Shin-Ichi Miyatake, MD., Ph.D. Shinji Kawabata, Motomasa Furuse, Gen Futamura, et al. Dept. of Neurosurgery, Cancer Center Osaka Medical College 16 th ICNCT PaC1-02, June 18 th, 2014 BNCT for recurrent malignant gliomas, with the special combination of bevacizumab

2M after BNCT Prior to BNCT Anaplastic oligodendroglioma Gd-T1 RPA class 3, estimated MST ： 3.8 months

10M after 14M After BV strated 17 M After 6 cycles BV

FLAIR images showing cerebral edema 10M after 14M After 17 M After 6 cycles BV

Kaplan-Meier survival curves for the recurrent MG cases treated by BNCT. A blue line shows the survival of all patients after BNCT (n=34). A red line shows the survival of GBM (on-site histology) after diagnosis of GBM (n=26). Survival of BNCT-treated recurrent gliomas Survival from the diagnosis of GBM BNCT has the characteristics of cell-selectivity, This is quite different from other particles ー from diagnosis(n=26) ー from BNCT(n=34) Survival from BNCT All patients received full-dose XRT

J Clin Oncol 18: , 2007 A recursive partitioning analysis for recurrent malignant gliomas was advocated. RPA is a stratified grouping of the patients with prognosis.

J Clin Oncol 18: , 2007 RPA

All (median, (95%CI)RPA 3+7 (median, (95%CI) a J Clin Oncol7.0( )(n=310)4.4( )(n=129) a BNCT 10.8( )(n=22)9.1( )(n=11) a J Clin Oncol 25: , 2007 b J Neuro-Oncol 91: , 2009 Survival of BNCT-treated recurrent gliomas There is no over-lap in 95 % CI between JCO data and our BNCT data. Department of Neurosurgery Osaka Medical College

Survival of BNCT-treated recurrent gliomas Patients characteristics median(range) Age51( ) KPS at the relapse80( ) GTV at the relapse36.6( )mL No. of cases(%) Radiation therapy at initially diagnosedEBRT*25(86.2%) SRS** only3 (10.3%) EBRT+SRS1(3.4%) *: fractionated external beam radiation therapy, **: stereotactic radiosurgery Cause of DeathCSF dissemination (D)15(51.7%) Local tumor progression (TP)8 (27.6%) Radiation necrosis3(10.3%) Both (TP+D)2(6.9%) Other cause2(6.9%) Good local control With CSF dissemination Good local control

Malignant Cycle Bevacizumab Surgery Vascular damage in early phase of RN Radiation Disruption of BBB Hemorrhage Angiogenesis VEGF production in reactive astrocytes Hypoxia Peri-lesional edema Increase of interstitial fluid pressure Gd-enhancement Corticosteroid Anti-coagulants Vitamin E Treatment strategy for radiation necrosis based on our hypothetical mechanisms Patho-Physiology Treatments :Inhibition

A radiation necrosis case, newly diagnosed GBM treated by hypo-fractionated IMRT The patient was referred for us for the purpose of BNCT, with the Dx of tumor recurrence. CE T2 After Op. (partial rem.) 4 M after IMRT 13 M after IMRT Dx. as Rec. GBM Aphasia and hemiparesis After BV, 5 times Now, we are negotiating to Japanese FDA to get approval of on-label use of BV for symptomatic radiation necrosis

“Pseudoprogression” 40% of GBM patients treated by Stupp’s regimen （ TMZ+RTX) shows aggravation on MRI at the end of concomitant Ctx. Half of them are true progression. The other half shows spontaneous regression without additional treatments and is called as “pseudoprogression”. This is good predictor of prognosis and is seen in mainly MGMT methylation positive ones. Pseudoprogression can be seen after mere RTX, but intensive treatments, such as BNCT augmented the incidence of it. Pseudoprogression can be seen frequently not only in GBM but also in MM, treated by BNCT. Therefore, this is treatment-related intra-tumoral necrosis in sub-acute phase in BNCT (personal opinion ）. Pseudoprogression in boron neutron capture therapy for malignant gliomas and meningiomas. Neuro-Onocology 11(4):430-6, 2009., Miyatake S, et al.

T1-Gd T2-WI I Effects of Bevacizumab on symptomatic pseudoprogression Recurrent AOA, RPA class3, reported MST 3.8M. Pre-BNCT2 M after BNCT Bed-ridden 6 M after BNCT 3 cycles after BV

Recurrent GBM RPA class 4, MST anticipated as 10.4 M He is now still alive 32 M after BNCT

Five consecutive patients of recurrent malignant glioma treated with BNCT W/O BV Case Hist. RPA BV cyclesPsPD or RNSurvival No (MST) (Months from BNCT) (Months from BNCT) 1AA 3(3.8M) 3 (11 M) RN28M, dead 2GBM 4(10.4M) 4 (14M) RN32M, alive 3AA 3(3.8M) 6 (4 M) PsPD 16.5M, dead 4AOA 3(3.8M) 6 (2 M) PsPD 14M, dead 5GBM 6 (6.4M) 1 (5 M) RN8M, dead

AVAglio: Study Design n=463 n=458 Randomisation N=921 Stratification RPA class Region Last patient in: March 2011 BEV = bevacizumab; PD = progressive disease; q28d = every 28 days; q2w = every 2 weeks; q3w = every 3 weeks; ; qd = daily; RPA = recursive partitioning analysis; RT = radiotherapy; TMZ = temozolomide; Tx = treatment Tx start 4–7 weeks post-surgery RT 2Gy; 5 days/week TMZ 75mg/m² qd Placebo q2w TMZ 150–200mg/m² qd days 1–5 q28d Placebo q2w RT 2Gy; 5 days/week TMZ 75mg/m² qd BEV 10mg/kg q2w TMZ 150–200mg/m² qd days 1–5 q28d BEV 10mg/kg q2w BEV 15mg/kg q3w Placebo q3w Debulking surgery or biopsy Concurrent phase 6 weeks Tx break 4 weeks Maintenance phase 6 cycles Monotherapy phase until PD NCT Protocol no. BO21990

Pseudoprogression Rates* Patients RT/TMZ/Plb (n=463) RT/TMZ/BEV (n=458) End of treatment break Potential pseudoprogression, % End of second maintenance cycle Confirmed pseudoprogression, % Confirmed progression, % Missing, % *Investigator-assessed Plb = placebo

What is Ava-Boron ? Bevacizumab is used in this study continuously, just after BNCT for recurrent malignant gliomas (RMGs). This is aimed for prevention of PsPD and radiation necrosis. Its rationale As introduced, incidence of PsPD in bevacizumab (BV) treatment arm is significantly low in Avaglio study. Phil Gutin reported the safety and efficacy of BV just after hypo-fractionated SRT for RMGs. (Red J 2009).

FLAIR Gd-T1 Rec. AOA RPA class 2 Pre BNCT 2M after 7M after