
All 22 subjects experienced one or more adverse events during the trial. Myelosuppression was evidenced by thrombocytopenia (46%), granulocytopenia (32%) and leukopenia (14%), most of which were grade 3–4, as well as grade 1–2 anemia (27%). Febrile neutropenia was not observed. The most common non-hematological toxicities observed were nausea, fatigue and anorexia, which were usually grade 1 or 2 (Table 3). Other common toxicities included coughing, dyspnea, pain, asthenia, dehydration, rhinitis and tachycardia. Other grade 3 non-hematological adverse events included vomiting (9%) and hypokalemia (9%). Two patients developed acute impairment of renal function during treatment. One patient was a 74-year-old woman with a history of hypertension who had previously been treated with carboplatin and etoposide. On day 36 of treatment she was hospitalized with chills and was noted to have impaired renal function, lymphopenia and anemia. She received no further study drug, and died due to progressive disease 30 days later. The creatinine level remained elevated until the time of her death, and was deemed to be drug-related. The second patient was a 71-year-old man with a history of headaches secondary to brain metastases, who had previously been treated with carboplatin, etoposide and radiotherapy to the chest. After 13 days of treatment at a dose of 400 mg BID, the trial drug was discontinued because of grade 4 neutropenia and thrombocytopenia, grade 3 mental status changes and dehydration, and grade 3 acute impaired renal function. The mental status changes were attributed to progressive brain metastases. The other adverse effects all resolved after discontinuation of the study drug. The impaired renal function was thought to probably be drug-related. One patient developed optic neuritis on day 37 that was confirmed by ophthalmological examination and improved after discontinuation of R115777. No cataracts were observed.


View this table:
[in this window]
[in a new window]
 
Table 3. Commona or severe (grade 3/4) adverse events

 
Six patients discontinued treatment for drug-related adverse events: grade 4 neutropenia and/or thrombocytopenia (n=2), grade 3 rash (n=1), grade 3 renal function impairment (n=1), grade 4 fatigue (n=1) and grade 3 optic neuritis (n=1). Four patients required dose reduction, primarily for neutropenia or thrombocytopenia. There were no drug-related deaths. Five patients were escalated to a dose of 500 mg BID. Two of these discontinued for PD at the next cycle, two patients subsequently received dose reductions for nausea or fatigue, while one received a total of three cycles at this dose.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In this phase II trial we assessed the activity of the farnesyl protein transferase inhibitor R115777 in patients with sensitive-relapse SCLC. None of the 20 evaluable patients achieved an objective tumor response.

It has been postulated that many targeted agents would be primarily cytostatic rather than cytotoxic. Therefore, time to progression has been proposed as a more appropriate indicator of biological activity than objective response rate [23Go]. Out of 14 patients who discontinued for PD, only three did so beyond two cycles, yielding a median time to progression (TTP) of 1.4 months. In recent trials using topotecan in recurrent SCLC, a longer median TTP as well as objective tumor responses were observed [17Go–19Go, 24Go]. For example, in a trial comparing topotecan versus cyclophosphamide, doxorubicin and vincristine (CAV) in patients who relapsed at least 60 days after first-line therapy, objective response rates of 24% and 18% were reported, with a median TTP of 3.1 and 2.8 months, respectively [19Go]. In sensitive-relapsed patients treated with cisplatin and topotecan, a response rate of 29% and median TTP of 4.7 months was observed [25Go]. Hence, as judged by response rate or TTP, R115777 did not appear to have antitumor activity comparable to conventional chemotherapy in sensitive-relapsed SCLC. Despite this observed lack of antitumor activity, the overall survival of 6.8 months was comparable to that observed in trials of sensitive-relapse patients treated with either CAV, topotecan or topotecan combined with cisplatin [17Go, 19Go, 25Go]. This is consistent with prior studies of patients with extensive stage SCLC in which it was observed that treatment with an investigational agent did not appear to have an adverse effect on survival, even if the agent had little or no antitumor activity [26Go, 27Go]. This may be due to the availability of salvage chemotherapy for patients with PD.

R115777 has shown evidence of antitumor activity against several different types of malignancies, including breast cancer [12Go], glioblastoma [28Go], acute leukemias [14Go], myelodysplastic syndrome [29Go] and chronic myelogenous leukemia [30Go]. In contrast, it has shown little or no antitumor activity as front-line therapy in phase II trials in patients with advanced NSCLC [31Go] and pancreatic adenocarcinoma [32Go]. Preliminary reports also suggest a lack of activity in previously treated colorectal cancer [33Go] and hormone-refractory prostate cancer [34Go]. The molecular basis for this spectrum of activity is not yet understood.

One possible explanation for lack of antitumor activity in SCLC is the absence of activating Ras mutations. However, several lines of evidence suggest that the presence of Ras mutations does not predict responsiveness to FTIs. For example, despite the presence of K-ras mutations in virtually all pancreatic adenocarcinomas and 30% of NSCLC, R115777 showed no significant single-agent antitumor activity in these diseases [31Go, 32Go]. Clinical activity has, however, been observed in leukemias and other malignancies lacking known ras mutations [11Go, 14Go, 30Go]. These data suggest that other potential targets for FTIs, such as RhoB, the phosphatidylinositol 3'-kinase /AKT pathway, or wild-type Ras protein are likely to play a role in their antitumor activity [4Go–6Go]. Therefore, while SCLC may lack one potential target for FTIs (mutated Ras) this target does not appear to be the sole determinant of FTI antitumor activity.

Another possible explanation for the lack of antitumor activity observed in this study could be that the degree, or duration, of FPT inhibition achieved in the target tumor cells was inadequate. However, several studies have demonstrated at least a partial inhibition of FPT activity in surrogate tissues at doses comparable to or lower than those used in this study [14Go, 31Go, 32Go]. For example, Cohen et al. demonstrated a 49.8±9.8% inhibition of FPT activity in peripheral blood mononunuclear cells on day 1 of treatment at a dose of 300 mg BID for 21 of 28 days [32Go]. The PK analysis suggests that the mean plasma concentration observed in our study (724 ng/ml) was higher than that observed in the Cohen et al. study. Adjei et al. also showed evidence of FPT inhibition in buccal mucosa and peripheral blood mononuclear cells in >80% of patients after 8 days of treatment at a dose of 300 mg BID [31Go]. Moreover, antitumor activity has been observed at doses comparable to those used here. In a phase II study of 76 patients with advanced breast cancer, partial response rates of 10% and 15% were observed using either a continuous (300 or 400 mg orally BID) or intermittent (300 mg orally BID for days 1–21, with 7 days rest) dosing regimen, respectively, with the continuous regimen showing significantly greater hematological and neurological toxicity [12Go].

To avoid the toxicities observed with continuous dosing, an intermittent schedule was tested with a dose of 400 mg BID for 14 of 21 days. Six patients were discontinued for toxicities that were thought to be drug related (neutropenia and/or thrombocytopenia in two patients; fatigue, rash, elevated creatinine and optic neuritis in one each). There were no cases of febrile neutropenia, thrombocytopenia leading to bleeding events, or life-threatening drug-related toxicities observed. Non-hematological adverse events rarely exceeded grade 2. Overall toxicities were similar to those reported in phase II trials for other solid tumors using different dosing regimens [12Go, 31Go, 32Go], although these studies are not directly comparable because of differences in the patient populations and degree of pretreatment.

The PK analysis demonstrated significant inter- and intra-patient variability in plasma levels of R11577. High inter-patient variability has also been observed in prior phase I studies of R115777 [11Go, 13Go] and was thought to possibly be due to the interindividual differences in oral bioavailability. Differences in renal function may also play a role in this variability as R115777 is eliminated in part through urinary excretion of a metabolite [13Go].

In summary, this trial demonstrates that R115777 had no significant activity as a single agent at a dose of 400 mg BID for 14 of 21 days in patients with sensitive-relapsed SCLC. Preclinical studies suggest that FTIs may enhance the in vitro activity of chemotherapeutic agents such as cisplatin and paclitaxel against a variety of human cell lines including A549 NSCLC cells [35Go]. FTIs may also reverse the resistance of certain cancer cells to ionizing radiation [36Go]. Moreover, by interfering with Ras signaling, FTIs may augment the therapeutic effect of receptor tyrosine kinase inhibitors and other targeted agents. If such combinations were to show promising activity they may merit consideration for further assessment in SCLC.


    Acknowledgements
 
The authors would like to thank Edward Mckoy for his assistance in tabulating clinical trial data. This study was supported by Johnson and Johnson Pharmaceutical Research and Development.

Received for publication March 16, 2004. Revision received April 14, 2004. Accepted for publication April 15, 2004.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Grunewald K, Lyons J, Frohlich A et al. High frequency of Ki-ras codon 12 mutations in pancreatic adenocarcinomas. Int J Cancer 1989; 43: 1037–1041.[ISI][Medline]

2. Rodenhuis S, Slebos RJ. Clinical significance of ras oncogene activation in human lung cancer. Cancer Res 1992; 52: 2665s–2669s.[Abstract]

3. End DW, Smets G, Todd AV et al. Characterization of the antitumor effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001; 61: 131–137.[Abstract/Free Full Text]

4. Lebowitz PF, Casey PJ, Prendergast GC, Thissen JA. Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB. J Biol Chem 1997; 272: 15591–15594.[Abstract/Free Full Text]

5. Du W, Liu A, Prendergast GC. Activation of the PI3’K-AKT pathway masks the proapoptotic effects of farnesyltransferase inhibitors. Cancer Res 1999; 59: 4208–4212.[Abstract/Free Full Text]

6. Ashar HR, James L, Gray K et al. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J Biol Chem 2000; 275: 30451–30457.[Abstract/Free Full Text]

7. Wistuba II, Gazdar AF, Minna JD. Molecular genetics of small cell lung carcinoma. Semin Oncol 2001; 28: 3–13.

8. Salgia R, Skarin AT. Molecular abnormalities in lung cancer. J Clin Oncol 1998; 16: 1207–1217.[Abstract]

9. Mitsudomi T, Viallet J, Mulshine JL et al. Mutations of ras genes distinguish a subset of non-small-cell lung cancer cell lines from small-cell lung cancer cell lines. Oncogene 1991; 6: 1353–1362.[ISI][Medline]

10. Sepp-Lorenzino L, Ma Z, Rands E et al. A peptidomimetic inhibitor of farnesyl protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res 1995; 55: 5302–5309.[Abstract]

11. Crul M, de Klerk GJ, Swart M et al. Phase I clinical and pharmacologic study of chronic oral administration of the farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 2002; 20: 2726–2735.[Abstract/Free Full Text]

12. Johnston SR, Hickish T, Ellis P et al. Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer. J Clin Oncol 2003; 21: 2492–2499.[Abstract/Free Full Text]

13. Zujewski J, Horak ID, Bol CJ et al. Phase I and pharmacokinetic study of farnesyl protein transferase inhibitor R115777 in advanced cancer. J Clin Oncol 2000; 18: 927–941.[Abstract/Free Full Text]

14. Karp JE, Lancet JE, Kaufmann SH et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 2001; 97: 3361–3369.[Abstract/Free Full Text]

15. Chute JP, Chen T, Feigal E, Simon R, Johnson BE. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol 1999; 17: 1794–1801.[Abstract/Free Full Text]

16. Janne PA, Freidlin B, Saxman S et al. Twenty-five years of clinical research for patients with limited-stage small cell lung carcinoma in North America. Cancer 2002; 95: 1528–1538.[CrossRef][ISI][Medline]

17. Ardizzoni A, Hansen H, Dombernowsky P et al. Topotecan, a new active drug in the second-line treatment of small-cell lung cancer: a phase II study in patients with refractory and sensitive disease. The European Organization for Research and Treatment of Cancer Early Clinical Studies Group and New Drug Development Office, and the Lung Cancer Cooperative Group. J Clin Oncol 1997; 15: 2090–2096.[Abstract]

18. Perez-Soler R, Glisson BS, Lee JS et al. Treatment of patients with small-cell lung cancer refractory to etoposide and cisplatin with the topoisomerase I poison topotecan. J Clin Oncol 1996; 14: 2785–2790.[Abstract]

19. von Pawel J, Schiller JH, Shepherd FA et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 1999; 17: 658–667.[Abstract/Free Full Text]

20. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47: 207–214.[ISI][Medline]

21. Perez-Ruixo JJ, Piotrovsky V, Cowan KH et al. Population pharamacokinetic analysis of Zarnestra using data from Phase I clinical trials. Proc IX Meeting of Population Approach Group in Europe 2002; (Abstr 21).

22. Cella D, Eton DT, Fairclough DL et al. What is a clinically meaningful change on the Functional Assessment of Cancer Therapy-Lung (FACT-L) Questionnaire? Results from Eastern Cooperative Oncology Group (ECOG) Study 5592. J Clin Epidemiol 2002; 55: 285–295.[CrossRef][ISI][Medline]

23. Korn EL, Arbuck SG, Pluda JM et al. Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol 2001; 19: 265–272.[Abstract/Free Full Text]

24. Schiller JH, Adak S, Cella D et al. Topotecan versus observation after cisplatin plus etoposide in extensive-stage small-cell lung cancer: E7593—a phase III trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2001; 19: 2114–2122.[Abstract/Free Full Text]

25. Ardizzoni A, Manegold C, Debruyne C et al. European Organization for Research and Treatment of Cancer (EORTC) 08957 phase II study of topotecan in combination with cisplatin as second-line treatment of refractory and sensitive small cell lung cancer. Clin Cancer Res 2003; 9: 143–150.[Abstract/Free Full Text]

26. Johnson BE, Fischer T, Fischer B et al. Phase II study of imatinib in patients with small cell lung cancer. Clin Cancer Res 2003; 9: 5880–5887.[Abstract/Free Full Text]

27. Ettinger DS, Finkelstein DM, Abeloff MD et al. Justification for evaluating new anticancer drugs in selected untreated patients with extensive-stage small-cell lung cancer: an Eastern Cooperative Oncology Group randomized study. J Natl Cancer Inst 1992; 84: 1077–1084.[Abstract]

28. Cloughesy TF, Kuhn J, Wen P et al. Phase II trial of R115777 (Zarnestra) in patients with recurrent glioma not taking enzyme inducing antiepileptic drugs (EIAED): a North American Brain Tumor Consortium (NABTC) report. Proc Am Soc Clin Oncol 2002; 21: (Abstr 317).

29. Kurzrock R, Kantarjian HM, Cortes JE et al. Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting. Blood 2003; 102: 4527–4534.[Abstract/Free Full Text]

30. Cortes J, Albitar M, Thomas D et al. Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies. Blood 2003; 101: 1692–1697.[Abstract/Free Full Text]

31. Adjei AA, Mauer A, Bruzek L et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with advanced non-small-cell lung cancer. J Clin Oncol 2003; 21: 1760–1766.[Abstract/Free Full Text]

32. Cohen SJ, Ho L, Ranganathan S et al. Phase II and pharmacodynamic study of the farnesyltransferase inhibitor R115777 as initial therapy in patients with metastatic pancreatic adenocarcinoma. J Clin Oncol 2003; 21: 1301–1306.[Abstract/Free Full Text]

33. Cunningham D, de Gramont A, Scheithauer W et al. Randomized double-blind placebo-controlled trial of the farnesyltransferase inhibitor R115777 (Zarnestra) in advanced refractory colorectal cancer. Proc Am Soc Clin Oncol 2002; 21: 502.

34. Haas N, Peereboom D, Ranganathan S et al. Phase II trial of R115777, an inhibitor of farnesyltransferase in patients with hormone refractory prostate cancer. Proc Am Soc Clin Oncol 2002; 21: 721.

35. Moasser MM, Sepp-Lorenzino L, Kohl NE et al. Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones. Proc Natl Acad Sci USA 1998; 95: 1369–1374.[Abstract/Free Full Text]

36. Delmas C, Heliez C, Cohen-Jonathan E et al. Farnesyltransferase inhibitor, R115777, reverses the resistance of human glioma cell lines to ionizing radiation. Int J Cancer 2002; 100: 43–48.[CrossRef][ISI][Medline]