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Sylvie Bonvalot1; Cécile Le Pechoux1 ; Thierry De Baere1 ; Guy Kantor2; Xavier Buy2; Paul Sargos2; Eberhard Stoeckle2; Philippe Terrier1; Nathalie Lassau1; Axel Le Cesne1; Antoine
Italiano2; Mikaela Dimitriu3; Laurent Levy3; Jean-Charles Soria1; Eric Deutsch1
1 Institut Gustave Roussy, Villejuif, France; 2 Institut Bergonié, Bordeaux, France; 3 Nanobiotix, Paris, France
THE IMPACT OF NBTXR3 NANOPARTICLES COMBINED WITH RADIOTHERAPY IN ADVANCED
SOFT TISSUE SARCOMA (STS): A PHASE I/II STUDY
THE IMPACT OF NBTXR3 NANOPARTICLES COMBINED WITH RADIOTHERAPY IN ADVANCED
SOFT TISSUE SARCOMA: A PHASE I/II STUDY
Conflict of Interest
I am the Principal Investigator of the clinical development supported by the Sponsor: NANOBIOTIX
NBTXR3 nanoparticles maximize Xray absorption in the tumor
NBTXR3 acts as a radioenhancer with a physical mode of action
NBTXR3 is a sterile aqueous suspension of functionalized hafnium oxide nanoparticles
Nanoparticles should exhibit 2 key features
1) Absorb X-ray
2) Good biocompatibility
Crystalline HfO2
coating
hnhn’
e-
Regular radiotherapy interaction with water
NBTXR3: a physical mode of action amplifying RTx
Ionizing radiation Interaction with hafnium oxide release of e- free radical generation cell damages
e-
e -
hnhn ’
e -
e-
Interaction with water generateslimited number of electrons
Radiotherapy alone Radiotherapy with NanoXray
Interaction with nanosized Hafnium generates much more electrons
Much more electrons generated at the same dose of radiation to healthy tissues and, hence, higher anticancer efficacy
NBTXR3 is a radioenhancer and thus different from a radiosensitizer
Antitumor efficacy in animal modelsCell lines and patient tumor fragment
NBTXR3 creates a significant difference in tumor response
Antitumor activity of NBTXR3 activated by X-rays (200kV) in fibrosarcoma
(HT1080 model)
Antitumor activity of NBTXR3 activated by high energy (Cobalt-60) in Ewing Sarcoma
family (A673 model)
Soft Tissue Sarcoma trial flowchart
Main objectives: feasibilty and safety for escalade of volume of NBTXR3 at fixed concentration (53.3 g/L)
CT Scan CT Scan
Safety evaluation
NBTXR3 dispersion and persistence
NBTXR3 injection feasibility
http://clinicaltrials.gov/ct2/show/NCT01433068?term=nanobiotix&rank=2
Treated population, Tumor Volume and Injected VolumeNBTXR3 Volume Escalation (53.3 g/L)
4 dose levels tested in various types and sizes of STShttp://clinicaltrials.gov/ct2/show/NCT01433068?term=nanobiotix&rank=2
NBTXR3 VolumeEscalation(53.3 g/L)
Tumor Histologytype
Tumor Volume
(mL)
Volumeinjected
(mL)
2.50%
Poorly differentiated sarcoma 212 5,3
Synovial sarcoma 55,06 1,4 Liposarcoma 1814,4 45 Liposarcoma 95,88 2,4
Synovial sarcoma 475,27 12Rhabdomyosarcoma 158,4 4
5%
Chondrosarcoma (Extraskeletal) 100,98 5
Liposarcoma 442,2 22 Liposarcoma 1760 88 Liposarcoma 3682,56 184 Liposarcoma 692,14 33 Liposarcoma 85,53 4,2
10%
(Evans sarcoma) 360 36 Liposarcoma 525 42,5
Chondrosarcoma 1005.5 100,5
Undifferentiated pleomorphic sarcoma 145,02 14,5
Leiomyosarcoma 443 44Differentiated liposarcoma 160 16
Pleomorphic sarcoma 250 25
Clear cell sarcoma 130 13
20%Undifferentiated Sarcoma 960 192
Myxofibrosarcoma 490 84,5
NBTXR3: related adverse events
AE occurrence by number of patientsNBTXR3 - related AE
NCI-CTCAE version 4
>=Grade 3 1 2 3 4 5LEVEL 1 : N=6 (NBTXR3 2.5% baseline tumor volume) 0
Abdominal pain 1
Hypotension 1
Injection site reaction 1
Paraesthesia 1
Pyrexia 1
LEVEL 2 : N=6 (NBTXR3 5% baseline tumor volume) 0
Headache 1
Injection site pain 2
Oedema peripheral 1
Pyrexia 1
LEVEL 3 : N=6 (NBTXR3 10% baseline tumor volume) 0
Injection site pain 1
LEVEL 4 : N=2 (NBTXR3 20% baseline tumor volume) 2
Injection site pain 1*
Postoperative wound complication 1*
* In green bold: One patient (n°0018) had early DLTs at Level 4
Quantification of NBTXR3 by ICP-MS
Marginal passage rate of NBTXR3 to the bloodstream during the injection procedure, and very short time of circulation.
Quantification of NBTXR3 by ICP-MS (Hafnium) in urine sample confirms the absence of renal excretion
NBTXR3 Phase IBody Kinetics of NBTXR3
NBTXR3: PK
Recommended Volume: 10% tumor volumeIntratumor bioavailability of NBTXR3 at 10% volume (53,3g/L)
Persistence of NBTXR3 during all session of RTx: optimal bioavailability over time
D1 NBTXR3administration
D2 1st RTx
Patient registration
D37end of RTxRadiotherapy
25 x 2Gy
D72-79Surgery
D95-102End of treatment
CT Scan CT Scan
Efficacy evaluation
Tumor volume change for resectability (% mean value)
Average tumor shrinkage (TV) increasing with NBTXR3 volume.Volume 2,5% average of tumor volume shrunk 18%
Volume 5% average of tumor volume shrunk 38%
Volume 10% average of tumor volume shrunk 32%
Volume 20% average of tumor volume shrunk 51%
All patients treated in the study had an enlarged tumorectomy
-40
-20
0
20
40
60
80
100
% S
hru
nk
Volume 2.5% Volume 5% Volume 10%
Average 18% Average 38% Average 32%
Volume 20%
Average 51%
Efficacy evaluation
Volume LevelNBTXR3
Patient NumberPathological Response
% viable cells
Average% viable cells
2.5%
1 07
39
2 563 07*4 90*5 286 45
5%
7 55
74
8 89*9 100
10 8011 20*12 99
10%
13 50
37
14 3015 10*16 2017 2120 90
20%18 0
0119 2
Recommended Volume
*Myxoid liposarcoma
Feasibility of the NBTXR3 injection within the tumor mass across different tumor types and volumes (from 55.06ml to 3682.56ml) is demonstrated
20% volume is considered not feasible owed to tissue expansion limitation
No leakage to the surrounding healthy tissues is confirmed
Persistence of NBTXR3 during all sessions of RTx with optimal bioavailability over time is demonstrated
Very good systemic tolerance and local safety of the product at volume 2,5%, 5%, 10% and 20% was observed
The recommended volume for further development is 10% of the tumor volume at baseline
Further development of NBTXR3 is warranted in this indication. A phase II/III trial is planned to start in the Q4 2014
NBTX3 Phase I CONCLUSION
