CILENT P Leblond, DIPG Meeting, Barcelone 2012

Transcription

1 CILENT-0902 Cilengitide (EMD121974) in combination with irradiation in children and adolescents with newly diagnosed diffuse intrinsic brainstem glioma : Phase I Study P Leblond, DIPG Meeting, Barcelone 2012

2 The targets : integrins Heterodimers crossing the membranes involved in : interaction with extracellular matrix proteins proliferation, migration, invasion, growth, cell survival, tumor cell survival Crucial for angiogenesis through 2 mechanisms : bfgf and/or TNFa signaling pathway (αvβ3 integrin) VEGF signaling pathway (αvβ5 integrin) Cilengitide (EMD , Merck KgaA) specific inhibitor of αvβ3 and αvβ5 integrins with high affinity antiangiogenic and apoptotic effects via FAK/src/Akt signaling pathways

3 RTK ECM Rho/Rac RAF Src FAK ERK PI3K-Akt activity NF-κB activity p53 activity Caspase 8 Apoptosis intrinsic pathway Apoptosis extrinsic pathway

4 Preclinical background for cilengitide dose-dependent inhibition on xenograft tumor growth (medulloblastoma, glioblastoma) angiogenesis inhibition, and apoptosis induction (glioblastoma, melanoma) in vitro synergy with temozolomide in vitro synergy with ionizing radiation (lung, breast) Tumor growth inhibition in orthotopic but not in heterotopic glioblastoma xenografts (particular tropism?)

5 U87MG (adult, grade IV) SF188 (grade IV) MFI = 2,66 ΔMFI = 2,48 ΔMFI = 4,65 UW479 (grade III) Res259 (grade II) ΔMFI = 0,01 ΔMFI = 1,37 Meignan, Leblond et al, AACR 2011

6 U87MG (Grade IV) UW 479 (Grade III) Res 259 (Grade II) A B no CGT SF188 (Grade IV) % adhered cells % adhered cells % adhered cells % adhered cells Vitronectine Collagen I CGT (µm) Vitronectine Collagen I CGT (µm) Vitronectine Collagen I CGT (µm) Vitronectine Collagen I CGT (µm) 150 µm 150 µm 150 µm 150 µm 150 µm 150 µm 150 µm 150 µm 1h CGT (50µM) Meignan, Leblond et al, AACR 2011

7 U87MG SF188 % of viable cells % of viable cells IC 50 = ND CGT (µm) UW479 % of viable cells % of viable cells IC 50 = 2.7 µm ± 0.30 CGT (µm) Res259 IC 50 = ND IC 50 = 1.88 µm ± 0.14 CGT (µm) CGT (µm) Uncoated Collagen I Meignan, Leblond et al, AACR 2011

8 Adults early clinical studies Phase I (Eskens 2003) : advanced metastatic solid tumors, no DLT Phase I (Nabors 2007) : 51 GBM, no DLT, 2 durable CR, 3 PR, 4 SD Phase I (Hariharan 2007) : all refractory tumors, 2 groups (600 vs 1200 mg) half-life : 4 hours very few toxicity (grade 1 and 2): fatigue, nausea, headache no difference for toxicity in the 2 groups Phase II (Reardon 2008) : relapse GBM after Stupp (or RT alone), 2 groups (500 vs 2000 mg) no toxicity > grade 3 liver transaminases elevation, arthralgia, weight increase, headache PR = 9%, median time to progression = 17 months

9 Reardon et al. JCO 2008;26:

10 NABTC-0302 : phase II trial Cilengitide 2000 mg/dose Day -8, -4, -1 Recurrent Glioblastoma Requiring tumor resection Randomization Resection day 0 Cilengitide plasma concentration day -1 EOI Cilengitide tumor concentration Cilengitide 500 mg/dose Day -8, -4, -1 SURGERY Primary endpoint PFS-6 Drug delivery All patients: Cilengitide 2000 mg twice weekly after resection Gilbert et al., SNO 2007

11 NABTC-0302: Preliminary results No episodes of post-operative hemorrhage nor wound healing issues The drug reaches the tumor tissues Drug delivery to the tumor appears to be dose related Grade 3/4 adverse events Cilengitide 500/2000 mg (n=30) Lymphopenia 8 Fatigue 1 Thrombocytopenia 1 Myalgia 1 Pulmonary edema 1 Gilbert et al., SNO 2007

12 NABTT-0306: Study design Glioblastoma newly diagnosed Concurrent Chemoradiation Safety Run-in Randomization Cilengitide 2000 mg/dose IV 2x/week Continue until: Progressive disease Significant toxicity Non-compliance Cilengitide 500 mg/dose IV 2x/week Primary endpoint OS Secondary Endpoint PFS Toxicity Nabors et al. ASCO 2009

13 NABTT-0306:Patient characteristics NABTT 0306 RT+TMZ+EMD All doses combined RT+TMZ +EMD 500mg RT+TMZ +EMD 2000mg NABTT Historical RT+Chemo Characteristics N=112 N=46 N=48 N=235 Age year Median Range Sex no.(%) Male 66 (59) 28 (61) 29 (60) 151 (64) Female 46 (41) 18 (39) 19 (40) 84 (36) Karnofsky Performance Status no. (%) (24 ) 8 (17) 15 (31) 33 (18 ) (46) 27 (59) 18 (38) 93 (50) (13) 3 (7) 7 (15) 31 (17) (13) 6 (13) 6 (13) 21 (11) 60 4 (4) 2 (4) 2 (4 ) 7 (4) Surgical Procedure no. (%) Biopsy 25 (22) 10 (22) 9 (19) 29 (16) Craniotomy 86 (77) 35 (76) 39 (81) 156 (84) Other 1 (1) 1 (2) Corticosteroid Therapy - no. (%) Yes 82 (74 ) 33 (72) 36 (77) 157 (67 ) No 28 (24) 13 (28) 11 (23) 24 (10) Data missing 2 (2) 54 (23) Histological Diagnosis - no. (%) Glioblastoma 112 (100) 46 (100) 48 (100) 181 (98) Other 3 (2 ) * Patient characteristics and prognostic factors were well balanced between treatment groups. Nabors et al. ASCO 2009

14 NABTT-0306: Grade 3/4 non-hematologic AEs Number of events Total (Patients with Gr3/4 Event, Relationship 2-4) Fatigue Cilengitide 500 mg (n=53) 5 2 Number of subjects Cilengitide 2000 mg (n=55) 7 0 Total (n=108) 12 2 Headache Thrombosis/embolism Arthralgia Uric acid Nabors et al. ASCO 2009

15 NABTT-0306: Grade 3/4 hematologic AEs Number of events Anemia 500 mg (n=53) Grade 3 / mg (n=55) Grade 3 / 4 0 Leukopenia 5 0 Febrile neutropenia 0 0 Thrombocytopenia 9 3 Nabors et al. ASCO 2009

16 NABTT-0306: Survival curves by randomized dose cohort Overall Survival Probability mg Cohort 500 mg Cohort Months Nabors et al. ASCO 2009

17 NABTT-0306: Summary and conclusions (by author at ASCO) Cilengitide is well tolerated with a favorable safety profile when combined with radiation and temozolomide No obvious differences between safety profile of the 2 dose groups Trend towards increased activity with higher dose cohort (2000 mg) in overall survival. The combination of cilengitide + RT + TMZ appears superior to RT + TMZ. A randomized controlled trial is underway to further delineate the role of cilengitide combined with RT +TMZ in newly diagnosed GBM. Nabors et al. ASCO 2009

18 Clinical feasibility of the combination Cilengitide /radiation therapy Confirmed by Stupp, J Clin Oncol 2010 Phase I/IIa trial of cilengitide in combination with temozolomide and RT in newly diagnosed GBM Cilengitide = 500 mg, IV twice a week well tolerated, no additional toxicity

19 Pediatric data Phase I MacDonald 2008 refractory brain tumors scheme with twice weekly infusion :120 to 2400 mg/m² 35 patients, no DLT 3 intratumoral hemorraghes, but 2 without symptoms 1 neutropenia, 1 thrombopenia grade 3 1 complete response (GBM), with durable CR one year after stop of treatment PK data were similar to adults systemic exposure correlated with renal clearance and ABCB1 genotype J Clin Oncol 2008;26:

20 CILENT : Study main objectives Primary : to determine the MTD of Cilengitide in combination with radiation therapy in children and adolescents with DIPG Secondary : toxicity profile of Cilengitide, safety PK efficacy in standard MRI imaging (CR, PR, SD,...), response rates PFS at 6 months, OS Other objectives and biological studies (extension of cohort) : expression levels of αvβ3 and αvβ5 integrins, angiogenic factors (VEGF, CD31 ), pakt pharmacogenetic study (polymorphisms), Illumina evaluation of the metabolic impact of the treatment (functionnal MRI, FDG- PET, sestamibi SPECT)

21 CILENT : Inclusion criteria Newly diagnosed DIPG age from 6 months to 18 years histological diagnosis of glioma grade > 2 (biopsy mandatory) no previous chemotherapy or radiotherapy Lansky score > 50 Usual biological criteria, no coagulopathy

22 Study design Phase I, multicentric, national, open label, non-comparative, nonrandomized study (8 french centers, pharmacology and BT groups SFCE) First part (real phase I study) : phase I objectives (toxicity) classical dose ranging levels of dosage (from 240 to 1800 mg/m²) about patients Second part (extension of cohort) : secondary objectives (response rates, functional imaging, biology) 20 patients at MTD, or at 1800 mg/m² if no toxicity twice a week infusion, IV over one hour RT (54 Gy, 1.8 fractionation) must begin between 3 and 7 hours after the end of infusion then alone in maintenance therapy until progression

23 Study plan Funding : French National Cancer Institute (INCa) Help from Merck KGaA laboratories: give the molecule do the PK trial included in their PIP for cilengitide Study timelines : First patient included : september 2010 last patient : end of 2012 Pathology central review planned MRI central review planned (end of the first part of the study) Biological investigations at the end of the study

24 RECRUITMENT STATUS ON JANUARY 2012 Centre No Patient Sexe Age (Years) Type histo Grade histo Date C1 Nb cycles DLT Level 1 = 240 mg/m² Marseille 1 (E-W) Boy 6 Oligodendroglioma II 7/sep/ Marseille 2 (M-C) Girl 15 Astrocytoma III 7/sep/ Villejuif 3 (P-L) Girl 5 Glioblastoma IV 5/oct/ Level 2 = 480 mg/m² Marseille 4 (A-J) Boy 3 Oligodendroglioma III 09/dec/ Villejuif 5 (O-L) Girl 4 Astrocytoma III 08/dec/ Lyon 6 (P-A) Boy 6 Oligoastrocytoma III 28/dec/ Level 3 = 780 mg/m² Nantes 7 (O-B) Boy 6 Anaplastic astrocytoma III 07/apr/ Nantes 8 (H-E) Boy 5 Oligo-astrocytoma IV 10/may/ Nantes 9 (B-N) Girl 7 Anaplastic astrocytoma III 17/may/ Level 4 = 1200 mg/m² Nantes 10 (M-J) Girl 6 Oligo-astrocytoma III 19/jul/ Curie 11 (N-O) Boy 6 Unknown 08/aug/2011 NA NE Villejuif 12 (L-A) Boy 14 Glioblastoma IV 30/aug/ NE Marseille 13 (G-M) Boy 7 Not classified 05/sep/ Nantes 14 (L-C) Girl 4 Unknown III 13/dec/ Level 5 = 1800 mg/m² Reservation Strasbourg