Development and pilot validation of a novel disfigurement severity scale for plexiform neurofibromas in children with neurofibromatosis type 1.

BACKGROUND/AIMS: We developed an observer disfigurement severity scale for neurofibroma-related plexiform neurofibromas to assess change in plexiform neurofibroma-related disfigurement and evaluated its feasibility, reliability, and validity. METHODS: Twenty-eight raters, divided into four cohorts based on neurofibromatosis type 1 familiarity and clinical experience, were shown photographs of children in a clinical trial (NCT01362803) at baseline and 1 year on selumetinib treatment for plexiform neurofibromas (n = 20) and of untreated participants with plexiform neurofibromas (n = 4). Raters, blinded to treatment and timepoint, completed the 0-10 disfigurement severity score for plexiform neurofibroma on each image (0 = not at all disfigured, 10 = very disfigured). Raters evaluated the ease of completing the scale, and a subset repeated the procedure to assess intra-rater reliability. RESULTS: Mean baseline disfigurement severity score for plexiform neurofibroma ratings were similar for the selumetinib group (6.23) and controls (6.38). Mean paired differences between pre- and on-treatment ratings was -1.01 (less disfigurement) in the selumetinib group and 0.09 in the control (p = 0.005). For the disfigurement severity score for plexiform neurofibroma ratings, there was moderate-to-substantial agreement within rater cohorts (weighted kappa range = 0.46-0.66) and agreement between scores of the same raters at repeat sessions (p > 0.05). In the selumetinib group, change in disfigurement severity score for plexiform neurofibroma ratings was moderately correlated with change in plexiform neurofibroma volume with treatment (r = 0.60). CONCLUSION: This study demonstrates that our observer-rated disfigurement severity score for plexiform neurofibroma was feasible, reliable, and documented improvement in disfigurement in participants with plexiform neurofibroma shrinkage. Prospective studies in larger samples are needed to validate this scale further.

Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas.

BACKGROUND: Selumetinib shrank inoperable symptomatic plexiform neurofibromas (PN) in children with neurofibromatosis type 1 (NF1) and provided clinical benefit for many in our previously published phase 1/2 clinical trials (SPRINT, NCT01362803). At the data cutoff (DCO) of the prior publications, 65% of participants were still receiving treatment. This report presents up to 5 years of additional safety and efficacy data from these studies. METHODS: This manuscript includes data from the phase 1 and phase 2, stratum 1 study which included participants with clinically significant PN-related morbidity. Participants received continuous selumetinib dosing (1 cycle = 28 days). Safety and efficacy data through February 27, 2021 are included. PN response assessed by volumetric magnetic resonance imaging analysis: Confirmed partial response (cPR) ≥20% decrease from baseline on 2 consecutive evaluations. Phase 2 participants completed patient-reported outcome measures assessing tumor pain intensity (Numeric Rating Scale-11) and interference of pain in daily life (pain interference index). RESULTS: For the 74 children (median age 10.3 years; range 3-18.5) enrolled, overall cPR rate was 70% (52/74); median duration of treatment was 57.5 cycles (range 1-100). Responses were generally sustained with 59% (44) lasting ≥ 12 cycles. Tumor pain intensity (n = 19, P = .015) and pain interference (n = 18, P = .0059) showed durable improvement from baseline to 48 cycles. No new safety signals were identified; however, some developed known selumetinib-related adverse events (AEs) for the first time after several years of treatment. CONCLUSIONS: With up to 5 years of additional selumetinib treatment, most children with NF1-related PN had durable tumor shrinkage and sustained improvement in pain beyond that previously reported at 1 year. No new safety signals were identified; however, ongoing monitoring for known selumetinib-related AEs is needed while treatment continues.

Audiometric and Otologic Findings in Children and Young Adults with Neurofibromatosis Type 1 and Plexiform Neurofibromas.

OBJECTIVES: To characterize otologic and audiologic manifestations in our NF1 cohort and explore the relationship between otologic and audiologic findings in a subset of patients with ear-related plexiform neurofibromas (PNs). METHODS: Audiologic and otologic clinical evaluations were conducted on 102 patients with NF1 in a natural history study (5-45 years; M = 14.4 years; Mdn = 14). Testing included pure tone and speech audiometry, middle ear function, neurodiagnostic auditory brainstem response (ABR), auditory processing, and MRIs of the head and neck region. Patients referred to this study had an overall higher incidence and burden of PNs than the overall NF1 population. RESULTS: The majority of subjects in this cohort had normal hearing sensitivity (81%) and normal middle ear function (78%). Nineteen participants had hearing loss that ranged in degree from mild to profound, with the majority in the mild range. Hearing loss was twice as likely to be conductive than sensorineural. In patients with ear-related PNs (n = 12), hearing loss was predominantly conductive (60%). Seventy-five percent of ears with PNs had atypical tympanometric tracings that could not be characterized by the classic categories. In all 20 patients with a PN in the temporal bone, the ear canal was affected, and the PNs often extended to the surrounding soft tissue regions. CONCLUSIONS: People with NF1-related PNs in the temporal bone and adjacent skull base should have audiometric and otologic monitoring. Addressing hearing concerns should be part of routine clinical evaluations in patients with NF1. Magnetic resonance imaging (MRI) should be performed in patients with NF1 who have hearing loss. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:2770-2778, 2023.

Selumetinib in children with neurofibromatosis type 1 and asymptomatic inoperable plexiform neurofibroma at risk for developing tumor-related morbidity.

BACKGROUND: Selumetinib was recently approved for the treatment of inoperable symptomatic plexiform neurofibromas (PNs) in children with neurofibromatosis type 1 (NF1). This parallel phase II study determined the response rate to selumetinib in children with NF1 PN without clinically significant morbidity. METHODS: Children with NF1 and inoperable PNs, which were not yet causing clinically significant morbidity but had the potential to cause symptoms, received selumetinib at 25 mg/m2 orally twice daily (1 cycle = 28 days). Volumetric magnetic resonance imaging analysis and outcome assessments, including patient-reported (PRO), observer-reported, and functional outcome measures were performed every 4 cycles for 2 years, with changes assessed over time. A confirmed partial response (cPR) was defined as PN volume decrease of ≥20% on at least 2 consecutive scans ≥3 months apart. RESULTS: 72% of subjects experienced a cPR on selumetinib. Participants received selumetinib for a median of 41 cycles (min 2, max 67) at data cutoff. Approximately half of the children rated having some target tumor pain at baseline, which significantly decreased by pre-cycle 13. Most objectively measured baseline functions, including visual, motor, bowel/bladder, or airway function were within normal limits and did not clinically or statistically worsen during treatment. CONCLUSIONS: Selumetinib resulted in PN shrinkage in most subjects with NF1 PN without clinically significant morbidity. No new PN-related symptoms developed while on selumetinib, and PRO measures indicated declines in tumor-related pain intensity. This supports that selumetinib treatment may prevent the development of PN-related morbidities, though future prospective studies are needed to confirm these results. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01362803.

The MEK inhibitor selumetinib reduces spinal neurofibroma burden in patients with NF1 and plexiform neurofibromas.

BACKGROUND: Spinal neurofibromas (SNFs) in neurofibromatosis type 1 (NF1) can cause progressive spinal cord compression and neurological dysfunction. The MEK inhibitor selumetinib shrinks the majority of plexiform neurofibromas (PNs) in patients with NF1. We assessed the effect of selumetinib on SNF. METHODS: Pediatric and adult patients with NF1 and inoperable PN participating in phase 2 studies of selumetinib for PN were included in this analysis if they had SNF and serial spine magnetic resonance imaging (MRI). Selumetinib was administered orally at the recommended dose of 25 mg/m2/dose twice daily (max 50 mg b.i.d.; 1 cycle = 28 days). We qualitatively assessed the effect of selumetinib on SNF-related spinal canal distortion, cerebrospinal fluid distribution, and spinal cord deformity on MRI. RESULTS: Twenty-four patients (18 male), median age 16.9 years (range, 6.2-60.3), had SNF, 22 of which were associated with the same nerves as the target PN assessed on the clinical trial. Twenty patients had spinal cord deformity. Twenty-three patients completed at least 12 treatment cycles to date. Eighteen patients showed subtle to a marked improvement in SNF burden, 5 remained stable, and no worsening was observed during treatment. CONCLUSIONS: This is the first study describing the effect of selumetinib on SNF. Of 24 patients, 18 exhibited some improvement of SNF burden on imaging. These findings suggest that selumetinib may prevent the worsening of cord compression, potentially reducing the need for surgical interventions in select patients or benefitting patients who do not have a surgical option. Prospective evaluation of the clinical benefit of selumetinib for SNF is warranted.

Selumetinib in Children with Inoperable Plexiform Neurofibromas.

BACKGROUND: No approved therapies exist for inoperable plexiform neurofibromas in patients with neurofibromatosis type 1. METHODS: We conducted an open-label, phase 2 trial of selumetinib to determine the objective response rate among patients with plexiform neurofibromas and to assess clinical benefit. Children with neurofibromatosis type 1 and symptomatic inoperable plexiform neurofibromas received oral selumetinib twice daily at a dose of 25 mg per square meter of body-surface area on a continuous dosing schedule (28-day cycles). Volumetric magnetic resonance imaging and clinical outcome assessments (pain, quality of life, disfigurement, and function) were performed at least every four cycles. Children rated tumor pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). RESULTS: A total of 50 children (median age, 10.2 years; range, 3.5 to 17.4) were enrolled from August 2015 through August 2016. The most frequent neurofibroma-related symptoms were disfigurement (44 patients), motor dysfunction (33), and pain (26). A total of 35 patients (70%) had a confirmed partial response as of March 29, 2019, and 28 of these patients had a durable response (lasting ≥1 year). After 1 year of treatment, the mean decrease in child-reported tumor pain-intensity scores was 2 points, considered a clinically meaningful improvement. In addition, clinically meaningful improvements were seen in child-reported and parent-reported interference of pain in daily functioning (38% and 50%, respectively) and overall health-related quality of life (48% and 58%, respectively) as well as in functional outcomes of strength (56% of patients) and range of motion (38% of patients). Five patients discontinued treatment because of toxic effects possibly related to selumetinib, and 6 patients had disease progression. The most frequent toxic effects were nausea, vomiting, or diarrhea; an asymptomatic increase in the creatine phosphokinase level; acneiform rash; and paronychia. CONCLUSIONS: In this phase 2 trial, most children with neurofibromatosis type 1 and inoperable plexiform neurofibromas had durable tumor shrinkage and clinical benefit from selumetinib. (Funded by the Intramural Research Program of the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803.).

Safe marginal resection of atypical neurofibromas in neurofibromatosis type 1.

OBJECTIVE: Patients with neurofibromatosis type 1 (NF1) are predisposed to visceral neurofibromas, some of which can progress to premalignant atypical neurofibromas (ANFs) and malignant peripheral nerve sheath tumors (MPNSTs). Though subtotal resection of ANF may prevent malignant transformation and thus deaths with no neural complications, local recurrences require reoperation. The aim of this study was to assess the surgical morbidity associated with marginal resection of targeted ANF nodules identified via preoperative serial volumetric MRI and 18F-FDG-PET imaging. METHODS: The authors analyzed clinical outcomes of 16 NF resections of 21 tumors in 11 NF1 patients treated at the NIH Clinical Center between 2008 and 2018. Preoperative volumetric growth rates and 18F-FDG-PET SUVMax (maximum standardized uptake value within the tumor) of the target lesions and any electromyographic or nerve conduction velocity abnormalities of the parent nerves were measured and assessed in tandem with postoperative complications, histopathological classification of the resected tumors, and surgical margins through Dunnett's multiple comparisons test and t-test. The surgical approach for safe marginal resection of ANF was also described. RESULTS: Eleven consecutive NF1 patients (4 male, 7 female; median age 18.5 years) underwent 16 surgical procedures for marginal resections of 21 tumors. Preoperatively, 13 of the 14 (93%) sets of serial MRI studies and 10 of the 11 (91%) 18F-FDG-PET scans showed rapid growth (≥ 20% increase in volume per year) and avidity (SUVMax ≥ 3.5) of the identified tumor, respectively (median tumor size 48.7 cm3; median growth rate 92% per year; median SUVMax 6.45). Most surgeries (n = 14, 88%) resulted in no persistent postoperative parent nerve-related complications, and to date, none of the resected tumors have recurred. The median length of postoperative follow-up has been 2.45 years (range 0.00-10.39 years). Histopathological analysis confirmed significantly greater SUVMax among the ANFs (6.51 ± 0.83, p = 0.0042) and low-grade MPNSTs (13.8, p = 0.0001) than in benign neurofibromas (1.9). CONCLUSIONS: This report evaluates the utility of serial imaging (MRI and 18F-FDG-PET SUVMax) to successfully detect ANF and demonstrates that safe, fascicle-sparing gross-total, extracapsular resection of ANF is possible with the use of intraoperative nerve stimulation and microdissection of nerve fascicles.

A phase I/II trial and pharmacokinetic study of mithramycin in children and adults with refractory Ewing sarcoma and EWS-FLI1 fusion transcript.

PURPOSE: In a preclinical drug screen, mithramycin was identified as a potent inhibitor of the Ewing sarcoma EWS-FLI1 transcription factor. We conducted a phase I/II trial to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of mithramycin in children with refractory solid tumors, and the activity in children and adults with refractory Ewing sarcoma. PATIENTS AND METHODS: Mithramycin was administered intravenously over 6 h once daily for 7 days for 28 day cycles. Adult patients (phase II) initially received mithramycin at the previously determined recommended dose of 25 µg/kg/dose. The planned starting dose for children (phase I) was 17.5 µg/kg/dose. Plasma samples were obtained for mithramycin PK analysis. RESULTS: The first two adult patients experienced reversible grade 4 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevation exceeding the MTD. Subsequent adult patients received mithramycin at 17.5 µg/kg/dose, and children at 13 µg/kg/dose with dexamethasone pretreatment. None of the four subsequent adult and two pediatric patients experienced cycle 1 DLT. No clinical responses were observed. The average maximal mithramycin plasma concentration in four patients was 17.8 ± 4.6 ng/mL. This is substantially below the sustained mithramycin concentrations ≥50 nmol/L required to suppress EWS-FLI1 transcriptional activity in preclinical studies. Due to inability to safely achieve the desired mithramycin exposure, the trial was closed to enrollment. CONCLUSIONS: Hepatotoxicity precluded the administration of a mithramycin at a dose required to inhibit EWS-FLI1. Evaluation of mithramycin in patients selected for decreased susceptibility to elevated transaminases may allow for improved drug exposure.

Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas.

BACKGROUND: Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling. METHODS: We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. RESULTS: A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. CONCLUSIONS: Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).

Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma.

PURPOSE: Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET (REarranged during Transfection) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC. EXPERIMENTAL DESIGN: We conducted a phase I/II trial of vandetanib for children (5-12 years) and adolescents (13-18 years) with MTC to define a recommended dose and assess antitumor activity. The starting dose was 100 mg/m(2) administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m(2)/d after two cycles. Radiographic response to vandetanib was quantified using RECIST (v1.0), biomarker response was measured by comparing posttreatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient-reported outcome was used to assess clinical benefit. RESULTS: Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2-52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n = 15) the confirmed objective partial response rate was 47% (exact 95% confidence intervals, 21%-75%). Biomarker partial response was confirmed for calcitonin in 12 subjects and for CEA in 8 subjects. CONCLUSION: Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m(2)/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC.

(111)In-octreotide scintigraphy for identification of metastatic medullary thyroid carcinoma in children and adolescents.

CONTEXT: Most medullary thyroid cancers (MTC) express somatostatin receptors; therefore, (111)In-octreotide somatostatin receptor scintigraphy (SRS) may be useful in detecting sites of metastases in children with MTC. OBJECTIVE: The aim of the study was to evaluate tumor metastases in children and adolescents with MTC using SRS in comparison to conventional imaging. DESIGN AND SETTING: A case series was conducted as part of baseline evaluation for cancer treatment protocol at the National Institutes of Health Clinical Center. PATIENTS: Eleven patients with a median age of 15 (range, 9-17) yr participated in the study, 10 with histologically proven, metastatic MTC due to the M918T mutation of the RET protooncogene, and one with a known RET polymorphism. INTERVENTION: After receiving 0.086 mCi/kg (111)Indium-pentreotide, patients were examined with a single photon emission computed tomography scan 4 and 24 h after injection. Baseline conventional imaging, including computed tomography (neck, chest, abdomen, ± pelvis, adrenals), magnetic resonance imaging (neck), and bone scan, was performed on all patients. MAIN OUTCOME MEASURES: SRS results were compared with conventional imaging. RESULTS: Five of the 11 patients had abnormal findings on SRS. Of the 53 total target lesions present in the patients, only 24.5% were accurately identified through SRS. CONCLUSIONS: SRS appears to be less sensitive than conventional imaging at detecting the full extent of metastatic disease in children and adolescents with hereditary MTC. SRS incompletely identified sites of tumor and failed to visualize small sites of tumor or liver and lung metastases, and it has a limited role in the evaluation of metastatic disease in pediatric MTC patients.

Pediatric phase I trial design using maximum target inhibition as the primary endpoint.

The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 microg/m(2) dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 microg/m(2) of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents.

Phase I clinical trial of intrathecal gemcitabine in patients with neoplastic meningitis.

PURPOSE: A phase I study of intrathecal (IT) gemcitabine was performed to define a safe dose and characterize the toxicity profile and CSF pharmacokinetics of gemcitabine and its major metabolite 2',2'-difluoro-deoxyuridine (dFdU) in patients 3 years of age and older with neoplastic meningitis. EXPERIMENTAL DESIGN: Gemcitabine was administered via Ommaya reservoir or lumbar puncture at three dose levels: 5 mg weekly, 5 mg twice-weekly, and 10 mg twice-weekly using a standard phase I dose escalation design. Serial CSF samples were obtained for pharmacokinetic studies in seven patients with Ommaya reservoirs. Serial blood samples for pharmacokinetic studies were also obtained from three patients. RESULTS: Ten patients were enrolled in this study. Significant neurological toxicities occurred in two patients including myelitis in a patient at the 5 mg twice-weekly dose level and somnolence in a patient at the 10 mg twice-weekly dose level. No complete responses were seen; however, three patients had stable disease. Gemcitabine was rapidly eliminated from the CSF with a terminal half-life of 61 +/- 50 min. No gemcitabine or dFdU was detected in plasma. CONCLUSIONS: IT gemcitabine was associated with significant neurotoxicity; therefore, its further development for IT use is not recommended.

Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas.

PURPOSE: This pediatric phase I trial of tipifarnib determined the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of tipifarnib in children with refractory solid tumors and neurofibromatosis type 1 (NF1) -related plexiform neurofibromas. PATIENTS AND METHODS: Tipifarnib was administered twice daily for 21 days, repeated every 28 days starting at 150 mg/m2/dose (n = 4), with escalations to 200 (n = 12), 275 (n = 12), and 375 (n = 6) mg/m2/dose. The MTD was also evaluated on a chronic continuous dosing schedule (n = 6). Pharmacokinetic sampling was performed for 36 hours after the first dose and peripheral-blood mononuclear cells (PBMCs) were collected at baseline and steady state for determination of farnesyl protein transferase (FTase) activity and HDJ-2 farnesylation. RESULTS: Twenty-three solid tumor and 17 NF1 patients were assessable for toxicity. The MTD was 200 mg/m2/dose, and dose-limiting toxicities on cycle 1 were myelosuppression, rash, nausea, vomiting, and diarrhea. The 200 mg/m2/dose was also tolerable on the continuous dosing schedule. Cumulative toxicity was not observed in the 17 NF1 patients who received a median of 10 cycles (range, 1 to 32 cycles). The plasma pharmacokinetics of tipifarnib were highly variable but not age dependent. At steady state on 200 mg/m2/dose, FTase activity was 30% compared with baseline, and farnesylation of HDJ-2 was inhibited in PBMCs. CONCLUSION: Oral tipifarnib is well tolerated in children receiving the drug twice daily for 21 days and a continuous dosing schedule at 200 mg/m2/dose, which is equivalent to the MTD in adults. The pharmacokinetic profile of tipifarnib in children is similar to that in adults, and at the MTD, FTase is inhibited in PBMC in vivo.