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Journal of Clinical Oncology, Vol 25, No 21 (July 20), 2007: pp. 3137-3143 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.4243 Phase I and Pharmacokinetic Study of the Oral Farnesyltransferase Inhibitor Lonafarnib Administered Twice Daily to Pediatric Patients With Advanced Central Nervous System Tumors Using a Modified Continuous Reassessment Method: A Pediatric Brain Tumor Consortium Study
From the Dana-Farber Cancer Institute and Children's Hospital Boston, Boston, MA; Children's National Medical Center, Washington, DC; St Jude Children's Research Hospital, Memphis, TN; Baylor College of Medicine, Houston, TX; The Children's Hospital of Philadelphia, Philadelphia; Children's Hospital of Pittsburgh, Pittsburgh, PA; Children's Hospital and Regional Medical Center, Seattle, WA; Duke University Medical Center, Durham, NC; University of California at San Francisco, San Francisco, CA; Children's Memorial Hospital, Chicago, IL; and Schering-Plough Research Institute, Kenilworth, NJ Address reprint requests to Mark W. Kieran, MD, PhD, Dana-Farber Cancer Institute, Pediatric Neuro-Oncology, 44 Binney St, Room SW331, Boston, MA 02115; e-mail: mark_Kieran{at}dfci.Harvard.edu
Purpose: A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib (SCH66336) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured. Patients and Methods: Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m2/dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment. Results: Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m2/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m2/dose levels resulted in a recommended phase II dose of 115 mg/m2/dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer. Conclusion: Although the estimated MTD by the CRM model was 98.5 mg/m2/dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m2/dose administered twice daily by mouth with concurrent loperamide.
Ras is a central mediator in the regulation of cellular control that can involve proliferation, migration, and/or angiogenesis.1 Unlike adult carcinomas, most pediatric brain tumors have not demonstrated a significant incidence of ras mutation. However, these tumors are highly dependent on the receptor tyrosine kinase signals that are transmitted by Ras.2,3 Compounds that inhibit farnesylation might prevent Ras signaling, independent of its mutational status.4-7 Lonafarnib (SCH66336, Sarasar; Schering-Plough, Kenilworth, NJ) is a tricyclic nonpeptidyl, nonsulphydryl farnesyltransferase inhibitor (FTI).8-10 It inhibits H- and K-Ras farnesylation, and FTIs also prevent farnesylation of other critical proteins required for cell growth.11,12 These compounds have demonstrated broad antitumor activity in transgenic murine and human tumor xenograft models.4,13,14 Lonafarnib has undergone initial phase I and II testing in adult cancers,15-19 and FTIs are currently being evaluated in combination with cytotoxic agents.20-22 The predominate toxicities associated with lonafarnib in adults have included diarrhea, anorexia, nausea, vomiting, fatigue, and reversible elevations in blood urea nitrogen, creatinine, and transaminases.15-22 The maximum-tolerated dose (MTD) and phase II dose for adult patients was 200 mg/dose (115 mg/m2) twice daily by mouth without interruption and required the frequent use of loperamide to control drug-related diarrhea. Dose-limiting toxicities (DLTs) at 300 mg/dose included grade 4 neutropenia, grade 3 neurocortical toxicity and fatigue, and grade 2 nausea and diarrhea.15,18 Both hematologic and nonhematologic toxicities were dose related, with grade 3 or 4 events noted at doses  200 mg.15 In single-agents studies of lonafarnib in adults, prolonged stable disease (SD) in pseudomyxoma peritonei, metastatic follicular thyroid carcinoma, and colorectal cancer and other solid tumors and a partial response (PR) in a patient with metastatic non–small-cell lung cancer have been reported.15,18,19 This phase I protocol is the first pediatric experience with lonafarnib, and our report includes data on the pharmacokinetics (PK) of this compound.
Patients with malignant or progressive brain tumors refractory to standard treatment, who were 0 to 21 years of age at study entry, were eligible. In addition to being able to swallow pills, all patients were required to have a performance score of 60, a life expectancy of more than 8 weeks, more than third weight-for-height percentile, albumin more than 3 g/dL, and stable neurologic status for 1 week. Exclusion criteria included the following: use of enzyme-inducing anticonvulsants; myelosuppressive chemotherapy within the preceding 3 weeks (6 weeks for a nitrosourea agent); substantial bone marrow irradiation within 6 weeks, craniospinal (> 24 Gy) or total-body irradiation within 3 months, or focal irradiation within 2 weeks; bone marrow transplantation within 6 months; growth factors in the preceding week; and overt hepatic, cardiac, or pulmonary disease. Patients receiving dexamethasone were required to be on a stable dose for 1 week. Adequate organ and marrow function required for eligibility included the following: absolute neutrophil count more than 1,000/µL, platelets more than 75,000/µL, and hemoglobin more than 9 g/dL; liver function with ALT and AST less than 2.5x upper limit of normal (ULN) for age; bilirubin less than ULN; renal function (creatinine  1.5x ULN for age or glomerular filtration rate > 70 mL/min per 1.73 m2); and prothrombin time/partial thromboplastin time 120% ULN. The institutional review boards of each Pediatric Brain Tumor Consortium institution approved the protocol before initial patient enrollment, and continuing approval was maintained throughout the study. Patients or their legal guardians gave written informed consent, and patients gave assent according to local institutional review board guidelines.
Drug and Dosage Administration
Trial Design
Statistical Analysis Accrual was halted, and the protocol underwent a major revision after three of the first five patients treated at the 90 mg/m2 level experienced grade 3 DLTs (diarrhea, elevated ALT, and pain). Estimation of the MTD was reinitiated excluding these first five patients; changes included required use of prophylactic loperamide to prevent diarrhea and modification in transaminase elevation as a DLT as summarized in Results. Loperamide could be weaned after 48 hours in patients without significant diarrhea. PK and biologic correlates were performed in consenting patients. Blood samples were collected before dose and at 1, 2, 4, 6, and 8 hours after dose on day 28 of cycles 1 through 4. Plasma samples were analyzed using a validated liquid chromatography with tandem mass spectrometry.24 The lower limit of quantitation was 5 ng/mL with a linear standard curve over a concentration range of 5 to 2,500 ng/mL. The coefficient of variation and accuracy (% bias) were less than 11% and less than 10%, respectively. Individual plasma lonafarnib concentrations were used for PK analysis using model-independent methods.25 The area under the plasma concentration-time curve from time zero to 12 hours after dose [AUC(0-12)] was calculated using the linear trapezoidal method, where concentration at 0 hour was also used as an estimate of plasma concentration at 12 hours for each concentration-time profile. The apparent total-body clearance at steady-state was calculated by dividing the dose by AUC(0-12). Interpatient variability of the PK parameters was expressed as percent coefficient of variation. Serial plasma concentration values of patients who had multiple-cycle PK samples were modeled via a mixed-effects approach in an effort to explore dose and cycle effect. Inhibition of HDJ-2 farnesylation (a surrogate marker of FTI activity) was evaluated in blood samples before dose and 4 hours after dose on day 28 of courses 1 to 4, 6, 8, 10, and 12 in consenting patients. Peripheral-blood mononuclear cells were isolated, cell lysates were prepared, and the presence of unfarnesylated HDJ-2 was determined by Western blotting as previously described.26
Tumor Response
A total of 55 patients were enrolled onto this phase I dose-escalation study. One patient was ineligible because of incomplete baseline assessment, and one eligible patient failed to start therapy within 10 days of registration. Hence, fifty-three patients were eligible and assessable (Table 1). Five patients were enrolled before a major modification to the protocol was made and are included in the toxicity data (see Appendix Tables A1 through A5, online only) but not in the estimation of the MTD, resulting in a total of 48 potential assessable patients. Three patients withdrew without receiving treatment, and seven patients did not complete the first course (as a result of progressive disease, patient withdrawal after beginning protocol therapy, or noncompliance), resulting in a total of 38 patients. The MTD was based on the first 32 patients treated at the different dose levels. Once the initial estimate of the MTD was made, six additional patients were treated at that dose level.
DLTs occurred in three of the first five patients treated at the 90 mg/m2 dose level and included grade 3 diarrhea (n = 1), elevation of ALT for 4 days (n = 1), and pain (n = 1). As a result of these adverse events and the adult data, the protocol was amended to require prophylactic use of loperamide to prevent diarrhea. The definition of dose-limiting elevations in serum transaminases was modified to allow serum transaminases of 10x ULN as long as values returned to normal within 1 week. These first five patients were excluded from the dose-finding component of the analysis, as discussed earlier. Toxicities experienced and DLTs are listed in Table 2. No grade 3 to 4 episodes of either liver transaminase elevation or diarrhea, which were common in the adult studies of this agent, were reported as DLTs after the protocol amendment. After the study was closed to accrual, central review of all primary data retrospectively identified two toxicities that met criteria for DLTs: one grade 4 neutropenia at 79 mg/m2 (assigned 90 mg/m2) and one episode of grade 4 hypokalemia at 118 mg/m2 (assigned 115 mg/m2). On the basis of the new information, the CRM re-estimated the MTD to be 98.5 mg/m2. Using data for all 32 patients, the observed frequencies of DLTs were 20% (two of 10 patients), 25% (two of eight patients), 20% (one of five patients), 17% (one of six patients), and 100% (three of three patients) for patients assigned to 70, 90, 115, 150, and 200 mg/m2/dose, respectively.
Most grade 3 and 4 toxicities observed were nonhematologic, and the incidence of toxicities was less frequent during course 2 and later. One death as a result of Klebsiella infection with neutropenia occurred at the 200 mg/m2 dose level. Within the first cycle of therapy, three of three patients at the 200 mg/m2 dose level had grade 4 neutropenia compared with a single patient at the 90 mg/m2 dose level and no patients at the 70, 115, and 150 mg/m2 dose levels. In all patients after course 1 (29 patients receiving a combined total of 144 additional months of lonafarnib), only two additional episodes of grade 3 neutropenia at 90 and 150 mg/m2/dose and one grade 4 neutropenia at 150 mg/m2/dose were observed. Similarly, grade 3 or 4 thrombocytopenia was observed in a single patient at the 90 mg/m2 dose level and three of three patients at the 200 mg/m2 dose level during cycle 1; only one additional episode of grade 3 thrombocytopenia was observed (70 mg/m2/dose) after course 1. Cumulative toxicity was difficult to assess given the heterogeneous patient population, although none was clearly evident. Of the 14 patients who received three to 20 cycles of therapy, no specific patterns were identified. Only two patients required dose reductions, and two patients required transient interruption of therapy for recovery of their absolute neutrophil count before restarting at the same dose. All grade 3 and 4 toxicities for the 32 patients (after the amendment) for all cycles of therapy are listed in Table 2. In addition, all toxicities (grades 1 through 4) are provided in the Appendix tables for all 50 patients who received at least one dose of lonafarnib.
PK of Lonafarnib
The effect of corticosteroids on lonafarnib PKs was evaluated in four patients who were receiving dexamethasone when PK samples were collected. The results showed that chronic dexamethasone had no effect on lonafarnib systemic exposure; the AUC values in patients receiving dexamethasone were similar to the values in patients not receiving dexamethasone.
Pharmacodynamic Analysis
Tumor Response Forty-eight patients were assessable for response. One patient with anaplastic astrocytoma had a PR (at the 70 mg/m2 dose level) lasting 13 courses, and nine patients (18.8%) demonstrated SD from four to 20 courses (median, 13 courses) at the following dose levels: 70 mg/m2 (n = 1; low-grade glioma [LGG]), 90 mg/m2 (n = 3; one medulloblastoma and two LGG), 115 mg/m2 (n = 2; one LGG and one high-grade glioma), and 150 mg/m2 (n = 3; one high-grade glioma, one ependymoma, and one sarcoma). Seven patients remained on therapy without progression for at least 1 year (one patient each with medulloblastoma, anaplastic astrocytoma, brainstem glioma, juvenile pilocytic astrocytoma, ganglioglioma, cerebellar sarcoma, and anaplastic ependymoma).
We describe, to our knowledge, the first phase I study of the oral FTI lonafarnib in pediatric patients with progressive, recurrent CNS tumors and the first pediatric phase I trial to use the CRM model to control dose finding. Initially, the CRM estimated that the MTD was 140.6 mg/m2. After the trial was closed to accrual, toxicity data for two patients treated at lower doses were revised to reflect DLTs, resulting in a revised CRM-estimated MTD of 98.5 mg/m2 as the dose at which 20% of patients would be expected to experience a DLT. The observed frequencies of DLTs for the four lowest dose levels studies were 20%, 25%, 20%, and 17%, suggesting a rather flat toxicity–dose response distribution. The adult data at doses of 300 mg (175 mg/m2) and 400 mg (235 mg/m2) resulted in significant hematopoietic DLT,15,17 whereas 200 mg (115 mg/m2) resulted in reversible nausea, vomiting, and diarrhea15 and fatigue.18,19 Considering the flat toxicity profiles in pediatric patients, the PK data, and the tolerability of the drug in adults, we recommend 115 mg/m2/dose on a twice daily schedule as the dose for pediatric phase II/combination trials. The CRM design required 32 assessable patients to estimate the MTD among five a priori–specified dose levels, and given that DLTs were observed in the two lowest dose levels, a traditional design would have required approximately the same number of patients. Unlike a traditional design, the CRM method was able to incorporate the actual dose of medicine administered. In pediatric studies using oral formulations, this may be important because many patients' actual dose could differ from their assigned dose because of limited pill size (50 mg).
Reversible transaminase elevations were not clinically significant. Prophylactic use of loperamide prevented significant diarrhea. The limited hematologic toxicity at doses of Because FTIs bind reversibly to the farnesyltransferase enzyme, scheduled breaks in treatment aimed at reducing toxicities (required with other FTIs27-32) may permit growth of tumors through temporary reactivation of Ras signaling.27-32 Lonafarnib was slowly absorbed and eliminated with food. There was a decrease in plasma concentrations across courses, whereas the concentration versus time profile over the 12-hour dosing interval was relatively flat. One of the objectives of this study was to evaluate the effect of corticosteroids on the PKs of lonafarnib. Four patients were on dexamethasone, a known CYP3A4 inducer,33-35 and lonafarnib is substrate of CYP3A4.36 Chronic administration of dexamethasone had no apparent effect on plasma lonafarnib concentrations. The percent unfarnesylated HDJ-2 ranged from 10.7% to 24.5% in four of the six patients assessable for HDJ-2. There were no apparent correlations between percent unfarnesylated HDJ-2 and predose plasma concentrations. Although the trial was not designed specifically to measure activity, some patients seemed to derive benefit from treatment with lonafarnib. Of 48 patients assessable for response, one patient achieved a PR, and nine patients maintained SD (four to 20 courses). In conclusion, twice-daily, continuous oral lonafarnib in pediatric patients with refractory brain tumors demonstrated good tolerability and safety. The recommended dose for phase II studies is 115 mg/m2/dose administered twice daily with concurrent loperamide, and given the limited hematopoietic toxicity, lonafarnib may be suitable for combination with radiation and/or chemotherapy. The study also demonstrates the advantage of the CRM design for pediatric phase I studies of oral agents for which there are no pediatric formulations.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: Yali Zhu, Schering-Plough; Emily Frank, Schering-Plough; Paul Kirschmeier, Schering-Plough; Paul Statkevich, Schering-Plough; Antoine Yver, Schering-Plough Leadership: N/A Consultant: N/A Stock: Paul Kirschmeier, Schering-Plough; Antoine Yver, Sanofi Aventis, Schering-Plough Honoraria: Ian F. Pollack, Schering-Plough; Sri Gururangan, Schering-Plough Research Funds: N/A Testimony: N/A Other: Ian F. Pollack, Schering-Plough; Sri Gururangan, Schering-Plough
Conception and design: Mark W. Kieran, Roger J. Packer, Peter Phillips, James M. Boyett, Larry E. Kun Administrative support: James M. Boyett Provision of study materials or patients: Mark W. Kieran, Roger J. Packer, Susan M. Blaney, Peter Phillips, Ian F. Pollack, J. Russell Geyer, Sri Gururangan, Anu Banerjee, Stewart Goldman, Christopher D. Turner, Jean B. Belasco, Alberto Broniscer, Antoine Yver Collection and assembly of data: Mark W. Kieran, Arzu Onar, Peter Phillips, Anu Banerjee, Stewart Goldman, Christopher D. Turner, Paul Kirschmeier Data analysis and interpretation: Mark W. Kieran, Roger J. Packer, Arzu Onar, Jean B. Belasco, Yali Zhu, Emily Frank, Paul Kirschmeier, Paul Statkevich, Antoine Yver, James M. Boyett Manuscript writing: Mark W. Kieran, Roger J. Packer, Arzu Onar, Susan M. Blaney, Christopher D. Turner, James M. Boyett, Larry E. Kun Final approval of manuscript: Mark W. Kieran, Roger J. Packer, Arzu Onar, Peter Phillips, J. Russell Geyer, Sri Gururangan, Anu Banerjee, Stewart Goldman, Christopher D. Turner, Jean B. Belasco, Alberto Broniscer, Antoine Yver, Larry E. Kun
We and the Pediatric Brain Tumor Consortium acknowledge the statistical support of Jianrong Wu, PhD, and the protocol management of Lisa Rush.
Supported in part by National Institutes of Health Grant No. U01 CA81457 for the Pediatric Brain Tumor Consortium and the American Lebanese Syrian Associated Charities. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
