Pediatric CNS tumors represent a heterogeneous group of diseases with a wide range of outcomes. We must therefore balance aggressive treatment of tumors with anticipated toxicities of therapy. Whereas aggressive approaches are generally taken for those with malignant tumors, the goal of treatment for patients with indolent low-grade tumors is prevention of progression and alleviation of symptoms while minimizing effects of therapy. All survivors must deal with the effects of the tumor and its treatment-related consequences, and their effects on physical and social functioning are tremendous. The need for less toxic, more effective therapies for all children with CNS tumors is clearly evident. The pediatric neuro-oncology section participates in clinical trials developed within our section, within the Pediatric Oncology Branch, within other NIH institutions and within national consortia with the following specific research aims: a) Develop new anticancer agents for the treatment of childhood CNS tumors through the use of preclinical testing and pharmacokinetic modeling, performance of early clinical trials, and collaboration with national pediatric consortia b) Investigate highly innovative therapeutic approaches including alternate delivery methods. Recent accomplishments include: 1. Determination that activity of temozolomide was not improved when administered with the MGMT modulating agent, O6BG, in children with recurrent or progressive gliomas. Forty-three patients were enrolled on this Ph II study performed within the Pediatric Brain Tumor Consortium (PBTC), with 41 assessable for response. One sustained partial response was observed in the high grade glioma cohort, and no sustained objective responses were observed in the brainstem glioma cohort. We concluded that the combination of O6BG and TMZ did not improve efficacy of TMZ over TMZ alone in pediatric patients with recurrent or progressive HGG and BSG. An important aspect of this study was central pathology review. Five patients initially diagnosed as HGG who had an objective response or long-term stable disease were included and upon central review, the diagnoses for these cases included ganglioglioma (n=1), anaplastic astrocytoma (n=1), and one case classified differently by each neuropathologist as pilocytic astrocytoma, ganglioglioma, or astrocytic glioma. The fact that at least 2 of the 5 patients with objective response or long term stable disease did not have HGG demonstrates the importance of central review. 2. Established that low dose, continuous exposure to interferon alpha was safe and can possibly delay time to progression in children with Diffuse intrinsic pontine glioma (DIPG). We developed a single institution Phase II study of low-dose PEG-Intron in children with DIPG, administered after completion of radiation therapy, prior to disease progression. The primary objective was to determine 2-year survival compared to historical controls of children with DIPG who received radiation therapy alone. Children enrolled on this study received weekly subcutaneous injections of PEG-Intron beginning 2-10 weeks after completion of radiation therapy and continued until disease progression. Patients remained on study until death. Extensive neuroimaging was performed on these patients, and serum and urine were assayed for bFGF and VEGF as potential surrogate markers prior to each cycle. Thirty-two patients were enrolled and received a median of 7 cycles of therapy (range 1-52+). The two-year survival rate was 0.1429, median survival was 351 days, and 6 month PFS was 78.1% (95% CI: 63.8%-92.4%). This is in comparison to a similar group of patients treated on five PBTC investigational trials in which the 6 month PFS was 54.7%. PEG-Intron therapy was well tolerated. We concluded that although low dose PEG-Intron therapy did not significantly improve 2-year survival in children with DIPG, it was well tolerated and could potentially delay time to progression. This study was significant for several reasons. Patients were allowed to enroll on this study prior to disease progression given the dismal outcome of the population as a whole, which is unusual in pediatric neuro-oncology. There is a suggestion of activity of this agent in a population where no chemotherapeutic agent has ever been shown to improve outcome. 3. Determined that high doses of lenalidomide are tolerated in children and demonstrated preliminary evidence of activity in low grade gliomas. Although classified as an immunomodulatory agent, lenalidomide also has antiangiogenic and cytotoxic properties. It is FDA-approved for adults at a dose of 10-25 mg. The maximum tolerated dose in adults is 50 mg/m2/d on a 21-day schedule based on loosely defined dose-limiting toxicity criteria. Myelosuppression is the dose-limiting toxicity. A Phase I study of lenalidomide performed in adults with recurrent malignant gliomas utilized a predetermined maximum dose of lenalidomide of 20 mg/m2 (limit 40 mg) per day for 21 days of a 28-day schedule. No objective responses were observed; 7 of 36 patients had rapid radiographic and clinical progression within the first 4 weeks of treatment and the 6-month PFS for the 27 evaluable patients was 14.8% (95% CI 6.0-36.6%).We performed a Phase I trial of lenalidomide in children with recurrent, refractory and progressive CNS tumors within the PBTC. Eligible patients were treated on the same 21/7 day schedule as adults. Initial dosing was 75% of the adult MTD for adults with CNS tumors (i.e. 20 mg/m2). Fifty-one pediatric patients were enrolled. Lenalidomide was dose escalated over 10 dose levels from 15 mg/m2 to 116 mg/m2/d; no MTD was defined. Toxicities were similar to those reported in adults, but an increased incidence of venous thrombosis was not noted. The major toxicity observed in our study during the dose-finding period was myelosuppression but was generally mild. Pharmacokinetic (PK) analysis was performed, demonstrating linear PK, similar to those in adults, although we were able to evaluate PK at much higher dose levels. Although efficacy was not a primary endpoint, potential drug activity was assessed as a secondary endpoint. Forty-seven patients were evaluable for response. Two partial responses were observed. Fifty-two percent (n=23) of patients, primarily those with low-grade gliomas, had long-term (6 or more courses) stable disease. Of note, the 12-month progression free survival for patients with low-grade glioma was 67%. This study was important for several reasons. First, it demonstrated that tolerability of this agent appears to differ between adult and pediatric patients, despite similar pharmacokinetic parameters at the lower dose levels. Second, given its apparent efficacy in low-grade gliomas, we were able to evaluate longer-term toxicity, which is unusual in the Phase I setting. A Phase II study in low-grade gliomas is open within the COG. This project halted due to the PI departure.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011447-08
Application #
10014682
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Yuan, Ying; Lin, Ruitao; Li, Daniel et al. (2018) Time-to-Event Bayesian Optimal Interval Design to Accelerate Phase I Trials. Clin Cancer Res 24:4921-4930
Shah, Nirali N; Cole, Diane E; Lester-McCully, Cynthia M et al. (2016) Plasma and cerebrospinal fluid pharmacokinetics of vincristine and vincristine sulfate liposomes injection (VSLI, marqibo®) after intravenous administration in Non-human primates. Invest New Drugs 34:61-5
Akshintala, Srivandana; Marcus, Leigh; Warren, Katherine E et al. (2015) Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors. Pediatr Blood Cancer 62:603-10
Su, Jack M; Thompson, Patrick; Adesina, Adekunle et al. (2014) A phase I trial of veliparib (ABT-888) and temozolomide in children with recurrent CNS tumors: a pediatric brain tumor consortium report. Neuro Oncol 16:1661-8
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Fangusaro, Jason; Gururangan, Sridharan; Poussaint, Tina Young et al. (2013) Bevacizumab (BVZ)-associated toxicities in children with recurrent central nervous system tumors treated with BVZ and irinotecan (CPT-11): a Pediatric Brain Tumor Consortium Study (PBTC-022). Cancer 119:4180-7
Warren, Katherine E (2013) Novel therapeutic delivery approaches in development for pediatric gliomas. CNS Oncol 2:427-35
Fangusaro, Jason; Warren, Katherine E (2013) Unclear standard of care for pediatric high grade glioma patients. J Neurooncol 113:341-2

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