BackgroundDiffuse intrinsic pontine glioma (DIPG) is a devastating cancer of childhood and adolescence.MethodsThe study included patients between 3 and 20years with clinically and radiologically confirmed DIPG. Primary endpoint was 6-month progression-free survival (PFS) following administration of nimotuzumab in combination with external beam radiotherapy (RT). Nimotuzumab was administered intravenously at 150mg/m(2) weekly for 12weeks. Radiotherapy at total dose of 54Gy was delivered between week 3 and week 9. Response was evaluated based on clinical features and MRI findings according to RECIST criteria at week 12. Thereafter, patients continued to receive nimotuzumab every alternate week until disease progression/unmanageable toxicity. Adverse events (AE) were evaluated according to Common Terminology Criteria for Adverse Events (CTC-AE) Version 3.0 (CTC-AE3).ResultsAll 42 patients received at least one dose of nimotuzumab in outpatient settings. Two patients had partial response (4.8%), 27 had stable disease (64.3%), 10 had progressive disease (23.8%) and 3 patients (7.1%) could not be evaluated. The objective response rate (ORR) was 4.8%. Median PFS was 5.8months and median overall survival (OS) was 9.4months. Most common drug-related AEs were alopecia (14.3%), vomiting, headache and radiation skin injury (7.1% each). Therapy-related serious adverse events (SAEs) were intra-tumoral bleeding and acute respiratory failure, which were difficult to distinguish from effects of tumor progression.ConclusionsConcomitant treatment with RT and nimotuzumab was feasible in an outpatient setting. The PFS and OS were comparable to results achieved with RT and intensive chemotherapy in hospitalized setting.

9557 Background: Childhood MRI diagnosed diffuse pontine glioma have a universally known awful prognosis. After joining a previous trial with nimotuzumab and radiation, reported also at ASCO (2008), and continuing for a total of 37 patients from January 2006-June 2009 according to this new combination, we obtained median PFS 7 months, median OS 11 months, thus entirely consistent with best literature data and those previously reported by ourselves (Massimino 2008). All treatment was given on an outpatient basis, without any side effects correlated with the use of nimotuzumab. Two of 37 children were alive without tumor progression 17 and 27 months after diagnosis.METHODSIn a subsequent mono-institutional experience, exploring add-on strategies, we began a pilot protocol on a compassionate case-by-case basis, using nimotuzumab together with vinorelbine, combined with radiation, adopting consolidation courses with the same timing as in the previous international radiation plus nimotuzumab protocol. Vinorelbine was at a dose of 20 mg/sqm/weekly together with nimotuzumab at the standard dose of 150 mg/sqm during the 6 weeks of radiotherapy, and 25 mg/sqm in any other week, with the same dose of nimotuzumab during the consolidation courses, planned until tumor progression or for a duration of two years.RESULTSWe have so far treated 12 children, 7 males and 5 females, age range 3-13 years, enrolled according to the standard MRI inclusion criteria. After a mean follow-up of 10 months, 10/12 were alive, their PFS at 9 months was 69 ± 21% and their OS at 12 months was 81.5 ± 12 %. According to MRI evaluation, in 10/12 children evaluable for response, 7 had partial remission and 3 stable disease with 100% symptom amelioration. The nimotuzumab/vinorelbine combination was very well tolerated, with no acute side-effects. As in the case of nimotuzumab alone, all children were treated on an outpatient basis.CONCLUSIONSThe observation time for this new series is long enough to give the impression that this combination has promise, with statistically significant differences with previous reported experiences.

Introduction Nimotuzumab is a humanized monoclonal antibody that binds to the EGFR. Based on phase I data, the recommended dose has been established at 200 mg weekly. This study was aimed at evaluating the safety and efficacy of nimotuzumab monotherapy in patients (pts) with locally advanced or metastatic pancreatic cancer. Methods Pts who failed first line standard chemotherapy for advanced disease and had at least one measurable lesion were eligible for the study. Nimotuzumab was given intravenously at 200 mg once weekly for 6 weeks (wks). Follow up by CT scan was performed after 8 weeks. Pts continued receiving treatment 3-weekly until disease progression or unacceptable toxicity occurred. Endpoints included tumor response (RECIST), progression-free survival (PFS), and safety. Results A total of 56 pts were enrolled for treatment (ECOG status of 1 [n = 41] or 0 [n = 15]), the majority (47 pts) had metastatic disease. Nearly half of the pts [n = 26] received ≥2 regimens. Pts evaluable for response: n = 36; CR: 0; PR: 0; SD: 6 pts. Median PFS for pts with SD was 19.2 weeks, for all pts 6.7 weeks (95% CI: 6.43–7.14 weeks). PFS after 1 year was 10.3% with a median overall survival of 18.1 weeks. Treatment-related adverse events were generally mild including rash grade 1 in 5 pts. After a single dose of 200 mg, the t1/2 was calculated to 45 h. Conclusion These data confirm that nimotuzumab is safe and very well tolerated. To improve efficacy, a randomized, placebo-controlled trial with Gem has been initiated.

2056 Background: EGF-R is the most consistently expressed cell surface marker for glioblastoma. Therapies are directed against the intercellular signalling pathway or the cell surface binding of the cognate ligands. Because of the selectivity of this molecule for gliomas and promising preclinical and early clinical findings, to evaluate the therapeutic effect of a monoclonal antibody (nimotuzumab) which has a lower affinity than cetuximab, thus binding more specifically to highly overexpressing cells is warranted in a phase III design. Methods: Nimotuzumab (OSAG-101) is tested in an open label, randomized, multicenter phase III trial in patients with newly diagnosed glioblastoma. OSAG-101 is administered by i.v. infusion (weekly infusion of 400 mg) on top of the current standard radiochemotherapy with temozolamide followed by biweekly infusions of 400 mg thereafter until progression. Patients with histologically confirmed glioblastoma were included without specification of resection status. Patients under the age of 18 and over 70 years were excluded. Primary endpoint was time to progression as determined by centralized neuro-imaging review using a standardized evaluation protocol. Overall survival serves as a secondary endpoint with quality of life and safety as additional parameters. Results: Between August 2008 and December 2009, 130 patients were enrolled in 10 sites with 150 subjects. All except one patient were GBM on central histopathological review. 60 patients had a gross total resection with no residual contrast enhancement and 70 patients had partial resections with residual contrast enhancement, including patients with biopsy only. The observed adverse reaction pattern was the same in both study arms and both strata and reflecting the event pattern of the disease and its standard treatment. No rash, conjunctivitis or mucositis were reported. Conclusions: The intravenous administration of OSAG-101 for newly diagnosed glioblastoma is safe and free of additional toxicity to the standard radiochemotherapy regimen. With 75 patients just having reached their primary endpoint, an interim analysis will be available by march 2010. Accrual is expected to be complete by April 2010. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Oncoscience

12504 Background: Nimotuzumab (OSAG101, Theraloc) is a humanized monoclonal antibody (mAb) that binds to the EGFR. In preclinical studies the antibody has shown potent antitumor activity. Based on phase I data, the recommended dose has been established at 200 mg weekly. A previous phase II study in children with high grade brain tumors showed activity of nimotuzumab as a monotherapeutic agent, even in prognostically very unfavorable pontine glioma. No drug related side effects were reported. The present ongoing phase II study was aimed at evaluating the safety and efficacy of nimotuzumab monotherapy in patients (pts) with locally advanced or metastatic PC. Methods: Pts who failed standard chemotherapy with gemcitabine or another first line regimen for advanced disease and had at least one measurable lesion were eligible for the study. Nimotuzumab was given iv as induction therapy at 200 mg once weekly for 6 weeks. Follow up by CT was performed after 8 weeks. Pts continued receiving treatment 3-weekly until disease progression or unacceptable toxicity occurred. Endpoints included tumor response (RECIST), time to disease progression, and safety. Blood samples were collected prior to first dose, at end of infusion, and 3h, 6h, 48h, as well as every time before subsequent nimotuzumab doses were administered. Nimotuzumab concentrations in serum were measured by cellular ELISA. Results: Enrollment is complete, with treatment ongoing. In total, 55 pts were treated (28 women/ 27 men; ECOG status of 1 [n= 41] or 0 [n=14], median age 63.6 yrs [range 46–83 yrs]). Pts evaluable for response: n= 36; CR:0; PR:0; SD:6 pts (median TTP 19.2 weeks; 14.1–26.1). The only reported treatment-related adverse event was rash grade 1 in 1 pt. After 200 mg single dose, the mean value of Cmax was calculated to 141 ± 33 μg/ml. The t1/2 was calculated to 45 h, volume of distribution to 1.46 ± 0.3 l, respectively. The total clearance was determined to 23 ± 6 ml/h. The trough values after 168 h were 6.2 ± 6.3 μg/ml. Conclusions: These data confirm that nimotuzumab is safe and well tolerated. To improve efficacy, a combination trial with gemcitabine is planned. [Table: see text]

Cryopreservation of human tumour cells and tissue is a valuable tool for retrospective analysis and for the transport and handling of biopsy material. Tumour tissue consists of different cell types, which have different optimal freezing conditions, and extracellular matrix. A well-defined and authentic model system is required for developing new freezing protocols and media. This work describes the use of L929 and PC-3 spheroids as new model systems for freezing human tumours. Cell suspension and spheroids were frozen in different vessels (1ml cryovials and a special, cryo-compatible 30×25μl multi well plate) at slow rate (1°C/min). Freezing media were combinations of culture or tumour transport medium (Liforlab®) with the cryoprotective agents, Me2SO, trehalose and modified starch. We also present a new method of evaluating the viability of three dimensional multicellular systems to compare thawed spheroids objectively. Best viability (70%) of L929 spheroids occurred with a combination of Liforlab® and starch hydrolysis product. The best cryopreservation results for spheroids were found with extracellular cryoprotectants, while optimum viability of single cells was achieved with Me2SO.

2058 Background: Despite multimodal therapy children with newly diagnosed intrinsic pontine glioma (PG) have a dismal prognosis. Recently novel therapeutic approaches were taken in order to improve the survival of these patients while preserving a good quality of life. This multicentre phase III trial was designed following the excellent results of a phase II study in resistant diffuse intrinsic pontine gliomas (ASCO 2007; 2006) to explore the feasibility and efficacy of the monoclonal anti-EGFR antibody (Nimotuzumab) in the primary treatment of these patients. Methods: Pediatric patients with newly diagnosed PG with radiologically proven disease and a life expectancy of minimum 4 weeks were eligible to the study. The treatment consisted of an induction therapy including a weekly short infusion of 150 mg/m2 nimotuzumab for twelve weeks, concomitantly with radiotherapy at weeks 3 to 8 to a total dose of 54 Gy. In case of non-PD a consolidation therapy of 150 mg/m2 of nimotuzumab biweekly followed until dis...

BackgroundDespite multimodal therapy most children with high grade gliomas (HGG), including glioblastoma multiforme (GM), anaplastic astrocytoma (AA) and intrinsic pontine glioma (PG) have an infaust prognosis if they relapse or are refractory to the primary treatment. Recently novel therapeutic approaches are investigated in order to improve the survival of these patients while preserving a good quality of life.

1522 Background: Children and adolescents suffering from high grade gliomas (HGG) have a poor prognosis when they relapse during or after primary treatment. Thus novel therapeutic approaches as the inhibition of growth-signalling pathways are needed. This multicentre phase II trial was designed to explore the feasibility and efficacy of the h-R3 monoclonal anti-EGFR antibody (Nimotuzumab) in the treatment of these patients. Methods: Pediatric patients with glioblastoma multiforme, anaplastic astrocytoma or intrinsic pontine glioma (PG) with radiologically proven progressive disease following primary or relapse treatment were eligible to the study. The treatment consisted of an induction therapy including a weekly short infusion of 150 mg/m2 Nimotuzumab for six weeks, and in case of non-PD a subsequent consolidation therapy of four infusions in a three week interval. The response was documented by MRI in week 8 and 21. Results: Between June 2004 and August 2005 34 patients aged 5.0 to 17.4 years (median 10.9 years) were enrolled in this study. According to RECIST 12 out of 34 patients showed response (PR n=1, SD n=11) in the MRI of week 8 after the induction therapy with a median change in the largest diameter of the index lesion of −5% (−39 to +16%) accompanied by clinical deterioration in four and markedly clinical improvement in two patients. Surprisingly, 9 PR/SD were seen in the 14 patients with PG. Eight patients continued with the consolidation therapy. So far 5 out of 8 Patients are evaluable for response after consolidation therapy and showed three PR, one SD and one PD in week 21. Eight patients with consolidation therapy are free of progression for a median of 7.5 months (1.2–13.2 months). No severe side effects related to the study medication were observed. Conclusions: These data suggest that the repeated application of Nimotuzumab is well tolerated and safe. It has cytotoxic efficacy in heavily pre-treated relapsed HGG, especially in intrinsic pontine glioma. A phase III study for patients with newly diagnosed PG is warranted. [Table: see text]