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Phase II Study of the Efficacy and Tolerability of Two Dosing Regimens of the Farnesyl Transferase Inhibitor, R115777, in Advanced Breast Cancer

Stephen R.D. Johnston, Tamas Hickish, Paul Ellis, Stephen Houston, Lloyd Kelland, Mitch Dowsett, Janine Salter, Bart Michiels, Juan Jose Perez-Ruixo, Peter Palmer, Angela Howes

From the Departments of Medicine and Academic Department of Biochemistry, Royal Marsden Hospital; Department of Medical Oncology, Guy’s Kings & St Thomas’ Cancer Centre, Guy’s Hospital, London; Department of Haematology & Oncology, Royal Bournemouth General Hospital, Bournemouth; St Luke’s Cancer Centre, Royal Surrey County Hospital, Guilford; CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton; Johnson & Johnson Pharmaceutical Research & Development, Saunderton, United Kingdom; and Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium.

Address reprint requests to Stephen R.D. Johnston, MD, PhD, Royal Marsden Hospital and Institute of Cancer Research, Fulham Road, London SW3 6JJ, United Kingdom; email: stephen.johnston{at}rmh.nthames.nhs.uk.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: R115777 is an orally active farnesyl transferase inhibitor that specifically blocks farnesylation of proteins involved in growth-factor–dependent cell-signal–transduction pathways. We conducted a phase II study in 76 patients with advanced breast cancer.

Patients and Methods: Two cohorts of patients were recruited sequentially. The first cohort (n = 41) received a continuous dosing [CD] regimen of R115777 400 or 300 mg bid. The second cohort (n = 35) received 300 mg bid in a cyclical regimen of 21 days of treatment followed by 7 days of rest (intermittent dosing [ID]).

Results: In the CD cohort, four patients (10%) had a partial response (PR) and six patients (15%) had stable disease at ≥ 24 weeks (SD). In the ID cohort, five patients (14%) had a PR and three patients (9%) had prolonged SD. The first six patients in the CD cohort treated at 400 mg bid all developed grade 3 to 4 neutropenia, so the subsequent 35 patients were treated at 300 mg bid. The incidence of hematologic toxicity was significantly lower in the ID than in the CD (300-mg bid) cohort: grade 3 to 4 neutropenia (14% v 43%; P = .016) and grade 3 to 4 thrombocytopenia (3% v 26%; P = .013). One patient in the ID cohort developed grade 2 to 3 neurotoxicity compared with 15 patients in the CD cohort (3% v 37%; P = .0004).

Conclusion: The farnesyl transferase inhibitor R115777 has demonstrated clinical activity in patients with metastatic breast cancer, and the ID regimen has a significantly improved therapeutic index compared with the CD regimen.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
IN BREAST cancer, proto-oncogenes that result in overexpression or aberrant function of their encoded protein represent an obvious target for development of novel therapies.¹ Elucidation of the signal transduction cascade downstream of cell membrane growth factor receptors has revealed several key proteins involved in malignant transformation, including the 21-kd guanine nucleotide-binding proteins encoded by the ras proto-oncogene. Processed Ras proteins localize to the inner plasma membrane, and play a critical role in transmission of extracellular signals from the cell surface, including from growth factors that activate cell surface receptors (eg, epidermal growth factor receptor [EGFR] and human epidermal growth factor-2 [HER2]).² Although human breast carcinomas rarely contain ras mutations (< 2%),³ aberrant function of the Ras signal transduction pathway may be common because of enhanced upstream growth factor receptor activity.⁴ Posttranslational Ras processing involves transfer of a 15-carbon farnesyl group from farnesyldiphosphate to the C-terminal tetrapeptide CAAX sequence.⁵ This prenylation reaction is catalyzed by the farnesylproteintransferase enzyme, and several nonpeptide farnesyl transferase inhibitors have been developed to target this enzyme^6,7

R115777 (Zarnestra, Johnson & Johnson, Beerse, Belgium) is an imidazole-containing heterocyclic compound (Fig 1), which is a potent and selective, orally active, nonpeptidomimetic inhibitor of farnesylproteintransferase.⁸ The growth of several human tumor cell lines, including those with either wild-type or mutant ras, is inhibited by R115777 at inhibitory concentrations at 50% ranging between 1.7 and 50 nmol/L. In vivo bid dosing of R115777 shows dose-dependent growth inhibition of human colon and pancreatic cancer xenografts, with various histologic antitumor effects including apoptotic, antiproliferative, and antiangiogenic responses.⁸ Growth of hormone-sensitive wild-type ras MCF-7 breast cancer xenografts is inhibited by R115777, with evidence of apoptosis and enhanced expression of the cyclin-dependent kinase inhibitor p21.⁹ In phase I trials R115777 has been administered at doses up to 1,300 mg bid for 5 days every 2 weeks without significant toxicities.¹⁰ Long-term therapy with R115777 has been investigated in two additional phase I studies, either with bid dosing for 14 or 21 days followed by 7 days rest¹¹ or continuous oral dosing;¹² reversible myelosuppression was the dose-limiting toxicity.

View larger version (17K): [in this window] [in a new window]   Fig 1. Chemical structure of R115777.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility Criteria
Women were eligible for the study if they had locally advanced or metastatic breast cancer that was progressing at the time of study entry. Seventy-two patients had measurable lesions and four patients had disease that was considered assessable (eg, skin lesions < 10 mm or pleural disease). Patients were eligible if they had either estrogen-receptor–positive (ER-positive) disease and had experienced treatment failure from second-line endocrine therapy after prior tamoxifen or if they had ER-negative disease. One prior chemotherapy regimen for advanced disease was allowed. Concurrent bisphosphonate therapy was not permitted. Patients with life-threatening visceral metastases or extensive prior radiotherapy (> 25% of bone marrow reserve) were ineligible. Other eligibility criteria included Eastern Cooperative Oncology Group performance status ≤ 2, no chemotherapy or investigational drug ≤ 4 weeks, WBC count more than 3.5 x 10⁹/L, platelet count more than 100 x 10⁹/L, bilirubin and serum creatinine less than 1.5 times the normal upper limit, and AST less than 2.5 times the normal upper limit. All patients gave written informed consent, and the protocol was approved by the institutional review board or ethics committee at each participating institution.

Study Design and Drug Administration
When this study was initiated, available phase I data indicated a starting dose of 400 mg bid R115777 in a CD schedule. However, when the study was started, it became clear that the maximum-tolerated dose by CD schedule was 300 mg bid. Thus, after six patients had received 400 mg bid, the starting dose for subsequent patients was amended to 300 mg bid and the dose was reduced in the initial six patients. In addition, the protocol was amended to study a sequential cohort of 35 patients using an ID schedule of 300 mg bid for 21 days followed by 7 days of rest. R115777 {(B)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)-methyl]-4-(3-chlorophenyl)-1-methyl-2(quinolinone)} was supplied by Johnson & Johnson Pharmaceutical Research & Development (Beerse, Belgium) as 100-mg capsules. Patients took the capsules twice a day immediately after a meal, with morning and evening drug intakes approximately 12 hours apart. R115777 was taken until disease progression or unacceptable drug-related toxicity occurred.

Patient Evaluation
Before study entry, a complete medical and breast cancer history was taken and physical examination performed, together with an ECG, chest x-ray, and baseline assessment of hematology and biochemistry. Tumor measurements were assessed within 30 days before study entry either by computed tomography scan or clinical assessment of palpable or visible lesions (the latter were photographed). Because the retina contains several proteins that require farnesylation to function, a baseline ophthalmic examination (including slit-lamp biomicroscopy) was performed.

Patients were evaluated weekly (weeks 2 to 8), every 2 weeks (weeks 8 to 12), and monthly thereafter during treatment. Evaluations included physical examination, weekly hematology for the first 8 weeks, and monthly biochemistry. Toxicity was assessed according to the National Cancer Institute common toxicity criteria. Ophthalmic assessment was repeated at 3-month intervals. For all lesions being observed for response by radiologic assessment, repeat tumor measurements were taken every 3 months using the same technique. Objective tumor responses were confirmed by repeat assessment 4 weeks later and subjected to central peer review. Patients were withdrawn from the study if recovery from unacceptable toxicity required more than 3 weeks, consent was withdrawn, or there was clear disease progression.

Dose Modification
If grade 3 or 4 hematologic toxicity occurred, treatment was discontinued until recovery to grade 0 or 1. In the absence of disease progression, additional treatment could be given with a 100-mg bid lower dose. If grade 3 or 4 toxicity recurred, an additional subsequent dose reduction by 100 mg bid could be considered after recovery to grade 1 or better. The occurrence of grade 2 neurologic or any other grade 3 nonhematologic toxicity resulted in discontinuation of treatment until recovery to grade 1 or better. In the absence of disease progression, additional treatment could be given with a 100-mg bid lower dose. The occurrence of grade 4 nonhematologic toxicity (or grade 3 neurotoxicity lasting > 5 days) resulted in permanent discontinuation of treatment.

Pharmacokinetic Studies
A sparse sampling procedure was followed to characterize the pharmacokinetics of R115777. Venous blood samples (5 mL) were collected in heparinized tubes, centrifuged (2,500 rpm at 1,000 x g for 10 minutes), and separated plasma was stored at -20°C before transportation to Johnson & Johnson Pharmaceutical Research & Development (Beerse, Belgium) for determination of plasma R115777 concentration by a validated high-pressure liquid chromatography ultraviolet method (lower limit of quantification of < 1 ng/mL).¹² A Bayesian estimation of pharmacokinetic parameters of R115777 was implemented in NONMEM (GloboMax, Hanover, MD) software, using the POSTHOC option. The results of a previous population pharmacokinetic analysis of R115777 using data from six phase I trials were used to describe the time course of R115777 after oral and intravenous administration. The pharmacodynamic model is a three-compartment disposition model, with first-order elimination from a central compartment and a sequential zero-order to 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 were normalized for dosing of 300 mg bid¹³ The incidence of grade 3 to 4 neutropenia in relation to R115777 exposure (AUC) was analyzed by logistic regression,^14,15

Tumor Phenotyping
Paraffin-embedded blocks from the primary tumor were retrieved for 55 patients. All tumors were analyzed centrally for expression of steroid receptors (estrogen and progesterone) and growth factor receptors (EGFR and HER2) according to published methodologies.¹⁶ HER2 expression was assessed using the immunohistochemical HercepTest (DakoCytomation, Cambridge, UK), except for borderline positivity (2+) when gene amplification was tested using the PathVysion (Vysis, Downers Grove, IL) kit (fluorescence in situ hybridization analysis). The mutation status of the ras genes (K-, H-, N-ras) was determined by polymerase chain reaction analysis (Ortho-Clinical Diagnostics, Rochester, NY) of tumor DNA extracted from 2- x 5-µm-thick tumor sections from 35 patients in the CD cohort.

Statistical Considerations
The sample size was based on the primary end point of response rate. In addition to objective response rate (ie, complete responses or partial responses [PRs]), SD for ≥ 24 weeks was considered as a response. Therefore, a classic two-step design was not practical because this would have required accrual to be interrupted for up to 6 months after the first stage to evaluate response. However, an early stopping rule was applied such that if more than 20 of the first 22 enrolled patients showed disease progression, the trial could be stopped.¹⁷ The design parameters set a low (inactive) response rate (including SD) of 10% and a target response rate of 25%, which required a minimum of 40 patients to be treated in the first cohort. The size of the second cohort was determined from the incidence of dose-limiting neurotoxicity assuming an acceptable incidence of less than 5%, and a clinically unacceptable incidence of more than 20%. Using a one-sided test of this proportion, assuming a significance level of 7.4% and a power of 90.7%, the required sample size was 32 patients.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Enrollment started in February 1999 and 76 women were treated with R115777 in the two sequential cohorts. The median age of the patients was 53.5 years (range, 32 to 82 years). Baseline disease characteristics were similar between the two cohorts. Patients in the second cohort had received more prior systemic treatments (Table 1). All patients had confirmed evidence of disease progression at study entry.

View larger version (19K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curves for time to disease progression for continuous dosing and intermittent dosing cohorts.

Hematologic Toxicity
All of the first six patients in the CD cohort treated at 400 mg bid developed grade 3 to 4 neutropenia within the first 4 weeks of treatment (Table 3). Of the next 35 patients in the CD cohort treated at a starting dose of 300 mg bid, 15 patients (43%) developed grade ≥ 3 neutropenia with a median time to onset of 28 days (range, 11 to 105 days). Fever or infection associated with grade 3 to 4 neutropenia occurred in only three patients (9%) and lasted 2 to 12 days. The incidence of grade 3 to 4 thrombocytopenia and anemia was low (Table 3), and always occurred in association with grade 3 to 4 neutropenia. After dose reduction, 12 of 15 patients were re-treated and seven patients (58%) did not develop additional episodes of grade 3 to 4 hematologic toxicity. In contrast, there was significantly less (P < .016, Fisher’s exact test) hematologic toxicity seen in the ID cohort; only five patients (14%) developed grade ≥ 3 neutropenia, one of whom had associated fever (Table 3).

The ID regimen resulted in a significant (P < .0004, Fisher’s exact test) reduction in the incidence of neurotoxicity, with only one patient developing grade 2 peripheral neuropathy. The duration of treatment was similar between the two cohorts, and a similar proportion of patients had received more than 19.8 g, which was the lower limit of drug exposure for those who developed neurotoxicity in the CD cohort (Table 5). Thus, despite a similar treatment duration and minimum cumulative drug exposure, the ID schedule was associated with a significantly reduced incidence of neurotoxicity compared with the CD schedule.

View larger version (16K): [in this window] [in a new window]   Fig 3. Relationship between daily area under the curve of R115777, continuous versus intermittent dosing, and incidence of neutropenia (grade 0 to 2 v grade 3 to 4). Central horizontal line, median value; box, lower and upper quartiles; bars, full range.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Long-term oral administration of R115777 was well tolerated, although myelosuppression was the most frequent drug-related toxicity in the CD schedule. Dose-limiting myelosuppression has been reported in phase I studies of R115777^10–12 as well as phase I studies with other farnesyl transferase inhibitors^18–21 and seems to be a class effect. Myelosuppression was reversible and was associated with a low incidence of fever or septic complications. It was manageable by subsequent dose reductions. The ID schedule of 300 mg bid for 3 weeks on and 1 week off was associated with a significantly lower incidence of myelosuppression (14% grade 3 to 4 neutropenia), without influencing the clinical efficacy of R115777. A correlation between individual plasma AUC and the likelihood of developing grade 3 to 4 neutropenia was seen in this study (Fig 3), although there was interpatient variability in the pharmacokinetic parameters. A separate analysis of the R115777 database for all solid tumor studies has indicated that the development of grade 2 neutropenia in the first 2 to 3 weeks of commencing therapy is a strong predictor of subsequent worsening to grade 3 neutropenia and the need for dose adjustments. This model is now being tested prospectively in subsequent clinical studies.

After continuous dosing of R115777, grade 3 sensory neuropathy was seen in seven patients, although nerve conduction studies were often normal. The median time to onset of either grade 2 or 3 neurotoxicity was 12 weeks, with a median cumulative R115777 dose received by these patients of 45.9 g. There seemed to be no association with prior therapies and the risk of developing neurotoxicity. The data from the second cohort demonstrated that an intermittent dosing schedule significantly reduced this toxicity, with no patients developing grade 3 neurotoxicity and only one patient developing possible drug-related grade 2 sensory neuropathy. Both cohorts of patients were treated for a similar length of time, and a similar number of patients (85% and 74%) in either cohort received a cumulative R115777 dose of at least 19.8 g (the minimum dose associated with neurotoxicity). Thus, the main difference accounting for the significant reduction in neurotoxicity was intermittent dosing with a 1-week break from treatment every month. In the ID cohort, 12 patients (34%) received at least the median 45.9 g associated with neurotoxicity in the CD cohort (Table 5), and yet only one patient developed grade 2 neuropathy, which completely resolved. These data are consistent with those from the double-blind, randomized, phase III study of R115777 in advanced colorectal cancer (n = 368), in which a similar 300-mg bid ID schedule resulted in no significant increase in neuropathy compared with the placebo.²²

All primary tumors from the first cohort were assessed for mutations in either H-ras, N-ras, or K-ras, but only one tumor was found to have a mutation at codon 12 in H-ras. This is consistent with previous published data that breast carcinomas contain a low frequency of ras mutations.³ Clearly, cells are not required to have a mutated ras oncogene for farnesyl transferase inhibitors to inhibit growth,⁸ and farnesylated proteins other than Ras may be equally important in the mechanism of action of these drugs^23,24 For example, both the Rho family of proteins that regulate cell motility and adhesion, and the centromere binding proteins that coordinate chromosome alignment during mitosis, require farnesylation.^25,26

In this study there was no clear correlation between clinical response to R115777 and tumor phenotype. Responses were seen both in those with ER- and PR-positive/HER2-negative tumors, in addition to HER2-positive tumors. The antitumor activity of R115777 in this study would be consistent with two types of breast cancer that contain wild-type ras, either those initially hormone-sensitive tumors that develop acquired resistance and may be dependent on activated peptide growth factor pathways, or those ER-negative tumors with growth factor receptor overexpression. Activated growth factor pathways including EGFR and HER2 are known to signal through Ras in breast cancer,⁴ and emerging evidence indicates that several signal transduction pathways cross-talk with ER and become upregulated or activated in endocrine-resistant breast cancer.^27–29 Thus, regardless of their exact mechanism of action, farnesyl transferase inhibitors could modulate signal transduction pathways in breast cancer, including those activated during the development of resistance to endocrine therapy.

This study has demonstrated single-agent activity for a farnesyl transferase inhibitor in advanced breast cancer and recent experimental evidence indicates that these drugs may be more effective against breast cancer if given in combination with endocrine therapy.^30,31 Previous reports indicated that concurrent blockade of cell survival pathways either by serum starvation or a specific phosphatidylinositol-3-OH kinase inhibitor significantly enhanced the proapoptotic effects of farnesyl transferase inhibitors,³² and it is recognized that endocrine therapy may abrogate cell survival pathways by modifying the insulin-like growth factor–phosphatidylinositol-3-OH kinase pathway.³³ In view of this, a phase II clinical study in breast cancer has been initiated to investigate the efficacy of R115777 (300 mg bid ID schedule) in combination with an aromatase inhibitor in patients who have received a previous antiestrogen.

	ACKNOWLEDGMENTS

 
We thank the research nurses, Liz Miller, Dorothy Brett, Zoe Denyer, Charlotte Breen, Siobhan O’Brien, Lyn Purandare, Seonaid Wright, Sue Pike, and Therese Partridge-James, for their support, and Robert T. Belly, J. Toner, and M. Steinman (Ortho-Clinical Diagnostics, Rochester, NY) for analysis of the mutation status of the ras genes.

	NOTES

 
Supported by Johnson & Johnson Pharmaceutical Research & Development, Titusville, NJ.

	REFERENCES

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Submitted October 11, 2002; accepted March 14, 2003.

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