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Journal of Clinical Oncology, Vol 22, No 19 (October 1), 2004: pp. 3950-3957 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.10.037 Phase III Double-Blind Placebo-Controlled Study of Farnesyl Transferase Inhibitor R115777 in Patients With Refractory Advanced Colorectal CancerFrom the Royal Marsden Hospital, London and Surrey; Southampton General Hospital, Southampton, United Kingdom; Hospital Saint Antoine; Hospital Tenon, Paris, France; Vienna University Medical School, Vienna, Austria; Johnson & Johnson Pharmaceutical Research and Development, Beerse; St Luc University Hospital, Brussels, Belgium; National Oncological Centre, Sofia, Bulgaria; Oncology Institute, Plesi; Oncology Centre, Pardubice, Czech Republic; Medical University, Debrecen, Hungary; Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ Address reprint requests to David Cunningham, MD, FRCP, Department of Medicine, Royal Marsden Hospital, Downs Rd, Sutton, Surrey SM2 5PT, United Kingdom; e-mail: david.cunningham{at}icr.ac.uk
PURPOSE: To determine whether R115777 improves survival in patients with refractory advanced colorectal cancer (CRC) in a multicenter, double-blind, prospective randomized study. PATIENTS AND METHODS: Three hundred sixty-eight patients were randomly assigned to R115777 (300 mg twice daily) orally for 21 days every 28 days or placebo in a 2:1 ratio. All patients received best supportive care. The primary end point was overall survival; secondary end points were progression free survival, tumor response, toxicity, and quality of life. RESULTS: The two treatment groups were well balanced for baseline demographics, including previous chemotherapy for advanced CRC. The median overall survival for R115777 was 174 days (95% CI, 157 to 198 days), and 185 days (95% CI, 158 to 238 days) for those patients receiving placebo (P = .376). One patient achieved a partial response in the R115777 arm. Stable disease (> 3 months) was observed in 24.3% patients in the R115777 group compared to 12.8% in the placebo arm. This did not translate into a statistically significant increase in progression-free survival. Overall, treatment was well tolerated. There was an increased incidence of reversible myelosuppression (neutropenia, thrombocytopenia), rash, and grade 1 to 2 diarrhea in the R115777 arm. There was no statistically significant difference in quality of life between arms. CONCLUSION: Single agent R115777, given at this dose and schedule, has an acceptable toxicity profile, but does not improve overall survival compared to best supportive care alone in refractory advanced CRC.
Colorectal cancer (CRC) is the second largest cause of cancer death worldwide1 and accounts for 500,000 deaths annually. Although 70% to 80% of new cases of colon cancer undergo potentially curative surgery, 40% develop metastatic disease. Until recently, fluorouracil (FU), with a variety of modulating agents and schedules, has been the mainstay of treatment for these patients.2,3 Irinotecan, a topoisomerase I inhibitor, has demonstrated activity in first- and second-line treatment of patients with metastatic CRC. Irinotecan monotherapy demonstrated a survival benefit in patients pretreated with FU in two large randomized studies and is now an established second-line treatment for advanced CRC. The addition of irinotecan to FU (bolus or infused) has also resulted in prolonged survival as first-line treatment for this disease.4,5 Oxaliplatin, a third generation platinum analog, has also proved active in this disease, and in combination with FU/leucovorin (LV), has shown an improvement in response rate and disease-free survival compared to FU/LV alone.6 Furthermore, FU/LV/oxaliplatin has now demonstrated a significant survival advantage (hazard ratio, 0.67; P = .002) compared to FU/LV/irinotecan in a large randomized Intergroup study of 795 patients with advanced CRC.7 Thus, a number of treatment options are available for first- and second-line treatment for advanced CRC, and opinion is divided as to whether sequential or combination chemotherapy is appropriate. However, for patients who experience disease progression after second-line treatment, there is no standard therapeutic option. These patients are generally offered supportive care. R115777 (tipifarnib, Zarnestra; Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ) is a selective nonpeptidomimetic inhibitor of farnesyl protein transferase. Farnesyl transferase inhibitors (FTI) target the enzyme protein farnesyl transferase (Ftase), which catalyzes the addition of a farnesyl isoprenoid moiety to the cysteine residue of the c-terminal CAAX-box of a number of proteins, including the ras proteins. In preclinical models, R115777 has clear antiproliferative effects at clinically relevant concentrations. Originally, the ras oncoproteins were considered the target substrate responsible for the antiproliferative effects of Ftase inhibition, as farnesylation is a critical step in the membrane anchorage of ras proteins required for ras activity.8 K-ras point mutations are present in 40% to 50% of colorectal tumors and are believed to play an important role in tumorigenesis.9 In clinical phase I and II single-agent studies, R115777 was well tolerated during chronic or prolonged oral administration.10-12 Main side effects included reversible myelosuppression, fatigue, moderate nausea/vomiting, diarrhea, skin rash, and peripheral sensory neuropathy. Evidence of antitumor activity of R115777 has been reported in patients with CRC (decrease in serum carcinoembryonic antigen).13 The lack of treatment alternatives in patients with refractory CRC, the tolerability of R115777, and the attractiveness of the concept of inhibiting ras function through Ftase inhibition (supported by preclinical and early clinical indications of antitumour activity) led to the design of the randomized trial described in this report. The primary objective of this double-blind placebo-controlled trial was to test whether single agent R115777 would improve the overall survival of patients with advanced refractory CRC.
Study Conduct This multicenter, double-blind, randomized, placebo-controlled phase III study was conducted in 64 centers in 18 countries. Signed informed consent was obtained from all patients before random assignment. The study was approved by the local institutional review boards at all participating centers.
Main End Points
Patients Selection
Patients who received prior treatment with an FTI, prior extensive radiotherapy (> 30% of bone marrow reserve irradiated) or patients with bulky disease (
Randomization and Study Treatments Treatment was initiated no longer than 7 days after randomization. Patients in the R115777 group were given three tablets twice daily orally (total dose 300 mg bid) of R115777 for 21 days every 28 days. Patients continued on treatment until there was objective evidence of disease progression or unacceptable toxicity. In the placebo group, patients were given three tablets twice daily orally containing placebo for 21 days every 28 days. Supportive care was administered to all patients and was defined as the best care available as judged by the attending physician according to established institutional standards for each participating center. Supportive care included analgesics, antibiotics, blood transfusions, corticosteroids, antiemetics, antidiarrhoeals, or vitamins. Localized palliative radiotherapy was allowed, provided that no more than 30% of bone marrow reserve was irradiated.
Dose Modifications
Safety Evaluation During the study, full blood count was performed weekly and physical evaluation and serum chemistry were obtained every 28 days.
Efficacy Evaluation Tumor response was assessed by computed tomography scans according to Response Evaluation Criteria in Solid Tumors Group criteria after every third cycle of treatment.14. PFS was calculated for all randomly assigned patients from the date of randomization until the date progressive disease was initially documented. For patients who died before the assessment of progression of their disease, the date of death was considered as the date of progression. Patients who did not progress or die were censored at their last disease assessment date. Patients who came off study treatment and did not progress were censored at the date of the last objective disease assessment before the first day of the first subsequent anticancer therapy.
Quality of Life (QOL)
Pharmacokinetics In order to maintain the double-blind design of the study, blood samples were collected from all patients. On treatment day 15, one venous blood sample was collected before the morning intake of drug. Another plasma sample was collected on treatment day 22. On day 1 of the second cycle, two plasma samples were collected, and the second plasma sample was collected at least 1 hour after the first withdrawal. In order to adapt the sample collection to the convenience of the patient and investigator, no exact time points were specified. Instead patients and investigator were encouraged to have accurate recordings of the actual times of blood sampling and of the times of the last intake of drug before the blood sampling. All venous blood samples were collected in heparinized tubes, centrifuged (2,500 rpm at 1,000 g for 10 minutes), and separated plasma was stored at –20° C before determination of plasma R115777 concentration by a validated liquid chromatography with tandem mass spectrometry method (lower limit of quantification of < 2 ng/mL) in a centralized laboratory. Results were only made available after the treatment code was unblinded at final analyses. The pharmacokinetic analysis was only conducted for patients receiving R115777.
Ras Mutation Status Mutations at the first and second bases of codon 12 of the K-ras gene were detected, according to the method of Todd et al.15-17 Samples were analyzed in duplicate by electrophoresis on 4% w/v NUSieve agarose gel (FMC Bioproducts, Rockland, ME) and imaged by means of a Stratagene Eagle Eye II video system (Stratagene, La Jolla, CA). Several controls were included with each batch of samples analyzed.
Statistics An interim survival analysis by an independent panel was to be performed when 57 deaths had occurred, to allow for early stopping of the study if an extreme difference between treatment groups was obtained. Overall survival and PFS were compared between treatment groups using a two-sided log-rank test. For each treatment, Kaplan-Meier estimates of median survival and its 95% CI were computed. Hazard ratio and its 95% CI were estimated using a Cox regression model with treatment as the only covariate. The incidence of adverse events was compared between the two study arms. Summary statistics were performed for the safety parameters. Change from baseline in global QOL was assessed within each treatment group, using a paired t test. For treatment comparison, the change in global QOL index from baseline was compared using an analysis of covariance model. A Bayesian estimation of pharmacokinetic parameters of R115777 was implemented in NONMEM software, using the post-hoc option. The results of a previous population pharmacokinetic analysis of R115777 using data from six phase I trials were used as a prior information to describe the time course of R115777 plasma concentration. The pharmacokinetic 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 values were calculated from the individual Bayesian estimation of clearance and absolute bioavailability, and normalized for dosing of 300 mg bid.18
Two hundred thirty-five patients were randomly assigned to R115777, and 133 patients to placebo between March 2000 and February 2001 in 64 centers in 18 countries. The list of participating investigators is presented in the appendix. At the time of the clinical cut-off (August 2001), 16 patients (eight [6.0%] in the placebo group and eight [3.4%] in the R115777group) were still on treatment and 109 patients (42 [31.6%] in the placebo group and 67 [28.5%] in the R115777 group) were still alive. Two patients (both on the R115777 arm) were randomly assigned but were not treated. One patient randomly assigned to placebo received R115777 as a result of a logistical mistake. These patients are included in the analyses for efficacy, but not for safety. The patient baseline characteristics are shown in Table 1 and were well balanced between both groups. The median time from initial diagnosis to randomization was 20.9 months (range, 5.5 to 215.8 months) for the placebo group and 26.2 months (range, 2.9 to 163.6 months) for the R115777 arm. All patients had received at least one fluoropyrimidine-based regimen for advanced CRC and the proportion of subjects who had previously received oxaliplatin and/or irinotecan-based therapy were similar in both arms.
Treatment The mean duration of treatment was approximately three cycles in both arms. The median duration of treatment for both arms was 77 days for placebo (range, 4 to 431 days) and R115777 (range, 6 to 441 days). Only 27% of subjects received more than three cycles of therapy. Dose reductions occurred in 3.8% of patients receiving placebo compared with 24% of patients receiving R115777. Overall, 7.5% of patients in the placebo group and 21.9% in the R115777 group had at least one delay between cycles. For most cases, this was a delay of 1 to 2 weeks. In the R115777 arm, the main reason for dose reductions and cycle delays related to myelosuppression. Disease progression was the most frequent reason for treatment termination in both groups. Main R115777-related toxicities leading to treatment termination were neutropenia (6.0%), thrombocytopenia (4.7%), and rash (4.3%).
Tumor Response
Survival Approximately 7 months from the date of the first patient's random assignment, an efficacy interim analysis was performed for overall survival. At that time, 57 deaths were reported, almost 200 patients had been accrued onto the study, and the Independent Data Monitoring Committee recommended the study continue to completion for final analysis. At the time of final analysis, 259 patients (70.4%) had died; 168 (71.5%) on the R115777 arm and 91 (68.4%) on the placebo arm. Treatment with R115777 did not result in improved OS (Fig 1). The median OS for R115777 was 174 days (95% CI, 157 to 198 days) and 185 days (95% CI, 158 to 238 days) for patients receiving placebo (P = .376). The 1-year survival rates for the two treatment arms were similar: 23.5% (95% CI, 16.9% to 30%) for R115777 compared to 28.1% (95% CI, 19.1% to 37.2%) for the placebo group (Fig 1).
PFS Three hundred forty-five patients (97%) had developed disease progression by the time of the final analysis. There was a trend of increased PFS for the R115777 over the placebo (hazard ratio of placebo over R11577 = 1.22; log-rank test P value = .088). However, the median PFS rates were similar for the two groups (81 days for R115777 [95% CI, 79 to 84 days] and 80 days [95% CI, 79 to 82 days] for the placebo arm; Fig 2).
QOL The compliance of patients in the QOL analysis was similar between the two groups, with approximately 80% of patients completing at least one post-baseline assessment. There was no statistically significant difference between the two treatment arms (P = .712), and a similar evolution of QOL over time.
Pharmacokinetics
ras Mutation Status Of the 122 samples received, 46 (37.8%) were positive for a K-12 ras mutation. There was no correlation between mutation status and treatment outcome within each arm or overall, either in terms of overall survival, PFS, or response (stable disease v progressive disease).
Safety Results The incidence of adverse events (drug related or not) occurring in at least 10% of patients is shown in Table 3. The results confirm results from nonrandomized studies—that toxicity of R115777 is mainly limited to myelosuppression. Grade 3/4 neutropenia occurred in 27% of patients treated with R115777. Grade 3/4 thrombocytopenia was less common (17%). Hematologic nadirs usually occurred during the rest period (median day 22) with median time to recovery of 10 days (range, 1 to 30 days) for neutrophils and 6 days (range, 1 to 16 days) for platelets. There was no evidence of cumulative myelosuppression.
The incidence of nonhematologic adverse events was similar between the two treatment groups, except for diarrhea, which was more frequently reported in the R115777 group (25% v 11% for placebo) and was predominantly grade 1 or 2. A higher incidence of rash was also observed with R115777 (16%) compared with placebo (5%).
R115777 did not improve overall survival compared to best supportive care in patients with refractory advanced CRC. There was only one partial response observed. Although there was a trend in favor of R115777 for PFS, and more patients had stable disease, this did not translate in an improved QOL or survival advantage. This may have multiple explanations. FTIs were originally designed to target the ras pathway. K-ras point mutations are believed to have a pivotal role in cell transformation in CRC. However in the current study, with all patients in late-stage disease, there was no evidence that detection of such mutations is of prognostic value either in the overall population or within each treatment arm. Preclinical data have shown that cell lines containing K-ras mutations are more resistant to growth inhibition than cell lines containing H-ras or N-ras mutations. K-ras proteins can also be alternatively prenylated by geranyl geranyl protein transferase, and retain function.19,20 These studies also showed no correlation between the presence of a ras mutation and sensitivity to FTIs. These findings may be explained by the large number of intracellular proteins that require farnesylation for post-translational modification. Tumors in patients with advanced CRC appear to be less sensitive to Ftase inhibition than predicted from preclinical models. Since most preclinical models predicted a more cytostatic effect rather than a cytotoxic effect of Ftase inhibition, phase II studies with objective response as the end point were not performed in this indication. However, for the current trial, the guideline was maintained that patients were to be withdrawn from treatment once the criteria for progressive disease were reached. This could be potential criticism on the study design since it is possible that continued treatment could have still had a positive influence on survival by slowing the tumor growth rate. Since only approximately 25% of patients received four cycles or more, this issue can not be definitively addressed. The use of a placebo-controlled double-blind design, compared with an open label study, allowed for a good opportunity to better characterize the safety profile of R115777. However, it is clear that the occurrence of grade 3/4 myelosuppression in 27% of patients allowed for the investigator to deduce treatment assignment and this may have led to an assessment bias. Overall, R115777 was reasonably well tolerated. Hematologic toxicity was in the form of reversible myelosuppression, and the incidence of grade 3 or 4 neutropenia and thrombocytopenia was in keeping with other studies of R115777 utilizing the same dosing schedule.10,12,13,21 The neurotoxicity observed utilizing a continuous schedule of R1157710,13 was less frequently encountered in this study using intermittent dosing. In fact, the incidence of peripheral neuropathy was only slightly higher for the R115777 arm compared with placebo.13 Nausea, vomiting, and fatigue, other side effects that were attributed to R11577 in nonrandomized trials, were not shown to be increased in incidence or severity over placebo. In summary, this study demonstrates that nonhematologic toxicity of R115777 is mainly limited to rash (of which 4% is severe) and a relatively small increased incidence of grade 1 to 2 diarrhea. Population pharmacokinetic results were in keeping with other studies. R115777 is rapidly absorbed following oral administration, with the highest concentrations observed approximately 3 to 4 hours after dosing. At steady-state, the mean plasma concentration of R115777 of 452 ng/mL (924 nmol/L) is well in the range of concentrations that demonstrate in vitro antiproliferative activity (even when taking into account differential protein binding between the in vivo and in vitro situation).19 It may be possible to achieve more significant activity with R115777 in this setting by combining it with conventional chemotherapy. Phase I studies have been performed for the combination of R115777 plus capecitabine, irinotecan, and FU/LV.22-24 In each case, an maximum tolerated dose was identified, with a standard dose of the chemotherapeutic agent and a similar dose and schedule of R115777 as used in the current phase III study. Although phase I studies are not designed to evaluate efficacy, there were a significant proportion of patients with CRC enrolled, and the overall response rate was no higher than could be expected with chemotherapy alone. The absence of encouraging phase I efficacy, together with the lack of efficacy of single-agent R115777 as shown in the current study, make it difficult to embark on further studies of R11577 in this indication. R115777 has shown promising activity in relapsed and refractory acute myeloid leukemia,25,26 breast cancer,10 and glioma27 and clinical research efforts are now focusing in those indications.
The authors indicated no potential conflicts of interest.
Supported by Johnson & Johnson Pharmaceutical Research and Development, Titusville, NJ. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Parkin DM, Bray F, Ferlay J, et al: Estimating the world cancer burden: Globocan 2000. Int J Cancer 94:153-156, 2001[CrossRef][Medline]
2. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. Meta-analysis Group in Cancer. J Clin Oncol 16:301-308, 1998 3. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. Advanced Colorectal Cancer Meta-Analysis Project. J Clin Oncol 10:896-903, 1992[Abstract] 4. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355:1041-1047, 2000[CrossRef][Medline]
5. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905-914, 2000
6. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 7. Goldberg RM, Morton RF, Sargent DJ: N9741: Oxaliplatin (oxal) or CPT-11 + 5-fluorouracil (5FU)/leucovorin (LV) or oxaliplatin + CPT-11 in advanced colorectal cancer (CRC). Updated efficacy and quality of life (QOL) data from an Intergroup study. Proc Am Soc Clin Oncol 22:252, 2003 (abstr 1009)
8. Rowinsky EK, Windle JJ, Von Hoff DD: Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. J Clin Oncol 17:3631-3652, 1999 9. Forrester K, Almoguera C, Han K, et al: Detection of high incidence of K-ras oncogenes during human colon tumorigenesis. Nature 327:298-303, 1987[CrossRef][Medline]
10. Johnston SRD, Hickish T, Ellis P: 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 21:2492-2499, 2003
11. 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 18:927-941, 2000
12. 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 20:2726-2735, 2002 13. Schellens JH, de Klerk GJ, Swart M: Phase I and pharmacologic study with the novel farnesyltransferase inhibitor (FTI) R115777. Proc Am Soc Clin Oncol 19:715, 2000 (abstr 715)
14. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumours. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000
15. Ward R, Hawkins N, O'Grady R, et al: Restriction endonuclease-mediated selective polymerase chain reaction: A novel assay for the detection of K-ras mutations in clinical samples. Am J Pathol 153:373-379, 1998 16. Roberts NJ, Impey HL, Applegate TL, et al: Rapid, sensitive detection of mutant alleles in codon 12 of K-ras by REMS-PCR. Biotechniques 27:418-422, 1999[Medline]
17. Fuery CJ, Impey HL, Roberts NJ, et al: Detection of rare mutant alleles by restriction endonuclease-mediated selective-PCR: Assay design and optimization. Clin Chem 46:620-624, 2000 18. Perez-Ruixo JJ, Cowan KH, Weiner L: Population pharmacokinetics of ZarnestraTM using data from phase I trials. 9th Meeting of Population Approach Group in Europe, June 6-7, 2002, Paris, France (abstr 21)
19. End DW, Smets G, Todd AV, et al: Characterization of the antitumour effects of the selective farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 61:131-137, 2001
20. 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 tumour cell lines. Cancer Res 55:5302-5309, 1995 21. Punt CJ, van Maanen L, Bol CJ, et al: Phase I and pharmacokinetic study of the orally administered farnesyl transferase inhibitor R115777 in patients with advanced solid tumours. Anticancer Drugs 12:193-197, 2001[CrossRef][Medline] 22. Holden SN, Eckhardt SG, Fisher SA: Phase I pharmacokinetic (PK) and biological study of the farnesyl transferase inhibitor (FTI) R115777 and capecitabine in patients (PTS) with advanced solid malignancies. Proc Am Soc Clin Oncol 20:316, 2001 (abstr 316) 23. Verweij J, Kehrer DF, Planting A: Phase I trial of irinotecan in combination with the farnesyl transferase inhibitor (FTI) R115777. Proc Am Soc Clin Oncol 20:319, 2001 (abstr 319) 24. Verslype C, Van Steenbergen W, Humblet Y: Phase I trial of 5-FU/LV in combination with the farnesyltransferase inhibitor (FTI) R115777. Proc Am Soc Clin Oncol 20:681, 2001(abstr 681)
25. Karp JE, Lancet JE, Kaufmann SH, et al: Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukaemias: A phase 1 clinical-laboratory correlative trial. Blood 97:3361-3369, 2001 26. Harousseau JL, Stone R, Thomas X: Interim results from a phase II study of R115777 (Zarnestra) in patients with relapsed and refractory acute myelogenous leukaemia. Proc Am Soc Clin Oncol 21:265, 2002 (abstr 265) 27. Cloughesy TF, Kuhn J, Wen P: Phase II trial of R115777 (Zarnestra) in patients with recurrent glioma not taking enzyme inducing antiepileptic drugs (EIAED): A North American Brain Tumour Consortium (NABTC) report. Proc Am Soc Clin Oncol 21:80a, 2002 (abstr 317) Submitted October 9, 2003; accepted July 26, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
x 5 IUNL); and life expectancy > 3 months. 
10 cm diameter lesions) were not eligible. 
= 5%). 
