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Trent R Hummel,
Lars Wagner,
Charlotte Ahern, Maryam Fouladi,
Joel M Reid,
Renee M McGovern,
Matthew M Ames,
Richard J Gilbertson,
Terzah Horton,
Ashish M Ingle,
Brenda Weigel,
Susan M Blaney
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ABSTRACT: PURPOSE: We conducted a pediatric phase I study to estimate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic properties of vorinostat, a histone deacetylase (HDAC) inhibitor, when given in combination with temozolomide in children with refractory or recurrent CNS malignancies. PATIENTS AND METHODS: Vorinostat, followed by temozolomide approximately 1 hour later, was orally administered, once daily, for 5 consecutive days every 28 days at three dose levels using the rolling six design. Studies of histone accumulation in peripheral blood mononuclear cells were performed on Day 1 at 0, 6, and 24 hours after vorinostat dosing. Vorinostat pharmacokinetics (PK) and serum MGMT promoter status were also assessed. RESULTS: Nineteen eligible patients were enrolled and 18 patients were evaluable for toxicity. There were no DLTs observed at dose level 1 or 2. DLTs occurred in four patients at dose level 3: thrombocytopenia (4), neutropenia (3), and leucopenia (1). Non-dose limiting grade 3 or 4 toxicities related to protocol therapy were also hematologic and included neutropenia, lymphopenia, thrombocytopenia, anemia, and leucopenia. Three patients exhibited stable disease and one patient had a partial response. There was no clear relationship between vorinostat dosage and drug exposure over the dose range studied. Accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat. CONCLUSION: Five-day cycles of vorinostat in combination with temozolomide are well tolerated in children with recurrent CNS malignancies with myelosuppression as the DLT. The recommended phase II combination doses are vorinostat, 300 mg/m(2) /day and temozolomide, 150 mg/m(2) /day. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
Pediatric Blood & Cancer 03/2013; · 1.89 Impact Factor
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Maryam Fouladi,
Clinton F Stewart,
James Olson,
Lars M Wagner,
Arzu Onar-Thomas,
Mehmet Kocak,
Roger J Packer,
Stewart Goldman,
Sridharan Gururangan,
Amar Gajjar,
Tim Demuth,
Larry E Kun,
James M Boyett,
Richard J Gilbertson
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ABSTRACT: To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies.
MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m(2). The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752.
Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m(2)/dose. At 260 mg/m(2)/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non-dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m(2); apparent volume of distribution, 7.36 (24%) L/m(2); and k(a), 0.358 (99%) hr(-1).
MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m(2)/dose once daily.
Journal of Clinical Oncology 08/2011; 29(26):3529-34. · 18.37 Impact Factor
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Daphne A Haas-Kogan,
Anuradha Banerjee,
Tina Young Poussaint,
Mehmet Kocak,
Michael D Prados,
J Russell Geyer, Maryam Fouladi,
Alberto Broniscer,
Jane E Minturn,
Ian F Pollack,
Roger J Packer,
James M Boyett,
Larry E Kun
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ABSTRACT: We performed a phase II study to assess the efficacy and toxicity of tipifarnib, a farnesyltransferase inhibitor, administered with radiation therapy (RT) in children with newly diagnosed diffuse intrinsic pontine gliomas. Children 3-21 years old with pontine gliomas (BSGs) were treated with concurrent tipifarnib and RT, followed by adjuvant tipifarnib. Tipifarnib was taken orally twice daily (125 mg/m(2)/dose) during RT; after RT, it was taken at 200 mg/m(2) twice daily for 21 days, in 28-day cycles. Initial and follow-up neuroimaging was centrally reviewed. Forty eligible patients (median age, 5.5 years; range, 3.3-16.5 years) had a median progression-free survival of 6.8 months (range, 0.2-18.6 months) and median overall survival of 8.3 months (range, 0.2-18.6 months). Kaplan-Meier estimates (± standard error) of 1-year progression-free and overall survival were 12.9% ±4.9% and 34.3% ±7.4%, respectively. A single patient remained on tipifarnib without progression at the completion of the study, two years after initiation of treatment. Seven patients were without disease progression for at least six months, three of whom remained controlled for more than a year. The most frequent toxicity was grade 3 lymphopenia. We documented a single instance of "pseudoprogression" by neuroimaging review. We found no discordance among 3 approaches to defining disease progression: as interpreted by treating institutions (based on clinical status and/or imaging) and by central review (using bi-dimensional tumor "area" versus volumetric measurements). For children with diffuse BSGs, tipifarnib administered with irradiation offered no clinical advantage over historical controls. Biopsies and molecular analyses of pediatric BSGs are vital for identification of new agents and for rational use of targeted agents.
Neuro-Oncology 03/2011; 13(3):298-306. · 5.72 Impact Factor
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ABSTRACT: Medulloblastoma with melanotic differentiation, a rare variant of medulloblastoma, often carries a poor prognosis. We present such a case of a 4 year male with this rare, aggressive tumor. Additionally, we have reviewed the literature and report on the features important in the pathologic and radiologic diagnosis in this type of tumor, as well as review clinical outcomes. This subtype of medulloblastoma occurs more frequently in males, at a younger median age than the other subtypes of medulloblastoma. The prognosis is generally very poor. However, it is important to note, that a subset of patients with M0 disease who can achieve a gross total resection followed by radiation and platinum based chemotherapy can become long term survivors of this aggressive subtype of medulloblastoma.
Journal of Neuro-Oncology 10/2010; 103(3):759-64. · 3.21 Impact Factor
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ABSTRACT: To estimate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic properties of lapatinib, a selective epidermal growth factor receptor (EGFR) and ERBB2 inhibitor, in children with refractory or recurrent CNS malignancies.
Lapatinib was administered orally twice daily at escalating doses starting at 300 mg/m(2) to patients who were not (stratum I) or were (stratum II) receiving steroids. Pharmacokinetic studies were performed during the first two courses. Expression of the four ERBB receptors and downstream signaling elements in tumor tissue was evaluated by immunohistochemistry.
Fifty-nine patients were enrolled (stratum I, n = 32; stratum II, n = 27). Of 29 patients evaluable for toxicity in stratum I, one experienced a DLT (diarrhea) at 520 mg/m(2) twice daily, and all three receiving 1,150 mg/m(2) twice daily experienced DLTs (one each of rash, diarrhea, and fatigue). Two of 21 patients evaluable for toxicity in stratum II experienced DLTs of rash at 900 mg/m(2) twice daily. Lapatinib dosage was related linearly to area under the [concentration-time] curve from start time to 12 hours later (AUC(0-12)) and dose-normalized maximum serum concentration and AUC values for patients in stratum II were both significantly higher (P = .001) than those for patients in stratum I. Frequent, high-level expression of activated (phosphorylated) EGFR and ERBB2 receptors and downstream signal intermediates were observed in tumors, particularly in ependymomas that displayed prolonged stable disease on lapatinib therapy.
Lapatinib is well tolerated in children with recurrent CNS malignancies, with rash, diarrhea, and fatigue identified as DLTs. The recommended phase II dose, regardless of steroid use, is 900 mg/m(2) twice daily.
Journal of Clinical Oncology 09/2010; 28(27):4221-7. · 18.37 Impact Factor
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ABSTRACT: A sensitive and rapid HTLC-ESI-MS/MS method with an advanced online sample preparation was developed for determination of the gamma-secretase inhibitor MK-0752 in human plasma using an internal standard. Plasma samples (100 microL) were diluted and injected directly onto an online extraction column (Cohesive Cyclone MAX 0.5 mm x 50 mm, > 30 microm), the sample matrix was washed out with an aqueous solution, and retained analytes were eluted out and transferred directly to the analytical column (Phenomenex Gemini 3 micron C18 110A, 50 mm x 2.0 mm at 50 degrees C) for separation using a gradient mobile phase. The eluted analytes were then detected on an API-3000 LC-MS/MS System with ESI and a negative multiple reaction monitoring mode. The monitored ion transitions were m/z 441-->175 for MK-0752 and 496-->175 for the internal standard. Online extraction recoveries were 81%. The method was validated and was linear in the range of 0.05-50 microg/mL. Within-day and between-day precisions were<8.6%, and accuracies were 0.7 and 7.1%. This method was applied to the measurement of plasma MK-0752 levels in a Phase I study of pediatric patients with recurrent or refractory brain tumors.
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 09/2010; 878(25):2348-52. · 2.78 Impact Factor
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Maryam Fouladi,
Julie R Park,
Clinton F Stewart,
Richard J Gilbertson,
Paula Schaiquevich,
Junfeng Sun,
Joel M Reid,
Matthew M Ames,
Roseanne Speights,
Ashish M Ingle,
James Zwiebel,
Susan M Blaney,
Peter C Adamson
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ABSTRACT: The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children.
Vorinostat was administered orally daily starting at 180 mg/m(2)/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC).
Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m(2)/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m(2)/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m(2)/d 4 times per week and 13cRA 80 mg/m(2)/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m(2)/d for the capsule (range, 1,415 to 9,291 ng/mL x hr) and oral suspension (range, 1,186 to 4,780 ng/mL x hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination.
In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m(2)/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.
Journal of Clinical Oncology 08/2010; 28(22):3623-9. · 18.37 Impact Factor
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ABSTRACT: We evaluated the pharmacokinetics of amifostine and WR1065 in pediatric patients with newly diagnosed medulloblastoma to assess the influence of patient covariates, including demographics, clinical characteristics, and genetic polymorphisms, on amifostine and WR1065 pharmacokinetic parameters.
We assessed the pharmacokinetics of amifostine and WR1065 in 33 children who received amifostine (1-minute infusion, 600 mg/m(2)) just before the start of and 3 hours into a 6-hour cisplatin infusion. Serial blood samples were collected after doses 1 (0 hour) and 2 (3 hours) of course 1. Amifostine and WR1065 were quantitated by high performance liquid chromatography with electrochemical detection. A pharmacokinetic model was simultaneously fit to amifostine and WR1065 plasma or whole blood concentration-versus-time data. The influence of demographic, biochemical, and pharmacogenetic covariates on amifostine and WR1065 disposition was evaluated.
Body surface area was the primary size-based covariate for amifostine pharmacokinetics explaining 53% and 56% of interindividual variability in plasma and whole-blood amifostine clearance, respectively. The population-predicted values for amifostine clearance, volume, and apparent WR1065 clearance from the plasma data were 107 L/h/m(2), 5.53 L/m(2), and 30.6 L/h/m(2). The population-predicted values for amifostine clearance, volume, and apparent WR1065 clearance from whole blood data were 136 L/h/m(2), 7.23 L/m(2), and 12.5 L/h/m(2).
These results support using body surface area for calculating doses of amifostine in children. Similar to data in adults, amifostine and WR1065 are rapidly cleared from plasma and whole blood in children.
Clinical Cancer Research 02/2010; 16(3):1049-57. · 7.74 Impact Factor
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ABSTRACT: A carboplatin-based chemotherapy regimen was used as primary postoperative therapy in infants with central nervous system (CNS) tumors to limit renal and ototoxicity and to target systemic exposure.
Fifty-three patients aged <age 3 years with embryonal CNS tumor medulloblastoma (n = 20), ependymoma (EP, n = 21), choroid plexus carcinoma (CPCA, n = 5), and primitive embryonal neoplasms including atypical teratoid rhabdoid tumors (n = 7) were treated with cyclophosphamide, etoposide, and carboplatin. Radiation therapy was used only for residual disease at the end of chemotherapy or disease progression.
The response rate after 2 cycles of chemotherapy was 34% (complete response, 13.8%; partial response, 20.7%). Myelosuppression was the dominant toxicity; 2 patients had toxic deaths related to thrombocytopenia with trauma. The 5-year overall survival (OS) was 49% +/- 7%, and the progression-free survival (PFS) was 31% +/- 7%, with a median follow-up of 11.4 years (range, 5.2-15.0 years). For medulloblastoma, the 5-year PFS was 26% +/- 9%; for EP it was 33% +/- 10%; for CPCA it was 80% +/- 18%; and for primitive neuroectodermal and atypical teratoid rhabdoid tumors it was 0%. Localized EP patients with gross total resection who did not undergo radiotherapy had a 5-year PFS of 57% +/- 17% and OS of 71% +/- 16%. Two patients developed late second malignancies; 1 was associated with germline p53 mutation.
The results confirm that carboplatin has similar activity to cisplatin in otherwise similar regimens. Five-year survival data are comparable to those reported in other recent studies, including high-dose chemotherapy studies. Of note is the marked activity in CPCA and gross totally resected EP.
Cancer 05/2009; 115(14):3243-53. · 4.77 Impact Factor
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ABSTRACT: The combination of a platinating agent and etoposide has induced responses in various pediatric tumors. The study estimated the maximum tolerated dose (MTD) of an oxaliplatin and etoposide regimen in children with recurrent solid tumors.
Oxaliplatin was administered on Day 1 and etoposide on Days 1 to 3 of each 21-day course. Cohorts of 3 to 6 patients were enrolled at 3 dose levels: 1) oxaliplatin at a dose of 130 mg/m(2) and etoposide at a dose of 75 mg/m(2), 2) oxaliplatin at a dose of 130 mg/m(2) and etoposide at a dose of 100 mg/m(2), and 3) oxaliplatin at a dose of 145 mg/m(2) and etoposide at a dose of 100 mg/m(2). Calcium and magnesium infusions were used at dose level 3 in an attempt to escalate the oxaliplatin dose past the single-agent MTD.
The 16 patients received a total of 63 courses. At dose level 1, dose-limiting epistaxis, neuropathy, and neutropenia occurred in 1 of 6 patients. No dose-limiting toxicity (DLT) occurred at dose level 2 (n = 6). At dose level 3, 2 of 4 patients experienced dose-limiting neutropenia; none experienced grade 3 or 4 acute neuropathy. Six patients required prolongation of the oxaliplatin infusion because of acute sensory neuropathy. Responses were observed in patients with medulloblastoma (1 complete response) and pineoblastoma (1 partial response); 3 others with atypical teratoid rhabdoid tumor, ependymoma, and soft tissue sarcoma had prolonged disease stabilization.
The MTD of this regimen was found to be oxaliplatin at a dose of 130 mg/m(2) given on Day 1 and etoposide at a dose of 100 mg/m(2)/d given on Days 1 to 3. Neutropenia was found to be the DLT. Calcium and magnesium infusions did not allow escalation of the oxaliplatin dose. The combination was well-tolerated and demonstrated antitumor activity.
Cancer 01/2009; 115(3):655-64. · 4.77 Impact Factor
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Maryam Fouladi,
Murali Chintagumpala,
David Ashley,
Stewart Kellie,
Sridharan Gururangan,
Tim Hassall,
Lindsey Gronewold,
Clinton F Stewart,
Dana Wallace,
Alberto Broniscer,
Gregory A Hale,
Kimberly A Kasow,
Thomas E Merchant,
Brannon Morris,
Matthew Krasin,
Larry E Kun,
James M Boyett,
Amar Gajjar
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ABSTRACT: To determine the role of amifostine as a protectant against cisplatin-induced ototoxicity in patients with average-risk (AR) medulloblastoma treated with craniospinal radiotherapy and four cycles of cisplatin-based, dose-intense chemotherapy and stem-cell rescue.
The primary objective was to determine whether, in patients with AR medulloblastoma (n = 62), amifostine would decrease the need for hearing aids (defined as >or= grade 3 ototoxicity in one ear) compared with a control group (n = 35), 1 year from initiating treatment. Ninety-seven patients received craniospinal irradiation (23.4 Gy) followed by 55.8 Gy to the primary tumor bed using three-dimensional conformal technique, and four cycles of high-dose cyclophosphamide (4,000 mg/m(2)/cycle), cisplatin (75 mg/m(2)/cycle), and vincristine (two 1.5 mg/m(2) doses/cycle) and stem-cell rescue. When used, amifostine (600 mg/m(2)/dose) was administered as a bolus immediately before and 3 hours into the cisplatin infusion.
The median age of the 97 patients was 8.7 years (range, 3.2 to 20.2 years). The study and control groups were similar in age and sex distribution. Amifostine was well-tolerated. One year after treatment initiation, 13 patients (37.1%) in the control group versus nine (14.5%; one-sided chi(2) test P = .005) of the amifostine-treated patients had at least grade 3 ototoxicity, requiring hearing aid in at least one ear.
Amifostine administered before and during the cisplatin infusion can significantly reduce the risk of severe ototoxicity in patients with AR medulloblastoma receiving dose-intense chemotherapy.
Journal of Clinical Oncology 08/2008; 26(22):3749-55. · 18.37 Impact Factor
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Kathleen J Helton,
James K Weeks,
Nicholas S Phillips,
Ping Zou,
Larry E Kun,
Raja B Khan,
Amar Gajjar, Maryam Fouladi,
Alberto Broniscer,
Frederick Boop,
Chin-Shang Li,
Robert J Ogg
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ABSTRACT: Diffusion tensor (DT) imaging has been used to predict postoperative motor function in patients with supratentorial tumors. The authors sought to determine whether DT imaging and white matter tractography could detect axonal degeneration in patients with brainstem tumors.
A cross-sectional, retrospective study of 7 patients with brainstem tumors and 8 healthy volunteers was performed. The DT imaging data were normalized and regions of interest (ROIs) with the highest probability of sensory and motor connections were selected using the Talairach Atlas to identify the 3D millimetric coordinates of white matter tracts. An iterative process involving fractional anisotropy (FA), apparent diffusion coefficients (ADCs), and color maps was developed to precisely select ROIs in the bilateral sensory and motor tracts. The FA and ADC values were calculated for each ROI.
The FA values of sensory and motor tracts significantly differed between the patient and healthy volunteer groups (p < 0.05), whereas no significant changes were found in the splenium or genu of the corpus callosum. The FA values were altered proximal and distal to the brainstem tumors with a bimodal peak of antegrade decreased FA involving second- and third-order sensory axons and retrograde decreased FA of motor axons.
This study demonstrates changes in diffusion properties of sensory and motor tracts consistent with degeneration to further characterize brainstem tumors in children, and the results warrant the planning of prospective trials. The rigorous methods the authors describe may provide valuable information when planning biopsies or debulking of unusual brainstem tumors, as well as improve prognostication of the possible functional tract recovery following therapy.
Journal of Neurosurgery Pediatrics 05/2008; 1(4):270-6. · 1.53 Impact Factor
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Daphne A Haas-Kogan,
Anuradha Banerjee,
Mehmet Kocak,
Michael D Prados,
J Russell Geyer, Maryam Fouladi,
Tracy McKnight,
Tina Young Poussaint,
Alberto Broniscer,
Susan M Blaney,
James M Boyett,
Larry E Kun
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ABSTRACT: The purpose of this study is to estimate the maximum-tolerated dose (MTD) and describe toxicities and preliminary clinical effects of tipifarnib, a farnesyltransferase (FTase) inhibitor, administered concurrently with radiation therapy in children with newly diagnosed intrinsic diffuse brainstem glioma (BSG). Children >or=3 and <or=21 years of age with newly diagnosed nondisseminated intrinsic diffuse BSG were treated with concurrent tipifarnib and radiation, followed by adjuvant tipifarnib. Escalating doses of tipifarnib were administered orally twice daily, continuously, for the entire duration of radiation, followed by a 2-week break. Postradiation tipifarnib, 200 mg/m(2)/dose, was administered twice daily for 21 consecutive days, in 28-day cycles. Seventeen patients, median age 5.9 years (range, 3.6-13.8), received external beam radiation therapy administered concurrently with tipifarnib at dose levels ranging from 100 to 150 mg/m(2)/dose, followed by adjuvant tipifarnib for up to 24 months in the absence of tumor progression or unacceptable toxicity. Dose-limiting toxicities were grade 3 skin rash in one patient at the 125 mg/m(2) dose level and two patients at the 150 mg/m(2) dose level, and grade 3 pneumonia with a normal absolute neutrophil count (ANC) in one patient at the 150 mg/m(2) dose level. One patient had isolated grade 4 neutropenia at the 150 mg/m(2) dose level. The MTD of tipifarnib administered was estimated as 125 mg/m(2)/dose b.i.d. When administered concurrently with radiation, the dose-limiting toxicities of tipifarnib are rash, infection with normal ANC, and neutropenia. The MTD of tipifarnib with concurrent radiation is 125 mg/m(2)/dose b.i.d. One-year survival and progression-free survival estimates are 36.4% (SE 16.7%) and 9.4% (SE 6.3%), respectively.
Neuro-Oncology 04/2008; 10(3):341-7. · 5.72 Impact Factor
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ABSTRACT: High-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) has been reported to be effective in treating children with recurrent central nervous system (CNS) malignancies.
To evaluate the efficacy and toxicities of HDCT and ASCR, the medical records of 27 children with recurrent CNS malignancies who received such therapy at St. Jude Children's Research Hospital between 1989 and 2004 were reviewed.
The median age at diagnosis was 4.5 years (range, 0.4-16.6 years) and that at ASCR was 6.7 years (range, 1.1-18.5 years). Diagnoses included medulloblastoma (13 patients), primitive neuroectodermal tumor (3 patients), pineoblastoma (2 patients), atypical teratoid rhabdoid tumor (2 patients), ependymoma (3 patients), anaplastic astrocytoma (2 patients), and glioblastoma multiforme (2 patients). The 5-year overall and progression-free survival (PFS) rates were 28.2% and 18.5%, respectively. The 5-year PFS rate for patients aged<3 years at diagnosis (57.1%) was significantly better than older patients (5.0%) (P=.019). Among the 6 long-term survivors (5 with M0 disease and 1 with M3 disease at diagnosis), 5 received both radiotherapy and HDCT as part of their salvage regimen; 4 were aged<3 years at diagnosis and had received chemotherapy only as part of frontline therapy. Two patients died of transplant-related toxicities; 44% experienced grade 3 or 4 transplant-related toxicities (toxicities were graded according to the National Cancer Institute Common Toxicity Criteria).
HDCT with ASCR is not an effective salvage strategy for older children with recurrent CNS malignancies. The significantly better outcome in the younger cohort was most likely related to the use of radiotherapy as part of the salvage strategy.
Cancer 04/2008; 112(6):1345-53. · 4.77 Impact Factor
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Stephen J Laughton,
Thomas E Merchant,
Charles A Sklar,
Larry E Kun, Maryam Fouladi,
Alberto Broniscer,
E Brannon Morris,
Robert P Sanders,
Matthew J Krasin,
John Shelso,
Zang Xiong,
Dana Wallace,
Amar Gajjar
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ABSTRACT: To estimate the cumulative incidence of specific hormone deficiencies and the influence of hypothalamic-pituitary (HP) axis radiation dose in a cohort of children with embryonal brain tumors treated with risk-adapted craniospinal irradiation (CSI), conformal primary site irradiation, and high-dose chemotherapy.
Clinical data and HP axis radiation dosimetry data were obtained from 88 eligible children. All patients received regular endocrine follow-up that included screening tests of thyroid function and stimulation testing for growth hormone deficiency (GHD), and adrenocorticotropin hormone deficiency.
The cumulative incidence of GHD, thyroid-stimulating hormone (TSH) deficiency, adrenocorticotropic hormone deficiency, and primary hypothyroidism at 4 years from diagnosis was 93% +/- 4%, 23% +/- 8%, 38% +/- 6%, and 65% +/- 7%, respectively. Radiation dosimetry to the HP axis was associated only with the development of TSH deficiency; the 4-year cumulative incidence was 44% +/- 19% and 11% +/- 8% (P = .014) for those receiving more or less than the median dose to the hypothalamus (>or= 42 v < 42 Gy), respectively. The median dose of CSI for the average-risk (AR) patients was 23.4 and 39.6 Gy (36 to 40.5 Gy) for the high-risk patients. The estimated mean decline in height Z-score after radiation therapy was greater in high-risk patients (-0.65 units/yr) when compared with AR patients (-0.54 units/yr; P = .039).
Pediatric patients with CNS embryonal tumors are at high risk for treatment-related hormone deficiencies. GHD and primary hypothyroidism were diagnosed in a majority of subjects relatively soon after the completion of therapy. Radiation dose to the hypothalamus in excess of 42 Gy was associated with an increase in the risk of developing TSH deficiency.
Journal of Clinical Oncology 03/2008; 26(7):1112-8. · 18.37 Impact Factor
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ABSTRACT: 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 >or=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 12/2007; 110(11):2535-41. · 4.77 Impact Factor
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Maryam Fouladi,
Fred Laningham,
Jianrong Wu,
Melinda A O'Shaughnessy,
Kristen Molina,
Alberto Broniscer,
Sheri L Spunt,
Inga Luckett,
Clinton F Stewart,
Peter J Houghton,
Richard J Gilbertson,
Wayne L Furman
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ABSTRACT: To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic and pharmacodynamic properties of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in children with refractory or recurrent solid tumors.
Everolimus was administered orally at a daily dose of 2.1, 3, 5, or 6.5 mg/m2 in cohorts of three to six patients per dosage level. Pharmacokinetic and pharmacodynamic studies were performed during the first course. The phosphorylation status of various components of the mTOR signal pathway was assessed in peripheral-blood mononuclear cells (PBMCs) isolated from treated patients.
There were 26 patients enrolled; 18 were assessable. DLTs included diarrhea (n = 1), mucositis (n = 1), and elevation of ALT (n = 1) at 6.5 mg/m2. At the MTD of 5 mg/m2, the median everolimus clearance was 15.2 L/h/m2, with a plasma everolimus concentration-time area under the curve (AUC) from 0 to infinity of 239.6 ng/mL x h. Significant inhibition of mTOR pathway signaling was observed in PBMCs from patients achieving AUCs 200 ng/mL x h, equivalent to dosages of 3 to 5 mg/m2 of everolimus. No objective tumor responses were observed.
Continuous, orally administered everolimus is well tolerated in children with recurrent or refractory solid tumors and demonstrates similar pharmacokinetic properties to those observed in adults. Everolimus significantly inhibits the mTOR signaling pathway in children at the MTD. The recommended phase II dose in children with solid tumors is 5 mg/m2.
Journal of Clinical Oncology 11/2007; 25(30):4806-12. · 18.37 Impact Factor
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E Brannon Morris,
Amar Gajjar,
James O Okuma,
Yutaka Yasui,
Dana Wallace,
Larry E Kun,
Thomas E Merchant, Maryam Fouladi,
Alberto Broniscer,
Leslie L Robison,
Melissa M Hudson
[show abstract]
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ABSTRACT: To describe the pattern of survival and late mortality among contemporary long-term survivors of pediatric CNS tumor.
The study population comprised 643 pediatric patients with primary CNS tumor treated at St Jude Children's Research Hospital (Memphis, TN) from 1985 to 2000 who survived > or = 5 years from diagnosis. Patients were classified according to primary tumor type, location of tumor, and survival. Cause of death was obtained from the medical record and categorized as progression, malignant transformation, second malignancy, medical complication, or external cause.
Overall survival estimates for patients who survived at least 5 years postdiagnosis was 91.3% +/- 2% and 86% +/- 3% at 10 and 15 years postdiagnosis, respectively. A significant difference in the survival rates according to original tumor type (P = .001) was seen. Sixty-six (10%) of 643 patients experienced late mortality: 38 patients (58%) died of progressive disease while 14 patients (21%) died of second malignant tumor. Twelve patients (18%), predominantly with diencephalic tumor location, died of a specific medical cause: cardiovascular disease (n = 2), cerebrovascular accident (n = 1), metabolic collapse and/or sepsis (n = 7), respiratory failure (n = 1), or shunt malfunction (n = 1).
Late mortality occurs in a substantial number of long-term survivors of pediatric CNS tumors and is most influenced by the initial tumor histopathology. Progressive disease remains the most common cause of death within the first decade of diagnosis. Teenage patients requiring treatment for panhypopituitarism may be especially vulnerable and deserve significant medical surveillance.
Journal of Clinical Oncology 05/2007; 25(12):1532-8. · 18.37 Impact Factor
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Maryam Fouladi,
Susan M Blaney,
Tina Young Poussaint,
Burgess B Freeman,
Roger McLendon,
Christine Fuller,
Adekunle M Adesina,
Michael L Hancock,
Mary K Danks,
Clinton Stewart,
James M Boyett,
Amar Gajjar
[show abstract]
[hide abstract]
ABSTRACT: An open-label Phase II study of oxaliplatin was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB), supratentorial primitive neuroectodermal tumors (SPNET), and atypical teratoid rhabdoid tumor (ATRT).
Patients were stratified as follows: stratum IA, first recurrence MB with measurable disease; IB, recurrent MB with only cerebral spinal fluid (CSF) positivity or linear leptomeningeal disease (LLD); IC, MB > or =second recurrence; stratum II, recurrent SPNET; stratum III, recurrent ATRT. Patients received oxaliplatin, 130 mg/m(2) intravenously over 2 hours every 3 weeks. The primary objective was to estimate the sustained response rate in stratum 1A. Plasma ultrafiltrate platinum pharmacokinetics were evaluated.
A total of 43 patients with a median age of 8.5 years (range, 0.6-18.9 years) were enrolled. In stratum 1A, 2 of 15 had partial responses (PRs, 1 sustained PR). No responses were observed in other strata. The most frequent Grade 3 and 4 toxicities included thrombocytopenia (25.6%), neutropenia (16.3%), leukopenia (12%), increase in serum alanine transaminase (ALT) (7%), vomiting (4.7%), and sensory neuropathy (4.7%). No severe ototoxicity or nephrotoxicity was reported. Plasma ultrafiltrate platinum pharmacokinetic parameters were similar to adults, with a median clearance of 12.2 L/hr (range, 4.4-30 L/hr) and median area under the curve (AUC(0-infinity)) of 9.4 microg/mL/hr (range, 6.2-13.9 microg/mL/hr).
Oxaliplatin was well tolerated in children but has limited activity in children with recurrent CNS embryonal tumors previously treated with platinum compounds.
Cancer 11/2006; 107(9):2291-7. · 4.77 Impact Factor
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Maryam Fouladi MD,
Susan M. Blaney MD,
Tina Young Poussaint MD,
Burgess B. Freeman III PharmD,
Roger McLendon MD,
Christine Fuller MD,
Adekunle M. Adesina MD,
Michael L. Hancock MS,
Mary K. Danks PhD,
Clinton Stewart PharmD, [......],
Tina Young Poussaint,
Burgess B. Freeman III,
Roger McLendon,
Christine Fuller,
Adekunle M. Adesina,
Michael L. Hancock,
Mary K. Danks,
Clinton Stewart,
James M. Boyett,
Amar Gajjar
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND.An open-label Phase II study of oxaliplatin was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB), supratentorial primitive neuroectodermal tumors (SPNET), and atypical teratoid rhabdoid tumor (ATRT).METHODS.Patients were stratified as follows: stratum IA, first recurrence MB with measurable disease; IB, recurrent MB with only cerebral spinal fluid (CSF) positivity or linear leptomeningeal disease (LLD); IC, MB ≥second recurrence; stratum II, recurrent SPNET; stratum III, recurrent ATRT. Patients received oxaliplatin, 130 mg/m2 intravenously over 2 hours every 3 weeks. The primary objective was to estimate the sustained response rate in stratum 1A. Plasma ultrafiltrate platinum pharmacokinetics were evaluated.RESULTS.A total of 43 patients with a median age of 8.5 years (range, 0.6–18.9 years) were enrolled. In stratum 1A, 2 of 15 had partial responses (PRs, 1 sustained PR). No responses were observed in other strata. The most frequent Grade 3 and 4 toxicities included thrombocytopenia (25.6%), neutropenia (16.3%), leukopenia (12%), increase in serum alanine transaminase (ALT) (7%), vomiting (4.7%), and sensory neuropathy (4.7%). No severe ototoxicity or nephrotoxicity was reported. Plasma ultrafiltrate platinum pharmacokinetic parameters were similar to adults, with a median clearance of 12.2 L/hr (range, 4.4–30 L/hr) and median area under the curve (AUC0-∞) of 9.4 μg/mL/hr (range, 6.2–13.9 μg/mL/hr).CONCLUSIONS.Oxaliplatin was well tolerated in children but has limited activity in children with recurrent CNS embryonal tumors previously treated with platinum compounds. Cancer 2006. © 2006 American Cancer Society.
Cancer 10/2006; 107(9):2291 - 2297. · 4.77 Impact Factor
