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A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: A children's oncology group study
Article first published online: 11 OCT 2007
Copyright © 2007 American Cancer Society
Volume 110, Issue 11, pages 2535–2541, 1 December 2007
How to Cite
Fouladi, M., Nicholson, H. S., Zhou, T., Laningham, F., Helton, K. J., Holmes, E., Cohen, K., Speights, R. A., Wright, J. and Pollack, I. F. (2007), A phase II study of the farnesyl transferase inhibitor, tipifarnib, in children with recurrent or progressive high-grade glioma, medulloblastoma/primitive neuroectodermal tumor, or brainstem glioma: A children's oncology group study. Cancer, 110: 2535–2541. doi: 10.1002/cncr.23078
- Issue published online: 19 NOV 2007
- Article first published online: 11 OCT 2007
- Manuscript Accepted: 13 JUL 2007
- Manuscript Revised: 22 JUN 2007
- Manuscript Received: 16 APR 2007
- National Cancer Institute. Grant Number: U01 CA97452
- National Center for Research Resources. Grant Number: M01 RR00188
- recurrent central nervous system malignancies;
- Phase II trial;
- farnesyl transferase inhibitor
An open-label Phase II study of tipifarnib was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB)/primitive neuroectodermal tumor (PNET), high-grade glioma (HGG), and diffuse intrinsic brainstem glioma (BSG).
Between January 2004 and July 2005, patients were enrolled and stratified as follows: Stratum 1, recurrent or refractory MB/PNET; Stratum 2, recurrent or refractory HGG; and Stratum 3, recurrent or refractory BSG. Patients received tipifarnib 200 mg/m2 per dose twice daily for 21 days repeated every 28 days. Patients who received enzyme-inducing anticonvulsants and other CYP3A4/5 inducers or inhibitors were excluded. The primary objective was to estimate the sustained response rate in all strata.
Ninety-seven patients with a median age of 11.2 years (range, 3.2–21.9 years) were enrolled on the study, and 81 patients were evaluable for response. One of 35 patients with BSG and 1 of 31 patients with HGG had a sustained partial response. No responses were observed in 15 patients with MB/PNET. Eight patients (3 HGG, 1 MB, and 4 BSG) remained stable for ≥4 courses (range, 4–25 courses). The median number of courses received was 2 (range, 1–25 courses). The most frequent grade 3 and 4 toxicities included neutropenia (18.7%), thrombocytopenia (14.3%), and leukopenia (14.3%). The 6-month progression-free survival rate (±standard deviation) was 14% ± 6% for HGG, 6% ± 6% for MB/PNET and 3% ± 3% for BSG.
Tipifarnib tolerated well but had little activity as a single agent in children with recurrent central nervous system malignancies. Cancer 2007. © 2007 American Cancer Society.
Despite significant progress in the treatment of children with some central nervous system (CNS) malignancies, the prognosis for patients with recurrent CNS malignancies after radiotherapy remains dismal.1–6 The Ras protein is a key intermediate in the signal-transduction pathways that control growth, differentiation, apoptosis, and membrane trafficking. Ras is over activated in various types of cancer, including astrocytoma and glioblastoma (GBM),7–10 and it has a functional role in medulloblastoma (MB) metastasis.11 The over activation of Ras may be caused by deregulation of growth factors and growth factor receptors, including epidermal growth factor receptor (EGFR), which is overexpressed in adult and pediatric high-grade gliomas (HGG) and leads to activation of the Ras mitogenic pathway.8, 9, 12 Taken together, these observations suggest that targeted inhibition of Ras-dependent signaling may constitute a therapeutically useful strategy for recurrent primitive neuroectodermal tumor (PNET) and malignant glioma.8–10
Ras is synthesized as a propeptide (pro-Ras) and undergoes several posttranslational modifications to associate with the inner surface of the plasma membrane. Farnesylation, the addition of a farnesyl group to the cysteine residue on the COOH terminus, is catalyzed by the protein farnesyl transferase and is essential for Ras function.13 Although farnesyl transferase inhibitors (FTIs) inhibit Ras farnesylation, their antiproliferative effects are not caused exclusively by the effects on Ras, because they target other multifunctional proteins,14–18 including Rho-B,19 members of the phosphatidylinositol 3′kinase/AKT pathway,20 and the centromere-associated proteins CENP-E and CENP-F,21 which may mediate the antitumor effects of FTIs.
In preclinical studies, Glass et al.22 reported that FTIs inhibit human glioblastoma cell lines in vitro at a 50% inhibitory concentration (IC50) from 10 μM to 30 μM through a signal-transduction pathway that involves the down-regulation of phosphorylated microtubule-activated protein kinase levels, and the cell lines that overexpressed EGFR were more sensitive to FTIs. Feldkamp et al.23 also demonstrated that astrocytomas were amenable to growth inhibition by FTIs at an IC50 < 20 μM through a combination of antiproliferative, proapoptotic, and antiangiogenic effects despite the lack of oncogenic ras mutations. Tipifarnib (R115777; Zarnestra; Johnson and Johnson Pharmaceutical Research and Development LLC, Titusville, NJ) is an orally bioavailable methyl-quinolone, and it has been demonstrated that tipifarnib is a potent and selective, nonpeptidomimetic inhibitor of farnesyl protein transferase with potent activity in vitro (IC50 < 0.1 μmol/L) and in vivo against many human cancer cell lines and xenograft models, respectively.24
In adult Phase I trials, the maximum tolerated dose (MTD) of tipifarnib was established at 300 mg orally twice daily for 21 days of a 28-day cycle with myelosuppression as its dose-limiting toxicity (DLT).25–27 Other toxicities included fatigue, nausea, vomiting, and diarrhea. In Phase II studies in hematologic malignancies, tipifarnib showed significant activity in patients with multiple myeloma28 and myelodysplastic syndrome29 and in older adults with poor-risk acute myelogenous leukemia.30 Generally, the results from Phase II31–34 and III trials35, 36 in adults with solid tumors have been disappointing. However, some clinical activity of tipifarnib as a single agent was reported in patients with metastatic breast cancer37 and in patients with recurrent GBM who were not receiving enzyme-inducing anticonvulsant drugs (EIACDs).38 Phase I trials in children with recurrent solid tumors have established the MTD at 200 mg/m2 twice daily for 21 of 28 days, and the DLTs were myelosuppression, rash, nausea and vomiting.39
In this article, we report the results from an open-label, Phase II trial of tipifarnib in children with recurrent or progressive HGG (Stratum 1); MB/PNET (Stratum 2); or diffuse, intrinsic brainstem glioma (BSG) (Stratum 3). The primary objective of this trial was to estimate the objective response rate (ORR) in children with recurrent or progressive HGG, MB/PNET, and BSG. The secondary objectives were to estimate the time to progression and the time to death in these strata. A tertiary objective was to estimate the toxicities of tipifarnib.
MATERIALS AND METHODS
The eligibility criteria were as follows: age < 22 years; and histologically verified, recurrent or progressive HGG, including anaplastic astrocytoma, GBM, gliosarcoma, anaplastic oligodendroglioma (Stratum 1), and MB/PNET (Stratum 2). Patients with diffuse intrinsic BSG did not require histologic verification. Patients were required to have measurable disease on magnetic resonance imaging (MRI) studies; a Lansky or Karnofsky performance status > 50%; life expectancy ≥8 weeks; recovery from acute toxic effects of prior therapy; no myelosuppressive chemotherapy within 2 weeks before study entry (4 weeks if they received nitrosourea or temozolamide); no biologic antineoplastic agents for 7 days; no local palliative small-port radiotherapy for at least 2 weeks or craniospinal radiotherapy for at least 3 months; no substantial bone marrow radiation for at least 6 weeks; ≥1 month from autologous stem cell transplantation; and no growth factors within 1 week. Corticosteroid therapy was permissible only for the treatment of increased intracranial pressure and must have been administered at a stable or decreasing dose for ≥1 week before study entry. The use of EIACDs or other CYP3A4/5 inducers or inhibitors listed in the protocol was not permissible; and the use of cimetidine, ranitidine, and omeprazole was permissible only in conjunction with corticosteroids in the setting of increased intracranial pressure. Patients had to have adequate bone marrow function, which was defined as a peripheral absolute neutrophil count (ANC) ≥1000/μL; a platelet count ≥100,000/μL (transfusion independent); hemoglobin ≥8 g/dL; adequate renal function (serum creatinine ≤1.5 times normal for age or glomerular filtration rate ≥70 mL/minute/1.73 m2); adequate liver function (total bilirubin ≤1.5 times the institutional upper limit of normal for age; alanine aminotransferase [ALT] and aspartate aminotransferase [AST] levels ≤2.5 times the institutional upper limit of normal for age); adequate cardiac function (shortening fraction ≥27% by echocardiogram or left ventricular ejection fraction ≥50% by gated radionucleotide study); adequate pulmonary function, which we defined as no evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry > 94% if there was a clinical indication for determination; and no seizures or well-controlled seizures on non-EIACDs. Patients were excluded if they were receiving other anticancer or experimental drug therapy, had allergies to azoles, had an uncontrolled infection, or were pregnant or breastfeeding. Informed consent was obtained from patients, parents, or guardians; and assent was obtained as appropriate according to institutional guidelines. The protocol was approved by the institutional review boards of participating institutions.
Tipifarnib (supplied by the Cancer Therapy Evaluation Program) was supplied in 50-mg and 100-mg tablets and was administered orally after a meal every 12 hours for 21 days followed by a 7-day rest period for a 28-day treatment cycle. Each patient's dose was rounded to the nearest 50 mg using a dosing nomogram in the protocol based on body surface area. The dose of tipifarnib was 200 mg/m2 per dose given twice daily (400 mg/m2 per day).
If patients experienced grade ≥3 thrombocytopenia (<50,000/μL) or grade 4 neutropenia (<500/μL), drug was held. Drug was resumed at the same dose when platelets recovered to >100,000/μL or neutrophils recovered to >1000/μL. If grade ≥3 thrombocytopenia or grade 4 neutropenia recurred, then the dose was resumed at a reduced dose of 150 mg/m2 per dose twice daily after hematologic recovery. Further dose reductions were not permitted.
If patients experienced grade ≥3 hyperbilirubinemia, AST or ALT, then drug was held and was resumed at 150 mg/m2 twice daily when the parameters had recovered to grade ≤1. Further dose reductions were not permitted.
If patients experienced other grade 3 and 4 nonhematologic toxicities, then tipifarnib was withheld until the toxicity had resolved to grade ≤1, and drug was resumed at a dose of 150 mg/m2. Patients who experienced grade 2 toxicity that did not resolve despite symptomatic treatment had the drug withheld. If the toxicity resolved to grade ≤1 within 7 days, then the drug was resumed at the reduced dose of 150 mg/m2 per dose twice daily. Further dose reductions were not permitted.
Pretreatment Evaluation and Evaluations During Therapy
Pretreatment evaluations included a history, physical and opthalmologic examinations, performance status, echocardiogram, complete blood count, electrolytes, renal and liver function tests, and serum protein and albumin levels. Complete blood counts were obtained twice weekly during the first course and weekly thereafter. Physical examinations and laboratory studies were obtained weekly during the first course and before the start of each subsequent course. Disease evaluations occurred at baseline, after Courses 2 and 4, and after every third course thereafter. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria Adverse events (version 3.0). Patients had to demonstrate hematologic recovery before commencing subsequent courses of therapy with a hemoglobin level ≥8 g/dL, an ANC ≥1000/μL, and a platelet count ≥100,000/μL (transfusion independent).
Patients had to receive ≥2 courses of tipifarnib to be considered evaluable for response. Responses were assessed by MRI. Patients must have had tumor measurable in 3 dimensions.
A complete response (CR) was defined as the disappearance of all target lesions. A partial response (PR) was defined as a decrease ≥65% in the sum of the products of the 3 greatest perpendicular dimensions of all target lesions (up to 5). Stable disease (SD) was defined as neither a sufficient decrease in the sum of the products of the 3 greatest perpendicular dimensions of target lesions to qualify for PR nor sufficient increase in a single target lesion to qualify for progressive disease (PD), which was defined as an increase ≥40% in the products of the greatest perpendicular dimensions of any target lesion or the appearance of any new lesions. Responses or prolonged SD ≥4 courses were confirmed by central review by 2 neuroradiologists (F.L. and K.J.H.).
Several patients were taken off therapy for presumed clinical progression without obtaining confirmatory off-therapy scans, as required in the protocol. Because the deteriorating clinical status of many patients at the time of clinical progression made reimaging difficult, patients who died within 2 weeks of being taken off study for clinical progression without confirmatory neuroimaging were considered to have experienced PD and were considered evaluable for response (n = 9 patients). Those who died > 2 weeks after they were taken off therapy and who did not have a scan confirming PD were not considered evaluable for response (n = 4).
The primary endpoint of the study was to estimate the ORR after a minimum of 2 months of treatment in patients with HGG, MB, and BSG. A Simon optimal 2-stage design40 was used to test the null hypothesis that the response rate was ≤5% (vs ≥25%) with an α level of .05 and 90% power.41 Fifteen evaluable patients were to be enrolled on the first stage of each stratum. If at least 1 patient had a confirmed objective response (CR + PR), then an additional 15patients would be enrolled.
Table 1 summarizes the characteristics of the 97 patients who were enrolled on this study. The median age was 11.2 years (range, 3.2–21.9 years). The median number of courses of tipifarnib administered was 2 (range, 1–25 courses). All 97 patients were eligible. Sixteen patients were not evaluable for response and did not complete the first 2 courses of therapy because they did not receive the correct medication dose (n = 5 patients), died 5 days into therapy (n = 1 patient), were receiving contraindicated medications (n = 2 patients), were taken off therapy at parents' request (n = 2 patients) or at the discretion of the physician (n = 1 patient), were treated concurrently with other anticancer agent (imatinib mesylate; n = 1 patient), or did not undergo off-therapy scan evaluations to confirm PD and died > 2 weeks after cessation of therapy (n = 4 patients).
|Characteristic||No. of patients (%)|
|Black/African American||17 (18)|
|Brainstem glioma||41 (42)|
|HGG diagnosis (N = 38)|
|Anaplastic astrocytoma||20 (53)|
|Glioblastoma multiforme||15 (39)|
|Anaplastic oligodendroglioma||1 (3)|
|Glioma, other malignant||2 (5)|
|MBL/PNET diagnosis (N = 18)|
|Mean age [range], y||11.2 [3.2–21.9]|
|No. of cycles [range]||2 [1–25]|
Table 2 summarizes the number and percentage of patients who experienced various treatment-related toxicities. In general, tipifarnib appeared to be tolerated well. The most common grade 3 and 4 adverse events included neutropenia (18.7%), thrombocytopenia (14.3%), leucopenia (14.3%), and diarrhea and vomiting (4.4%). Six patients were not evaluable for toxicity because they were assigned mistakenly to receive a dose that was too high (n = 3 patients) or because they received a concomitant contraindicated medication during therapy (n = 3 patients).
|Toxicity||Grade 3||Grade 4||Total|
|Infection (documented clinically)||3||3.3||—||3||3.3|
|Infection with normal ANC or grade 1 or 2 neutrophils||2||2.2||—||2||2.2|
|Fatigue (asthenia, lethargy, malaise)||1||1.1||—||1||1.1|
|Hemorrhage, pulmonary/upper respiratory-nose||1||1.1||—||1||1.1|
|Pain abdomen NOS||1||1.1||—||1||1.1|
Response to Therapy
Among the 31 evaluable patients with recurrent or progressive HGG, 1 patient had a confirmed PR, and 3 patients continued on therapy for at least 4 cycles (10%). Among the 35 patients with BSG, 1 patient had confirmed PR, and 4 patients continued on therapy with SD for ≥4 cycles (11%). Among the 15 patients with MB/PNET, no objective response was observed, and only 1 patient received therapy for at least 4 cycles (7%).
The role of chemotherapy in children with HGG and BSG remains limited, and there is no standard chemotherapy regimen that offers a clear survival advantage.41 In patients with MB/PNET, standard frontline therapy currently includes adjuvant, platinum-based chemotherapy.42–45 However, cisplatin-related toxicities (nephrotoxicity and ototoxicity) and carboplatin-related toxicities (myelosuppression) have remained significant problems. Thus, the development of novel treatment strategies to improve survival and minimize sequelae in patients with MB/PNET, HGG, and BSG is a major objective in pediatric neuro-oncology.
Although malignant astrocytomas and MBs do not harbor oncogenic ras mutations, it has been established that Ras is over activated in astrocytomas and GBMs,8–10, 12 as well as MBs because of overexpression and/or deregulation of upstream growth factors and their receptors, such as EGFR and platelet-derived growth factor receptor. Thus, FTIs represent a novel treatment strategy for patients with these malignancies.
The current study demonstrated that tipifarnib administered orally at 200 mg/m2 per dose twice daily for 21 days every 28 days was tolerated well in children but had little activity as a single agent in children with recurrent CNS malignancies; 1 patient with BSG (2.9%) and 1 patient with HGG (3.2%) had a PR, and 17 patients remained on therapy for > 4 courses. A similar Phase II trial of tipifarnib in adults with recurrent GBM demonstrated slightly better but still modest activity in patients who did not receive EIACDs, and 4 patients (11%) experienced a PR.38 The slightly better ORR observed in adult studies among patients with GBM may be related to differences between the biology of high-grade gliomas in children and adults.46, 47 Amplification of the EGFR gene, which may lead to activation of the Ras mitogenic pathway, was observed in 30% to 40% of adult HGG but is rare in children.46, 48, 49 Furthermore, in adults, EGFR overexpression and amplification go hand-in-hand; whereas, despite the finding that 85% of pediatric HGG overexpress EGFR, EGFR amplification was observed only in approximately 7% of patients.39, 50, 51 Thus, different mechanism may be responsible for EGFR overexpression in childhood high-grade gliomas compared with adults.
Overall, our data on the use of single-agent tipifarnib are similar to those from reports of Phase II and III trials among adults with solid tumors—results that generally have been disappointing.31–36 In contrast, data on patients with hematologic malignancies have been more encouraging.28–30
Similar to what has been observed in most previously published studies, the main toxicity of tipifarnib reported was myelosuppression. In the adult Phase II trial in patients with recurrent malignant gliomas, rash was reported as the DLT in patients who received EIACDs, and myelosuppression was the DLT in the group that did not receive EIACDs. However, the incidence and severity of rash in both groups were similar.38 One patient experienced grade 4 skin ulceration in the current study with no other reported grade 3 or 4 rashes. It is noteworthy that we excluded patients who were on EIACDs, because tipifarnib undergoes extensive hepatic metabolism and would be anticipated to have an increased clearance in the presence of EIACDs. In fact, Cloughesy et al. confirmed this assumption by demonstrating a clear difference in the pharmacokinetic parameters between the 2 groups, with an area under the plasma concentration time curve that was 2-fold lower for patients who were on EIACDS.38 Similarly, Siegel-Lakhai et al. reported that, in patients with moderately impaired hepatic function, tipifarnib led to significant grade 3 or 4 hematologic toxicity and could not be administered safely.52
In summary, in this Phase II pediatric trial, tipifarnib was tolerated relatively well but demonstrated minimal single-agent antitumor activity in children with recurrent CNS malignancies. Efforts should focus on determining whether combination treatment with tipifarnib and other cytotoxic or molecularly targeted therapies (eg, epidermal growth factor inhibitors) may be of potential benefit in patients with CNS malignancies. Currently, based on preclinical data supporting the use of FTIs as radiosensitizers,53 the Pediatric Brain Tumor Consortium is conducting a study to determine the efficacy of tipifarnib used concurrently with radiotherapy and continued after radiotherapy in children with newly diagnosed, diffuse intrinsic BSG.
- 45Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol. 2006; 7: 813–820., , , et al.