Milan DIPG in nimotuzumab era

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1 DIPG EUROPEAN MEETING Barcelona, February 23 th - 24 th 2012 Milan DIPG in nimotuzumab era Elisabetta Schiavello Pediatric and Radiotherapy Unit, Milan

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3 concomitant RT/CT vp16/ara-c/ifo/cddp/d-act HD CT, TTP, ASCT, RT, vcr/ccnu concomitant RT/cddp-vp-16 concomitant RT/vnb SIMILAR SURVIVAL IN SPITE OF 4 VERY DIFFERENT APPROACHES

4 PEI-N 225/05 225/05

5 METHODS From January 2006 to March 2009 we treated 37 consecutive children with DIPG The treatment - continuation of a phase 3 multicentric trial - consisted of an induction therapy with weekly infusions of 150 mg/m 2 nimotuzumab (anti-egfr monoclonal antibody) for 12 weeks, concomitantly with standard radiotherapy (54 Gy) at weeks 3 to 8 a consolidation therapy with nimotuzumab biweekly followed until disease progression

6 RESULTS median age at diagnosis was 7.5 years ( ) M/F was 0.8 median PFS was 7 months, median OS 10 months similar data has already been published The major advantage we found was: NO toxicity relating to Nimo/RT on an outpatient basis NO need to admit patients QoL improvement but not very encouraging results...

7 VINORELBINE s efficacy in the treatment of recurrent/refractory pediatric solid malignancies its radio-enhancing activity its proven efficacy in treating adult tumours in which EGFR is present (advanced NSCLC) our experience in treating a case of relapsing GBS responding to VNB

8 New strategy from July 2009 Risonanza Magnetica Radiologia di riferimento Induzione Applicazione settimanale: 150 mg/m²/giorno di nimotuzumab Breve infusione di 30 minuti 20 mg/mq/die di vinorelbina Breve infusione di 30 minuti Esame clinico Accertamento effetti collaterali Risonanza Magnetica Radiologia di riferimento Prospetto terapeutico - induzione Cognome e nome: Data di nascita: trattamento di glioma intrinseco del ponte encefalico con radioterapia e nimotuzumab Giorno Settimana Cimaher/vinorelbina Irradiazione Effetti collaterali/particolarità Diagnosi: glioma intrinseco del ponte Inizio irradiazione settimana 3 termine settimana Dose singola: Gy Dose totale: Gy Il tumore è cresciuto =>interruzione della terapia con anticorpi / cambio di terapia Il tumore si è ridotto o è rimasto uguale => proseguimento della terapia con anticorpi Prospetto terapeutico Consolidamento I + II Consolidamento I Applicazione settimanale: 150 mg/m²/giorno di nimotuzumab Breve infusione di 30 minuti 25 mg/mq/die di vinorelbina Breve infusione di 30 minuti Esame clinico Effetti collaterali Cognome e nome: Data di nascita: trattamento di glioma intrinseco del ponte encefalico con radioterapia, nimotuzumab e vinorelbina Giorno Settimana OSAG 101 (data) Effetti collaterali/particolarità Risonanza Magnetica Radiologia di riferimento Consolidamento II Applicazione settimanale: 150 mg/m²/giorno di nimotuzumab Breve infusione di 30 minuti 25 mg/mq/die di vinorelbina Breve infusione di 30 minuti Esame clinico Effetti collaterali Il tumore è cresciuto =>interruzione della terapia con anticorpi / cambio di terapia Il tumore si è ridotto o è rimasto uguale => proseguimento della terapia con anticorpi CONSOLIDATION PERIOD NIMO 150 mg/m 2 weekly (12 doses) VNB 25 mg/m 2 weekly (12 doses) RT (54 Gy) from week 3 to 8 NIMO 150 mg/m 2 biweekly VNB 30 mg/m 2 biweekly for 2 yrs/until PD

9 Very early results 20 patients on treatment so far 12 males, 8 females median age 5 years (2-16 yrs) median follow-up 12 months for the 14 alive children (1-29 months) and 1 early death after the 1st radiation dose

10 PFS OF DIPG 119 PATIENTS TREATED ,8 Nimo vino 10/20 relapsed Rank Tests for pfs Censor Variable: status efs Grouping Variable: nimo vino s n Chi-Square DF P-Value Logrank (Mantel-Cox) Breslow -Gehan-Wilcoxon Tarone-Ware Peto-Peto-Wilcoxon Harrington-Fleming (rho =,5) 2,873 1,0901 2,413 1,1204 2,557 1,1098 2,458 1,1169 2,557 1,1098 Cum. Survival,6,4,2 0 Nimo 35/37 relapsed Previous series 60/62 relapsed Time

11 Cum. Survival 1,8,6,4 10/20 relapsed, nimo vino PFS 33% at 12 months Rank Tests for PFS Censor Variable: status PFS Grouping Variable: nimo vino Logrank (Mantel-Cox) Breslow -Gehan-Wilcoxon Tarone-Ware Peto-Peto-Wilcoxon Harrington-Fleming (rho =,5) Chi-Square DF P-Value 2,470 1,1161 1,841 1,1748 2,126 1,1448 1,851 1,1737 2,164 1,1413,2 0 PFS 16% at 12 months 35/37 relapsed, nimo Time

12 OS OF DIPG 119 PATIENTS TREATED ,8 OS 1 yr 81% 2 yrs 52% Nimo/vino patients Rank Tests for os Censor Variable: status os Grouping Variable: nimo vino s n Chi-Square DF P-Value Logrank (Mantel-Cox) Breslow -Gehan-Wilcoxon Tarone-Ware Peto-Peto-Wilcoxon Harrington-Fleming (rho =,5) 6,945 1,0084 4,276 1,0387 5,543 1,0186 4,396 1,0360 5,736 1,0166,6,4,2 0 Previous patients Time OS only NIMO 1 yr 45% 2 yrs 5%

13 CONCLUSIONS I feasible no toxicity from either drug all treatment on an out-patient basis QoL improvement

14 CONCLUSIONS II early high rate of responses: 12 PR 4 SD 1 early PD 3 too early for MRI 33% PFS at 12 months and 25% at 24 months 81% OS at 12 months and 52% at 24 months median OS has not yet been reached

15 AF at diagnosis and after ONE YEAR, PFS 23+ months

16 AF at diagnosis and after ONE YEAR, PFS 23+ months

17 AF at diagnosis and after ONE YEAR, PFS 23+ months

18 GS, glioblastoma, after operation and after 1 year

19 GS, glioblastoma, after operation and after 1 year

20 GS, glioblastoma, after operation and after 1 year

21 CB at diagnosis and at therapy end, after 2 years

22 CB at diagnosis and at therapy end, after 2 years

23 FUTURE PLANS COLLECT BIOPSY SPECIMENS WHERE POSSIBLE COLLECT PATIENTS PLASMA SAMPLES DURING THE TREATMENT (at every step) AND CORRELATE WITH CLINICAL STATUS

24 PONTINE GLIOMAS Tissue Bank

25 AIMS 1) To retrospectively evaluate DIPG patients previously treated (Massimino 2008 J Neurooncol. 87:355-61) and for which tumor material is available, in order to establish the correlation between patient characteristics and molecular markers that are involved in pathways frequently deregulated in gliomas: mitogenic signalling (EGFR, ERBB2, BRAF, PDGFRA, IDH1), neo-vascularization (VEGF, VEGFR2, HIF1A) and telomere/chromatin architecture (HTERT, Nucleolin, H3F3A, HIST1H3B, ATRX, DAXX). 2) To test the hypothesis that ERRB1-4 status (copy-number, mutations and activation status) impacts the clinical response of those patients treated with Nimotuzumab, a humanized monoclonal antibody targeting EGFR receptor kinase.

26 3) To verify if exone sequencing and gene expression/methylation profiling analyses are able to pinpoint relevant biological features and genetic aberrations of DIPG, that represent novel prognostic markers and therapeutic targets. 4) To evaluate a preclinical model testing the ability of morphine to generate a reversible disruption of BBB in rats in order to significantly increase the BBB penetration of chemotherapeutic drugs.(sardi 2011 Cancer Chemother Pharmacol. 67(6): )