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. 2014 Jun;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066

CLINICAL TRIALS

PMCID: PMC4046282
Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.1

CT-002. INTRAVENTRICULAR THERAPY WITH ETOPOSIDE IN RECURRENT MEDULLOBLASTOMAS, PINEOBLASTOMAS, CNS-PNETS AND EPENDYMOMAS - FINAL RESULTS OF A PHASE II STUDY

Stephan Tippelt 1, Ruth Mikasch 1, Monika Warmuth-Metz 5, Torsten Pietsch 6, Ralf Axel Hilger 3, Robert Kwiecien 7, Andreas Faldum 7, Stefan Rutkowski 4, Udo Bode 2, Nele Siegler 1, Gudrun Fleischhack 1

Abstract

BACKGROUND: In recurrent neuroectodermal brain tumors leptomeningeal disease manifestation was observed in about 50 to 75% of patients. The role and efficacy of intrathecal therapy in these patients is unclear. As the systemic administration of etoposide is efficacious in brain tumors a phase II study was initiated to evaluate the efficacy and safety of intraventricularly administered etoposide in recurrent CNS tumors with subarachnoid disease manifestation. METHODS: Between 2006 and 2013 forty-nine patients (35 medulloblastomas, 3 supratentorial CNS-PNETs, 4 pineoblastomas, 7 ependymomas) median age 9.1 years (range 1.9 to 30.7) were enrolled. Thirty-five patients suffered from their first relapse, 2 patients each from their second and third relapse, and 10 patients had progressive disease following primary treatment. The treatment consisted of three 5-day cycles of etoposide for 5 weeks without other concurrent treatment. The tumor response and safety were documented clinically, by CSF cytology and MRI between days 40 to 45 after start of therapy. CSF sampling for pharmacokinetics of etoposide was optional. Samples of 13 patients could be analyzed. RESULTS: At final analysis 42/49 patients were evaluable for primary objective, efficacy (1xPR, 13xSD and 28xPD): response rate (CR + PR + SD) exceeds 19.6% significantly (cutoff was 15%), i.e. therapy is relevant effective. The CSF was cleared in 5 out of 15 patients. Fourteen patients discontinued treatment early: before (n = 1) or during the first or second cycle of treatment due to rapid progressive disease (n = 10) or to toxicity reasons (n = 3). The adverse events were mostly mild (113xCTC°I/II, 20xCTC°III/IV) in form of headache, nausea, fatigue, fever, infection or seizure and other neurotoxicity. CSF pharmacokinetic analysis confirmed data (clearance, AUC and peak level) published before. CONCLUSIONS: Our data suggest that the repeated intraventricular etoposide application is well tolerated. It has moderate cytotoxic efficacy in recurrent brain tumors, especially in medulloblastomas. Supported by German Children Cancer Foundation.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.2

CT-003. TANDEM HIGH-DOSE CHEMOTHERAPY WITH STEM CELL RESCUE FOLLOWED BY RISK-ADAPTED RADIATION IN CHILDREN WITH HIGH-RISK CEREBRAL PRIMITIVE NEUROECTODERMAL TUMOR: RESULTS OF THE PROSPECTIVE SFCE-TRIAL PNET HR + 5

Christelle Dufour 1, Marie-Bernadette Delisle 2, Anne Geoffray 3, Agnes Laplanche 1, Didier Frappaz 4, Celine Icher 15, Anne-Isabelle Bertozzi 2, Pierre Leblond 5, François Doz 6, Nicolas Andre 7, Pascale Schneider 8, Emilie De Carli 9, Claire Berger 10, Odile Lejars 11, Pascal Chastagner 12, Christine Soler 3, Natacha Entz-Werle 14, Dominique Valteau-Couanet 1

Abstract

BACKGROUND: To assess the 3-year progression-free survival (PFS) rate of patients with newly diagnosed high-risk medulloblastoma (MB) or supratentorial primitive neuroectodermal tumor (sPNET) between 5-20 years treated according to the prospective multicenter trial PNET HR + 5. METHODS: Children received as postoperative induction chemotherapy two cycles of etoposide (500mg /m2) - carboplatine (800mg/m2), followed by two courses of thiotepa (600mg/m2 per course) with autologous stem cell rescue. Risk-adapted conventional radiotherapy (RT) was delivered around day 45 after second transplantation. Craniospinal RT dose was 36 Gy for patients with metastatic disease or with unfavourable histology (anaplastic MB, large cell MB, MB with myc amplification) followed by a tumor bed boost of 18 Gy. Patients with localized sPNET received focal RT at the dose of 54 Gy. Maintenance treatment with 6 cycles of temozolomide was planned to start between 1-3 months after the end of RT. RESULTS: From January 2009 to February 2012, 64 patients (MB = 51; sPNET = 13) between 5 and 19 years (median age, 9 years) were enrolled. Five patients didn't received RT due to progressive disease. Maintenance treatment was administered in 44 patients. The median follow-up was 32 months (range, 16-54 months). The 3-year PFS and overall survival (OS) were 80% (95% CI: 68-88%) and 85% (95% CI: 74-92%), respectively. The 3-year PFS was 79% (95% CI: 65-88%) for children with MB and 85% (95% CI: 58-96%) for those with sPNET. No major unexpected toxicities and no treatment-related deaths were reported. CONCLUSIONS: This treatment based on high-dose chemotherapy and conventional RT resulted in a high overall survival rate in children and adolescent with newly diagnosed high-risk cerebral PNET.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.3

CT-004. A PHASE II STUDY OF ANTINEOPLASTONS A10 AND AS2-1 IN CHILDREN WITH RECURRENT, REFRACTORY OR PROGRESSIVE PRIMARY BRAIN TUMORS BASED ON PROTOCOL BT-22

Stanislaw Burzynski 1, Tomasz Janicki 1, Gregory Burzynski 1, Ania Marszalek 1

Abstract

Primary malignant brain tumors are the leading cause of cancer-related deaths in children. This single arm, two-stage phase II study, evaluated the efficacy and safety of Antineoplastons A10 and AS2-1 (ANP) in children who developed progression of primary brain tumors during standard treatment. A total of 43 children were recruited under Protocol BT-22, but only 29 met eligibility criteria. There were eight cases of glioblastoma multiforme, six cases of anaplastic astrocytoma (AA), ten cases of diffuse intrinsic pontine gliomas (DIPG), four cases of primitive neuroectodermal tumors, and one case each of atypical teratoid rhabdoid tumor, and disseminated pilocytic astrocytoma. ANPs were administered intravenously daily every four hours (median dose of A10 10.4 g/kd/d and AS2-1 0.36 g/kg/d), until objective response was documented, and then a further eight months. All enrolled patients (n = 43) were included in safety, but only eligible patients in the efficacy evaluation. A total of 17% of patients obtained objective response (OR) to ANP; complete response 3% and partial response 14%. Stable disease was determined in 28% of cases, progressive disease in 38% of cases, with 17% of nonevaluable cases due to premature discontinuation. Four OR patients were diagnosed with recurrent DIPG and one with recurrent AA. The longest survivor is a patient diagnosed with DIPG and disseminated gliosarcoma who remains alive more than 13 years from treatment start. A small group of patients reported grade 3 and 4 toxicity; hypernatremia grade 4 in 14% and grade 3 in 5%, somnolence grade 4 an d3 in 2% each and hypokalemia in 2% of patients. There were no chronic toxicities, and the quality of survival is very good. It is concluded that antineoplastons showed efficacy within an acceptable profile in this group of patients with recurrent, refractory or progressive primary brain tumors.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.4

CT-005. PERSONALIZED PEDIATRIC ONCOLOGY: TARGETED THERAPY AND CLINICAL FEASIBILITY

Alica Deiss 1, Andrey Korshunov 2, David Capper 2, Hendrik Witt 3, Cornelis van Tilburg 4, Andreas von Deimling 2, Andreas E Kulozik 4, Stefan M Pfister 3, Olaf Witt 1, Till Milde 1

Abstract

The Heidelberg “Pediatric Targeted Therapy” (PTT) program identifies presence and activity of druggable structures in relapsed tumors on an individual basis for targeted therapies. The PTT program aims at the evaluation of and of the clinical benefit of a personalized treatment approach. To this aim, we analyzed 13 molecular targets for specific inhibition in experimental treatment settings (HDAC2,5,8 and 9, p-AKT, p-ERK, p-S6, p-EGFR, PDGFR-alpha/beta, p53, Integrin avb5 and BRAFV600E), as well as 12 markers for therapeutic or risk stratification (HR23B, beta-catenin, SFR1, NPR3, KCNA1, LAMA2, NELL2, nestin, tenascin C, FOXG1, OLIG2, LIN28). Pediatric tumors independent of the histological diagnosis from 35 pediatric oncology centers were included. All Patients had been treated with at least one standard protocol treatment and had experienced relapse or progression. Only formalin fixed paraffin embedded (FFPE)-material was used. Based on the resulting immunohistochemical (IHC) information a suggestion for treatment in an experimental setting was deduced. Between 2009 and 2013 n= 130 cases were analyzed. Average turnover time from submission to final report was 5,0 weeks. The most common entities were brain tumors: ependymoma (22%), medulloblastoma (18%), glioblastoma (8%), Astrocytoma WHO II (8%), anaplastic astrocytoma (6%). The most commonly expressed or activated pathways were HDACs (93,7%, of cases positive, suggestive of being non-informative markers), pEGFR (83 %) and PDGFR (81%), MAPK/ERK (47%). A suggestion for individualized treatment was possible in 98 % of the cases. 88% of tumors analyzed displayed more than one targetable alteration, implying the need for a combination strategy employing several targeted therapies. Follow-up revealed implementation of partial or full recommended treatments in 41% of the cases. Promising responses in individual cases were observed. The transition from IHC to next-generation diagnostics such as whole genome sequencing and methylation arrays is ongoing and will further improve diagnostic and predictive accuracy.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.5

CT-006. PHASE 1 TRIAL OF DASATINIB, LENALIDOMIDE, AND TEMOZOLOMIDE IN CHILDREN WITH RELAPSED OR REFRACTORY CENTRAL NERVOUS SYSTEM TUMORS

Girish Dhall 1, Kelley Haley 1, Jonathan Finlay 1, Teresa Rushing 1, Richard Sposto 1, Robert Seeger 1

Abstract

BACKGROUND: Dasatinib is a tyrosine kinase inhibitor that inhibits SRC kinases, EGFR, PDGFR-β, c-KIT, and BCR-ABL, and has antiangiogenic and immunomodulatory functions. Lenalidomide is an immunomodulatory agent that inhibits angiogenesis and various pro-inflammatory cytokines and chemokines. Temozolomide is a chemotherapeutic agent with activity against a variety of pediatric central nervous system (CNS) tumors and when administered in metronomic doses, exerts an anti-angiogenic effect. METHODS: We performed a phase I trial of this combination using a modified 3 + 3 phase I dose escalation design with a continuous 21-day schedule q 28 days to determine the maximum tolerated dose (MTD) and toxicity in children with recurrent/refractory CNS tumors. The starting dose level (DL 1) of dasatinib was 65 mg/m2 BID, lenalidomide 70 mg/m2 daily, and temozolomide 75 mg/m2 daily, from which dasatinib or lenalidomide would be escalated or de-escalated in alternate patients. Blood was collected during cycle 1 (days 1, 8, 22 and 29) for NK/T cell subsets (flow cytometry), plasma cytokines and chemokines (cytometric bead arrays), and gene expression related to immune system and angiogenesis. RESULTS: 13 of 15 enrolled patients (2 high grade glioma, 2 ependymoma, 3 medulloblastoma, 1 AT/RT, 4 DIPG, 1 pilocytic astrocytoma, 1 glioneuronal tumor, 1 sPNET) were evaluable for toxicity and response. Dose limiting toxicity (DLT) occurred in 2 patients at DL 1 (somnolence and neutropenia), 2 at DL 0A (dasatinib 55mg/m2) (hypokalemia and thrombocytopenia), and 1 of 6 patients at DL 0B (lenalidomide 40mg/m2) (thrombocytopenia). 5/15 patients died of progressive disease, 10 are alive with disease and 1 patient had a partial response. CONCLUSION: DL 0B (dasatinib 65 mg/m2 BID, lenalidomide 40 mg/m2 daily, and temozolomide 75 mg/m2 daily) is the MTD and recommended phase 2 dose of this combination. Results of biology studies will also be presented.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.6

CT-007. PHASE 1 TRIAL OF p28 (NSC745104), A NON-HDM2 MEDIATED PEPTIDE INHIBITOR OF p53 UBIQUITINATION IN CHILDREN WITH RECURRENT OR PROGRESSIVE CNS TUMORS: A PEDIATRIC BRAIN TUMOR CONSORTIUM REPORT

Rishi R Lulla 1, Stewart Goldman 1, Craig Beattie 2, TK DasGupta 2, Ian Pollack 3, Paul Graham Fisher 4, Shengie Wu 5, James M Boyett 5, Maryam Fouladi 6

Abstract

BACKGROUND: Wild type and mutated TP53 are common in pediatric CNS tumors. p28 is a cell penetrating peptide that preferentially enters cancer cells and binds to wild type and mutant p53 protein inhibiting COP1 mediated ubiquitination and proteasomal degradation. This results in an increase in levels of p53, which induces cell cycle arrest at G2/M. A Phase I trial in 15 TP53 positive, adult patients with stage IV tumors reported no AEs and 1CR and 3PR with 4 patients alive greater than 40 weeks. Regression analysis suggested there was no relationship between the level of TP53 expression and patient response or survival suggesting p28 has activity in patients whose tumors express both wild type and mutated TP53. METHODS: Intravenous p28 is administered 3 times weekly for 4 consecutive weeks of a 6-week cycle at 4.16 mg/kg/dose (the adult MTD) using a rolling 6 study design. TP53 expression status is characterized by immunohistochemistry and serum pharmacokinetics are established on the second dose. RESULTS: To date, 11 patients (7 males, median age 8.5 years (range 3-19)) with malignant glioma (n = 5), DIPG (n = 2), AT/RT (n = 1), medulloblastoma (n = 1), pineoblastoma (n = 1) and other CNS malignancy (n = 1) have been enrolled at 4.16 mg/kg/dose. Nine patients are evaluable for toxicity and 6 have completed the DLT period, one of whom experienced a DLT (grade 4 neutropenia). Pharmacokinetic analysis of 8 patients revealed an overall t½ and t½α similar to adults. In contrast, a higher Cmax and longer t½αβ may contribute to the increased AUC observed in evaluable patients. TP53 expression status, toxicity assessment and pharmacokinetic data on the entire cohort will be presented. CONCLUSIONS: Preliminary data in this phase I study suggest that p28 is well tolerated in children with recurrent CNS malignancies at the adult MTD.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.7

CT-008. ETOPOSIDE PHARMACOKINETICS FOLLOWING INTRA-CEREBROSPINAL FLUID ADMINISTRATION IN PATIENTS WITH LEPTOMENINGEAL METASTASES

Lisethe Meijer 1, Gareth Veal 2, David Walker 1, Richard Grundy 1

Abstract

INTRODUCTION: Intra-cerebrospinal fluid (CSF) etoposide administration into the lateral ventricle and/or spinal canal circumvents the blood-brain-barrier, providing a potentially cytotoxic dose to leptomeningeal metastases with little or no systemic toxicity. The pharmacokinetics following etoposide administration via these two routes is poorly understood. CSF pharmacokinetics were analysed to determine the optimal route, investigating CSF flow dynamics and evaluating safety of intra-CSF administration. METHODS: Etoposide (0.75mg) was administered over 1-2 minutes through an Ommaya (IVT; tip in the right ventricle) and/or lumbar port (IT; tip in lumbar canal), on 5 consecutive days for 1-3 weeks with a subsequent rest week. 42 pharmacokinetic samples in total were obtained from a paediatric (36) and adult patient (6), at 4h (IVT: 3, IT: 3), 8h (IVT: 3, IT: 2), 18h (IVT: 1, IT: 1), 24h (IVT: 11, IT: 9), and 72h (IVT: 5, IT: 4). Etoposide concentrations were determined by LC/MS analysis, with a limit of detection of 0.1 µg/ml. RESULTS: No acute neurotoxicity was observed. Single IVT administration with IT sampling yields higher concentrations compared to IT administration with IVT sampling at 4h and 8h (1.73 and 0.93 µg/ml, compared to 1.42 and 0.76 µg/ml, respectively). This pattern was also observed with simultaneous IT and IVT administration (median IT concentration 5.11 and 1.77 µg/ml at 4h and 8h; median IVT concentration 3.64 and 1.48 µg/ml at 4h and 8h). Concentrations at 24h were <0.2 (median 0.15 µg/ml, -14 samples-) and at 72h <0.1 µg/ml (8 samples), irrespective of routes and sample sites. CONCLUSION: Intra-CSF etoposide administration at this dose level is safe, with almost complete clearence at 24h, and good distribution throughout the CSF compartment, irrespective of delivery route. Higher lumbar compared to intraventricular concentrations are probably related to reduced lumbar CSF flow. The rapid CSF etoposide clearance warrants investigation with continuous infusion approaches.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.8

CT-009. DEFINING A TARGET INTRA-CEREBROSPINAL FLUID (CSF) STEADY STATE ETOPOSIDE CONCENTRATION FOR A PHASE I STUDY IN CHILDREN WITH LEPTOMENINGEAL METASTASES (LM) (INTREPID), A FIRST IN MAN STUDY

Lisethe Meijer 1, Gareth Veal 2, Richard Grundy 1, Wojchiech Konczalik 1, Delyan Ivanov 3, Martin Garnett 3, Terry Parker 1, Pamela Kearns 4, David Walker 1

Abstract

INTRODUCTION: Continuous CSF drug administration optimises cytotoxic dose and exposure to LM by circumventing the blood-brain-barrier and offsetting CSF drug outflow. The target dose is limited by neurotoxicity and determined by personal clearance rate (complicated by shunt presence). INTREPID phase I study has a 3 + 3 design with escalation in target [CSF etoposide] (level 1 and 2) and infusion durations (7 to 10 to 14 days) in 35-70 children (<18 yrs.) with LM, including shunted patients. Infusion will be intra-ventricular via an Ommaya extended to a thoracic port, or, in shunted patients, via a lumbar catheter extended to an abdominal wall port. Personalising target [CSF etoposide] over sustained periods offers enhanced efficacy, whilst limiting neural and systemic toxicities. AIM: To define target [CSF etoposide] based on preclinical and early clinical studies for continuous intra-CSF etoposide administration in children with LM. METHODS: The target [CSF etoposide] is determined using human pharmacokinetic data from intra-CSF bolus studies and 3D tumour and human neural stem cell co-culture studies. [CSF etoposide] is measured by LC/MS analysis, with dose adjustment for individual clearance rate (dose = CL x target [CSF etoposide] x 60) if +/- 10% outside target. RESULTS: An AUC of 20-30 µg x h/ml over 24 hours showed limited neurotoxicity in 23 patients (Fleischhack group Germany), correlating with [etoposide] of 0.8-1.2 µg/ml in our 3D cell co-culture with 22% neural stem cells and 8% tumour cells viability. The 22% neural stem cell viability was accepted as the culture system promotes cell division rates in excess of predominantly quiescent human brain in-vivo. CONCLUSION: Level 1 target [CSF etoposide] in INTREPID will be 0.8 µg/ml increasing to 1.2 µg/ml (level 2). In the absence of dose limiting toxicity on level 2, the infusion durations will be extended from 7 to 10 to 14 days.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.9

CT-010. HATCH, MATCH, DESPATCH AND DELIVER - A DRUG DELIVERY PROGRAMME TO OPTIMISE MEDICAL THERAPY FOR BRAIN TUMOURS; A PROPOSAL FOR A COLLABORATIVE NETWORK

Richard Grundy 1, Martin Garnett 1, Ruman Rahman 1, Stuart Smith 1, Lisethe Meijer 1, David Walker 1

Abstract

INTRODUCTION: Successful brain tumour drug therapy requires effective agents to be delivered across the blood-brain-barrier (BBB) at suitable concentrations and sufficient duration to optimise their effect, whilst minimising their systemic and neuro-toxicity. AIM: To develop a translational drug delivery system (DDS) development framework for rapid adoption of novel DDSs into clinical practice through phase 1 trials in CNS tumours. METHODS: The HATCH, MATCH, DESPATCH and DELIVER model identifies stages of DDS development where in the HATCHING process, promising new targets or pathways from brain tumour biology are identified and MATCHED to both existing agents and an optimised delivery route or system (e.g. intra-cerebrospinal fluid (CSF), interstitial or across the BBB). The DDS is then prepared for DESPATCH by testing in pre-clinical models, simulating the steps along the route of delivery to the tumour. Once optimised through DESPATCHING, the DDS is prepared for DELIVERY to the clinic through Phase 1 human testing in parallel with commercialisation. The DESPATCHING process requires a range of experimental models using 3-dimensional human cell culture systems and in vivo orthotopic animal models as more realistic pre-clinical platforms for drug-testing. Access to expertise in advanced DDSs using both physical systems to bypass the BBB e.g. interstitial and intra-CSF delivery and drug loading of nanoparticles and polymer complexes for regional delivery is required. The programme requires combined expertise in molecular biology, bio-informatics, medical oncology, neurosurgery, pharmacology, project management, health economy, business and regulatory affairs. Exploring multiple DDSs in parallel permits selection of the best systems to be taken forward. Continued tumour bio-profiling and bio-informatics analyses sustain the selection of novel biological target and agents for the MATCHING process. CONCLUSION: Having developed 2 DDSs for clinical trial we recognise building collaborative capacity for each step is required to meet the need for novel therapies in neuro-oncology.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.10

CT-011. INFANTS WITH MEDULLOBLASTOMA: USE OF HIGH DOSE CHEMOTHERAPY AND AUTOLOGOUS STEM CELL RESCUE

Miriam Kimpo 1, Benedict Yan 1, Chou Ning 1, Mariflor Villegas 1, Ana Patricia Alcasabas 2, Yeoh Eng Juh 1, Quah Thuan Chong 1, Tan Poh Lin 1

Abstract

BACKGROUND: Infants and young children with brain tumors represent a therapeutic challenge. Radiation, deemed essential, has detrimental effects to the developing brain. Treatment is aimed at delaying radiation until age of three years or upon tumor progression. Early intensification of chemotherapy and use of autologous stem cell rescue has improved long term outcome and successfully delayed or avoided radiation, as demonstrated by the “Head Start” protocols. Five year event-free (EFS) and Overall Survival (OS) are 37% and 61% respectively. We reviewed the data of patients treated following this regimen in our institution. METHODS: Infants referred to our Division following resection of their brain tumors were staged with MRI of the brain and spine, cytology of cerebrospinal fluid and bone marrow biopsies/bone scan. Treatment based on the Head Start II protocol consists of five cycles of induction chemotherapy with cisplatin, cyclophosphamide, vincristine and etoposide. They proceeded to consolidation chemotherapy with carboplatin, thiotepa and etoposide followed by autologous stem cell rescue. Radiotherapy was planned as salvage in case of relapse. RESULTS: Five infants 1 to 3 years with posterior fossa tumors and a pathologic diagnosis of medulloblastoma (3 desmoplastic, 1 classical subtype) were treated from 2004 -2011. None had metastases on staging work up. All had gross total resection based on MRI of the brain. All tolerated induction chemotherapy and consolidation with high dose chemotherapy followed by stem cell rescue . Mean length of stay for the 5 patients for the stem cell rescue was 26.6 days (range 24 to 32 days). Median follow up of 72 (range 36-106) months, all patients remain in complete remission. CONCLUSION: Intensive chemotherapy with autologous stem cell rescue in infants with medulloblastoma entering consolidation in complete remission is well tolerated and provided sustained remission without need for radiation. We are currently assessing the neurodevelopmental outcome.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.11

CT-012. A PILOT STUDY OF BEVACIZUMAB-BASED THERAPY IN CHILDREN AND YOUNG ADULTS WITH NEWLY-DIAGNOSED HIGH-GRADE GLIOMAS (HGG) AND DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)

Mariko Dewire 1, Maryam Fouladi 1, Rachid Drissi 1, Lionel Chow 1, Stewart Goldman 2, Ahna Pai 1, James Leach 1, Adam Lane 1, Lori Backus 1, Laurie Grimme 1, Jillian Tabares 2, Shiva Kumar 1, Matthew Sobo 1, Trent R Hummel 1

Abstract

INTRODUCTION: Although bevacizumab has been used in adults with newly-diagnosed HGG, feasibility in newly-diagnosed children with HGG and DIPG has not been reported. METHODS: In a safety and feasibility study, children and young adults with newly-diagnosed HGG received conformal radiotherapy with bevacizumab (10 mg/kg: days 22, 36) and temozolomide (75-90 mg/m2/day for 42 days) followed by bevacizumab (10 mg/kg, days 1, 15), irinotecan (125 mg/m2, days 1, 15) and temozolomide (150 mg/m2/day days 1-5). DIPG patients did not receive temozolomide. MR perfusion, telomerase activity, gene expression profiling, quality of life (QOL), and functional outcomes were also assessed. RESULTS: 27 eligible and evaluable patients (15 DIPG, 12 HGG), median age 10 years (range: 3-26 years), were enrolled. Six discontinued therapy for toxicity: 2 during radiotherapy (grade 4 thrombocytopenia, grade 3 ALT) and 4 during maintenance therapy (grade 3: thrombosis, hypertension, skin ulceration, and wound dehiscence). Commonest ≥ grade 3 toxicities included lymphopenia, neutropenia, and leucopenia. Grade 3 hypertension occurred in 2 patients. No intracranial hemorrhages occurred. Two patients had nasal septum perforations. Median PFS and OS for DIPG patients were 8.3 and 10 months respectively, Median PFS and OS for HGG patients were 17 and 36 months, respectively, with a 3-year PFS and OS of 36% (SE ± 16%) and 45% (SE ±19%), respectively. Among 8 DIPG patients with MR perfusion data, tumor volume, diffusivity and enhancing tumor volume decreased during RT, while diffusivity increased at progression. Enhancement changes did not correlate with progression. Telomerase activity was evaluated. All samples demonstrated Histone H3.3 mutations. Mean baseline patient and parent-report QOL scores were 78 and 64 (range: 0-100), respectively; improving over time. Three of 4 patients maintained or improved their mobility. CONCLUSIONS: A bevacizumab-based regimen is feasible and tolerable in newly-diagnosed children and young adults with HGG and DIPG.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.12

CT-013. TREATMENT OF MEDULLOBLASTOMA AND PNET CHILDREN ABOVE THREE YEARS OF AGE IN SAUDI ARABIA. A PROSPECTIVE MULTICENTER STUDY

Musa Alharbi 1, Shaker Abdullah 2, Qasim Alharbi 3, Mohammad Alshahrani 4, Othman Mosleh 1, Ali Balbaid 1, Amani Alkofide 5, Nawaf Alkhayat 4, Kamelia AlFar 1, Abdullah Banyhamdan 1, Omyma Ahmed 3, Samy El-Badawy 3, Eric Bouffet 6

Abstract

BACKGROUND: Treatment for children with medulloblastoma in Saudi has been heterogeneous and essentially institution-based. A cooperative protocol was launched in 2009 between 4 tertiary centers PATIENT AND METHODS: Patients above 3 years with medulloblastoma and PNET received postoperative craniospinal radiation according to their risk group with concurrent oral etoposide 35mg/M2/days. They then received six cycles of chemotherapy alternating cycle A(Cisplatin 90 mg/m2/day, day 1 and Etoposide 35 mg/m2/day P.O. days 1-21 of a 4-week cycle) and Cycle B (Cyclophosphamide 1.5 g/m2/day, days 1-2 with Vincristine 1.5 mg/m2, days 1,8,15 for each 4weeks cycle). Post-chemotherapy, maintenance with Isotretinoin 160mg/M2/day1-14 was given for 6 months. RESULTS: 62 patients (36 males) were enrolled from 09/2009 to 02/2014. 56 patients had Medulloblastoma, 2 SPNET, and 4 pinealoblastoma . Median age was 7.1 years; 35 patients (56%) underwent gross total resection, 8 near-total, 12 subtotal, 2 partial and 5 patients underwent a biopsy only. 22 patients had M2/3 disease. 26 patients were treated as average-risk (AR,42%) and 36 treated as high-risk (HR,58%). Radiation started at a median interval of 35 days post-surgery (18-105). Etoposide was well tolerated during radiation, but most patients experienced grade3-4 hematological toxicity during post-radiation chemotherapy. Only 50% of the patients received isotretinoin. No toxic death occurred on treatment. Hearing assessment (Brock scale) was available for 51 patients and showed gr0 toxicity in 30 patients(48.4%), gr1-2 in 16, and gr3-4 in 5. At a median follow-up of 23 months, 56 patients are alive and 6 have died (3/26 AR patients, and 3/36 HR patients). The 2 year overall survival (OS) is 91.5 + 5% and the projected 5 year OS 80.7 + 8%. CONCLUSION: Although it is still too early to draw conclusions on survival with this approach, initial results are encouraging showing mild toxicity, in particular in terms of hearing loss.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.13

CT-014. PRELIMINARY RESULTS ON THE IDENTIFICATION OF GENOMIC MARKERS OF DRUG SENSITIVITY TO INDIVIDUALIZE THERAPY IN PEDIATRIC RECURRENT CENTRAL NERVOUS SYSTEM TUMORS TREATED WITH BEVACIZUMAB (BVZ) AND CHEMOTHERAPY

Ma-wei Jiang 1, Ren-hua Zhou 1, Qing Zhou 1, Xiao-jun Yuan 1, Jie Ma 1

Abstract

METHODS: Between February 2011 - July 2013, 11 children after surgery, radiation and chemotherapy, at Xin Hua hospital received therapy for brain tumor recurrence-tumor dissemination or residual tumor. Median age 5.5y (1-13). The histological diagnoses included: medulloblastoma (n = 3), brain stem diffuse astrocytoma (n = 2), atypical teratoid rhabdoid tumor (n = 2), glioblastoma (n = 1), Gliosarcoma (n = 1), anaplastic ependymoma (n = 1) and primitive neuroectodermal tumor - neuroblastoma (n = 1). To identify tumor and drug related molecular targets, we analysed matched tumor and peripheral blood samples using immunohistochemical, ELISA, FISH, PCR amplification and sequencing. 11 cases of tumor specimens with high expression of VEGFR - 2 and lower ICAM1 expression in peripheral blood correlated with high sensitivity to bevacizumab. Tumor specimens with high expression of the Tubulinβ3 molecular targets correlated with high sensitivity to paclitaxel/ VCR. Plan for bevacizumab, once every 2 weeks, 5 mg/kg'VCR every week, 1.5 mg/m2, in 3 weeks, 1 course = 4 weeks. Children were treated until they experienced progressive disease. RESULTS: All children to CR, 8 cases died, the median survival was 6.3 months; 3 cases survived and have received up to 2 years of Bevacizumab and VCR.Bevacizumab-related toxicity was mild.no serious side effects, 2 cases with Bevacizumab have abdominal pain, 1 case of fever. Further prospective trials are required to confirm the hypothetical efficacy of bevacizumab and to assess the risk of long-term toxicity especially in the youngest children. CONCLUSIONS: By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.The combination of BVZ and VCR was fairly well-tolerated, and most severe BVZ-related toxicities were rare, self-limiting, and manageable.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.14

CT-015. POPULATION PHARMACOKINETICS OF HIGH-DOSE METHOTREXATE IN INFANTS WITH MALIGNANT BRAIN TUMORS

David Turner 1, Karen Wright 1, Alberto Broniscer 1, Giles Robinson 1, Ibrahim Qaddoumi 1, Greg Armstrong 1, Amar Gajjar 1, Clinton Stewart 1

Abstract

The disposition of high-dose methotrexate (HDMTX) and factors contributing to pharmacokinetic variability in infants and young children with brain tumors are currently unknown. Specifically developmental changes in renal function during this age group introduce inter- and intra-patient variability not yet determined. Consequently, HDMTX dosing and supportive care measures may not be optimized for this patient population. Thus, we studied the pharmacokinetics of HDMTX in infants and young children with newly diagnosed primary CNS tumors. These patients received four 28-day cycles of induction chemotherapy including HDMTX given on the first day of each cycle as a 24-hour infusion of 5 g/m2 or 2.5 g/m2 for infants ≤ 31 days of age. Serial pharmacokinetic sampling was obtained after HDMTX infusion and samples analyzed for MTX concentration by an automated enzyme immunoassay. Population parameters for a two-compartment pharmacokinetic model were estimated by nonlinear-mixed effects modeling (NONMEM). A total of 78 patients with a median (range) age of 1.54 years (0.02–3.08 years) contributed 1,239 MTX pharmacokinetic samples to the dataset. The population MTX clearance estimate (CLt) in the covariate-free model was 90.5 ml/min/m2 with inter-individual variability (IIV) of 24.9%. Variables included in the final model for the prediction of MTX CLt were age, race, and estimated GFR (p < 0.05; stepwise forward addition). No relation was observed between duration or volume of pre-hydration and MTX concentration at 6 hr during the infusion. Physiological maturation in renal function was a significant determinant of HDMTX exposure in this patient cohort.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.15

CT-016. RISK MITIGATION APPROACH IN THERAPEUTICS DEVELOPMENT

Sanjay N Misra 1, Ashish K Misra 2

Abstract

Research and development of a new chemical moiety or biologic from bench to patient requires a demonstration of an acceptable benefit risk balance. The regulatory and scientific process forms the foundation for the development of a therapeutic option (drug, biologic, biopharmaceutical). The regulatory considerations must be satisfied prior to a novel oncological therapeutic option being approved for first in human trials or utilisation. An examination of the regulatory requirements published by the regulatory agencies of the European Union, Asia, North America, Latin America and Africa demonstrate significant commonalities. Attention to these commonalities early in the strategic development phase of a new therapeutic entity can facilitate a more rapid path to first in human trials on a global scale. Within these common requirements is the establishment of a strategic risk evaluation and mitigation plan for the entire life cycle of the proposed therapeutic entity. The inclusion of a risk management strategy from the early phases, to satisfy the demonstration of benefit risk balance can expedite the process from bench to patient. This impacts the early designs for the risk mitigating toxicology studies, species selection etc and is an ongoing process leading to demonstrated safe dose selection and beyond. The components of a risk evaluation mitigation and what is required within the early strategic plan, to achieve the target goal of approval for human use, are described. Generic guidelines for the inclusion of these strategies within the research development protocol submitted for human use approval of a new chemical moiety or biologic are discussed.

Neuro Oncol. 2014;16(Suppl 1):i10–i13. doi: 10.1093/neuonc/nou066.16

CT-017. ELIGIBILITY FOR UP-FRONT THERAPEUTIC STUDIES TO CHILDREN WITH CNS TUMOURS – DO CHILDREN WHO WILL DIE OF THEIR DISEASE HAVE AS MUCH ACCESS TO STUDIES AS THOSE WHO WILL SURVIVE?

Antony Michalski 1, Charles Stiller 1

Abstract

Reducing the death rate from childhood malignancy is a stated aim of all national cancer organisations. It is accepted that access to clinical trials of therapy is key in achieving that aim. One metric for success is the percentage of patients that have access to up-front therapeutic studies. The CNS Subgroup of the National Cancer Research Institute Children's Cancer and Leukaemia Clinical Studies Group, UK, investigated whether patients who will die of their disease have the same access to therapy as those who will survive their condition. The UK has a comprehensive system of population based cancer registration. Using data from the National Registry of Childhood Tumours we calculated the annual average number of patients diagnosed before the age of 15 years in 21 diagnostic categories that covered >95% of children diagnosed with a CNS tumour, and the annual number of deaths within 5 years from diagnosis in each category. Of all children in the 21 diagnostic categories: 45% were eligible for an open study, for 36% there were studies in late development and for 19% there were no open studies or studies in late development. However, for children who would die of their disease only 11% had access to open therapeutic studies, in49% there was a study in late development and in 40% there was no open study or study in late development. The diseases that result in the majority of deaths have a low annual incidence and running statistically meaningful studies of therapy within a reasonable time frame is difficult. However, therapeutic studies are essential if outcomes are to improve. The availability of up-front studies of therapy for children who will die of their disease is a useful metric in determining the success of a national cancer strategy.

Articles from Neuro-Oncology are provided here courtesy of Society for Neuro-Oncology and Oxford University Press

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