abstract #3005
DESCRIPTION
First-in-man Phase I study of the oral dual PI3K and mTORC1/2 inhibitor BEZ235 in patients with advanced solid tumors. Howard Burris 1 , Jordi Rodon 2 , Sunil Sharma 3 , Roy Herbst 4 , Josep Tabernero 2 , Jeffrey Infante 1 , Antonio Silva 5 , David Demanse 5 , Wolfgang Hackl 5 , Jose Baselga 2 - PowerPoint PPT PresentationTRANSCRIPT
First-in-man Phase I study of the oral dual PI3K and mTORC1/2 inhibitor BEZ235 in patients with advanced solid tumorsHoward Burris1, Jordi Rodon2, Sunil Sharma3, Roy Herbst4, Josep Tabernero2, Jeffrey Infante1, Antonio Silva5, David Demanse5, Wolfgang Hackl5, Jose Baselga2
1Sarah Cannon Research Institute, Nashville, Tennessee, USA; 2Vall d’Hebron University Hospital, Barcelona, Spain; 3Nevada Cancer Institute, Las Vegas, Nevada, USA; 4The University of Texas, MD Anderson Cancer Center, Houston, Texas, USA; 5Novartis Pharma AG, Basel, Switzerland
Abstract #3005
Howard Burris Jordi Rodon Sunil Sharma Roy Herbst Josep Tabernero Jeffrey Infante Jose Baselga
Antonio Silva, David Demanse, and Wolfgang Hackl
are employees of Novartis Pharma AGNovartis Pharma AG is the study sponsor
Disclosures
Study investigators
4EBP14EBP1
PI3K
TORC1TORC1
S6KS6K
Rheb Rheb
S6S6
PIP3PIP3
Tuberin
PTEN
TORC2TORC2 Akt PDK1PDK1
BKM120
BEZ235
BEZ235
BEZ235 inhibits the PI3K signaling pathway
BEZ235: Orally available potent dual inhibitor of PI3K and mTORC1/2
• Potent, specific, oral PI3K and mTORC1/2 inhibitor
• Broad antiproliferative effect across different tumor types
• Pro-apoptotic effect in PI3K-pathway activated tumor models
• Antiangiogenic
Maira et al. Mol Cancer Ther 2008;7:1851–63Serra et al. Cancer Res 2008;68:8022–30
Enzyme IC50 nM/L
Class I PI3K
p110α 4.0 ± 2
P110α-H1047R 4.6 ± 0.8
P110α-E545K 5.7 ± 1.0
p110β 75 ± 45
p110δ 7 ± 6
p110γ 5 ± 4
mTOR 20.7
Panel of 18 other protein kinases >10,000
N
N
N
N
N
O
BEZ235 Phase I: Study objectives• Primary
– MTD of oral BEZ235 administered on a once-daily continuous schedule
• Secondary– Safety and tolerability of BEZ235
• AEs per NCI-CTCAE v3.0, hyperglycemia per ADA guidelines (fasting plasma glucose ≥7.0 mmol/L)
– Pharmacokinetic profile • Days 1, 8, and 28 in Cycle 1
– Biomarker and pharmacodynamic assessments• PIK3CA (mutation) and PTEN (mutation and protein expression) status in
archival tumor samples• Fasting plasma C-peptide levels• Phospho-S6 and Ki-67 levels from pre- and on-treatment biopsies • 18FDG-PET for metabolic anti-tumor activity
– Overall response as per RECIST
NCI-CTCAE, NCI-Common Terminology Criteria for Adverse EventsADA, American Diabetes Association
BEZ235 Phase I: Study design
aDefined as the drug dosage expected to cause a medically unacceptable DLT in >33% of patients during the first treatment cycle; for declaration of MTD, ≥6 patients will have to be treated at this dose level for one treatment cycle OGTT, oral glucose tolerance test
Declaration of MTDa
• Key exclusion criteria:− Treatment with corticosteroids ≤2
weeks before starting study drug− Diabetes mellitus or history of
gestational diabetes− Prior treatment with a PI3K inhibitor
10 25 50 100
200
400
300
300
400
1100
700
Fasted, mg/day
Fed, mg/dayCombination with trastuzumab dose escalation
arm in patients with HER2+ mBC with a PIK3CA activating mutation
Single-agent dose-escalation Oral, once-daily BEZ235
28-day cycle (N≥24) MTD / safety expansion arm in patients with alterations
in PIK3CA/PTENOral, once-daily BEZ235
28-day cycle
• Special safety assessments:− Fasting plasma glucose− 2-hour plasma glucose during a 75 g
fasting OGTT− Hemoglobin A1C
BEZ235 Phase I: Patient characteristics
Characteristic N=59
Median age, years (range)
55 (29–81)
<65 years (%) 47 (80%)
Male / Female 20 (34%) / 39 (66%)
WHO PS, 0/1 29 (49%) / 30 (51%)
Prior antineoplastic therapy
56 (95%)
Median number of regimens (range)
3 (0–18)
Patients with >3 prior regimens
30 (51%)
Primary tumor type N=59
Colorectal 14 (24%)
Breast 13 (22%)
Lung 5 (9%)
Ovarian 4 (7%)
Skin melanoma 4 (7%)
Soft tissue sarcoma 3 (5%)
Prostate 2 (3%)
Endometrial 2 (3%)
Esophageal 2 (3%)
Pancreatic 2 (3%)
Head and neck 2 (3%)
Othera 6 (10%)aOne patient each (1.7%): kidney, adrenal, pleural, choroid, gallbladder, pararenal
Cut-off date March 2, 2009
BEZ235 Phase I: Retrospective analysis of tumor mutation status
a Population enrichment was not employed. Samples available for 51/ 59 patients, some analyses incomplete due to sample quantity or qualitybSNaPshot genotyping, exons 9 and 20cGenomic DNA sequencing of PTEN exons 1-9, Semiquantitative IHC
N=59 n
Tumor samplesa 51 (86%)
Evaluable for PIK3CA Statusb 48
Wild-type 43 (90%)
Mutation 5 (10%)
Evaluable for PTEN Statusc 51
Wild-type 39 (76%)
Mutated 7 (14%)
Protein level low (H-score < 40) 10 (20%)
Protein level medium (H-score 40-90) 12 (24%)
Protein level high (H-score >90) 26 (51%)
Tumors with PI3K pathway activation (any PIK3CA/PTEN alterations)
19 (37%)
BEZ235 Phase I: Dose escalation
ScheduleDose (mg)
Patients Exposure (wks)
>4 >12
Fasted
10 3 2 0
25 6 6 3
50 4 4 4
100 6 5 1
200 5 4 2
300 6 5 0
400 11 8 5
Fed
300 6 5 3
400 3 3 1
700 5 5 2 1100 4 1 1
All 59 48 (81%) 21 (36%)
• No DLTs observed in Cycle 1• Median duration of treatment was 8 weeks
– No relationship observed between treatment duration and dose or administration schedule
DLT definition• Hematologic AEs
−≥Grade 3 neutropenia for >7 consecutive days or febrile neutropenia
−Grade 3 thrombocytopenia for >7 consecutive days or Grade 4 thrombocytopenia
• Non-hematologic AEs− ≥Grade 3 toxicity − Grade 2 hyperglycemia that
cannot be resolved to Grade 0 in ≤14 consecutive daysa
− ≥Grade 2 pancreatitis
aAs per ADA guidelines.
BEZ235 Phase I: AEs in >20% of patients, regardless of causality
• AE incidence was similar in both schedules– Gastrointestinal disorders: 70%– General disorders: 66%– Hematologic disorders: 18%
Fasting, dose in mg Fed, dose in mg
10 n=3
25 n=6
50 n=4
100 n=6
200 n=5
300 n=6
400 n=11
300 n=6
400 n=3
700 n=5
1100 n=4
All n=59n (%)
Total events 3 6 2 6 5 5 11 6 3 5 4 56 (95)
Fatigue/Asthenia
2 1 2 4 3 5 2 3 3 25 (42)
Diarrhea 1 2 3 4 2 4 1 4 2 23 (39)
Nausea 1 2 2 2 3 3 1 2 3 1 20 (34)
Vomiting 1 1 1 2 1 1 3 2 4 1 17 (29)
Anemia 2 2 1 3 1 1 1 1 12 (20)
BEZ235 Phase I: most common AEs suspected to be related to study drug
Preferred Ter m, n (%) Grade 1 Grade 2 Grade 3 Grade 4 Total
Total events 16 (27) 21 (36) 4 (7) – 41(70)
Fatigue / Asthenia 8 (14) 4 (7) 2 (3) – 14 (24)
Diarrhea 13 (22) 1 (2) 1 (2) – 15 (25)
Nausea 9 (15) 3 (5) – – 12 (20)
Vomiting 6 (10) 4 (7) – – 10 (17)
Anemia 1 (2) 3 (5) – – 4 (7)
Abdominal pain 2 (3) – – – 2 (3)
Anorexia 3 (5) 2 (3) – – 5 (9)
• No drug-related SAEs or treatment-related deaths
• No treatment-related disturbances of glucose homeostasis, vital signs, or cardiac function
BEZ235 Phase I: clinical pharmacokinetics
• Non-proportional increase in systemic exposure and Cmax across all doses– High intra- and inter-patient
variability
• Apparent median Tmax 1–7 hrs
• Apparent t½ from 1–14.5 hrs
• No significant food effect on systemic exposure
• Plasma exposure for most patients treated at ≥400 mg/day BEZ235 was within range of steady state exposures in patients with radiologic response Partial response, Max AUC0-24
Partial response, Min AUC0-24
Day 28Day 8Day 1
Dose (mg)B
EZ
235
exp
osu
re (
AU
C0
-24 -
ng
.h/m
L)
10 50 100 500 1000
1
10
100
1000
10000
Individual AUC values
Time (hours post dose)
BEZ235 Phase I: Dose-dependent increases in plasma C-peptide with BEZ235• Dose-dependent increases in plasma C-peptide indicate
pharmacodynamic activity at Day 8 that is sustained at Day 28
Increase relative to 10-25 mg dose
50–100 mg
40% increase
200–400 mg
53% increase
Increase relative to Day 1 52% Day 8 56% Day 28
0
5
10
15
20
25
30
0 1 2 3 4
10–25 mgNumber of patients = 9
0 1 2 3 4
50–100 mg Number of patients = 8
0 1 2 3 4
200–400 mg Number of patients = 28
C-p
eptid
e (n
g/m
l)
Observations at Day 1Observations at Day 8Observations at Day 28
BEZ235 Phase I: BEZ235 decreases tumor phospho-S6 and Ki-67 levels
% Decrease
P-S6 (H-score) 240 120 50%
Ki-67 (% cells+) 15 2 87%
Tumor tissue from a patient with esophageal cancer with staining for P-S6
Baseline BEZ235 50 mg/dayCycle 1, Day 28
BEZ235 Phase I: Clinical activity
• 51 patients were evaluable for response– 2 patients with partial responses
• ER+ HER2 normal breast cancer, unknown PI3K pathway status (1100 mg/day, response duration 9+ months)
• Lung cancer, Cowden syndrome (700 mg/day, response duration 8 months on BEZ235, 10+ months off BEZ235)
– 14 patients (27%) with stable disease for ≥4 months
• 4 patients (29%) had breast cancer• 6 patients (43%) had tumors with alterations in the PI3K
pathway
CT
18F
DG
-PE
T
BL C1D28 C2D28
BEZ235 Phase I: Clinical PR in a patient with ER+ HER2 normal breast cancer
BEZ235 1100 mg/day
BL, Baseline; C, Cycle; D, Day
1 2
540
Tim
e (D
ays
)
0
60
120
180
240
300
380
420
480
600
660
720
3 4 5 6 7 8 9 10 11
TTP at last prior therapy
TTP on BEZ235 treatment according to local review
A,Tumor PI3K pathway alteration (PIK3CA / PTEN mutation, low/null PTEN expression); N, No identified PI3K pathway alterations
Fas
t 40
0 m
g/d
Fas
t 40
0 m
g/d
Fas
t 40
0 m
g/d
Fed
300
mg
/d
Fed
400
mg
/d
Fas
t 25
mg
/d
Fas
t 50
mg
/d
Fas
t 50
mg
/d
Fas
t 10
0 m
g/d
Fed
100
mg
/d
UNK
Patientsa aAs per data cutoff March 2009
Fas
t 40
0 m
g/d
TTP, time to progression; UNK, unknown
A
A
AA
A
A
NN
BEZ235 Phase I: comparison of TTP for patients with SD for ≥4 months
Eso
phag
eal
Col
orec
tal
Adr
enal
Lung
Lung
Col
orec
tal
Bre
ast
Col
orec
tal
Ova
rian
Mel
anom
a
Bre
ast
Bre
ast
Syn
ovia
l sar
com
a
40
20
0
–20
–40
Bes
t p
erce
nt
chan
ge
fro
m b
asel
ine
in S
LD
(m
easu
rab
le le
sio
ns)
Bre
ast
Col
orec
tal
Eso
phag
us
Col
orec
tal
Col
orec
tal
Cho
lang
ioca
rcin
oma
Nas
opha
ryng
eal
Mel
anom
a
Col
orec
tal
Col
orec
tal
Mel
anom
a
End
omet
rial
Lung
–50
–30
–10
10
30
50
Bre
ast
Bre
ast
Bre
ast
Bre
ast
Neu
roen
docr
ine
Pro
stat
e
Bre
ast
Bre
ast
Mes
othe
liom
a
BEZ235 Phase I: reduction in tumor burden as per CT
• 18 out of 35 evaluable patients had tumor shrinkage as per central review
Col
orec
tal
60
40
20
0
–20
–40
–60
BEZ235 Phase I: tumor metabolic response as per 18FDG-PETa
Per
cen
t ch
ang
e in
sS
UV
max
B
asel
ine
– C
1D28
Mel
anom
aC
olor
ecta
l
Col
orec
tal
Col
orec
tal
Bre
ast
Col
orec
tal
Col
orec
tal
Col
orec
tal
Ova
rian
Col
orec
tal
Adr
enal
Bre
ast
Lung
End
omet
rial
Bre
ast
Lung
Col
orec
tal
Bre
ast
Bre
ast
Bre
ast
Cho
lang
ioca
rcin
oma
Mes
othe
liom
aC
olor
ecta
lLu
ng
Col
orec
tal
Bre
ast
Ren
alE
soph
agea
lB
reas
t
Pan
crea
ticB
reas
tB
reas
tS
arco
ma
Bre
ast
Lung
Mel
anom
a
• 18 out of 37 patients demonstrated a detectable decrease in tumor 18FDG-uptake as per central review
C, Cycle; D, Day
aEnd of Cycle 1
BEZ235 Phase I: correlation between single-lesion responses by CT and PET
• Correlation between CT and PET responses at ≥400 mg/day BEZ235 suggests clinically active exposure levels have been achieved
% change in SLD
% c
han
ge
in s
SU
Vm
ax
10–300 mg dose group 10 patients with comparable lesions
400–1100 mg dose group 8 patients with comparable lesions
y=1.3549x + 0.0822R2=0.4474
y=0.1756x - 0.0563R2=0.0086
–1.0–1.0 -0.5 0 0.5 1.0
–0.8
–0.6
–0.4
–0.2
0
0.2
0.4
0.6
0.8
1.0
No correlation Significant correlation
–1.0
–0.8
–0.6
–0.4
–0.2
0.2
0.4
0.6
0.8
1.0
0
–1.0 –0.8 –0.6 –0.4 –0.2 0 0.2 0.4 0.6 0.8 1.0
BEZ235 Phase I: summary• No DLTs were observed: MTD not identified• SAEs were not reported with BEZ235 treatment• Rapid absorption and highly variable systemic exposure • Evidence of single-agent activity in patients with heavily
pretreated advanced cancer – 2 PRs, 16 cases of tumor shrinkage, 14 SD of ≥4 months
– Activity in patients with and without PI3K pathway alterations
• Pharmacologically active exposure levels reached at doses of BEZ235 400–1100 mg/day – Dose-dependent effects on plasma C-peptide
– Decrease in tumor phospho-S6
– Correlation between CT and PET response
BEZ235 Phase I: conclusions
• BEZ235 is a potent inhibitor of the PI3K pathway
• BEZ235 has a favorable safety profile
• BEZ235 demonstrates clinical activity in patients, including those with alterations in the PI3K pathway
• Ongoing studies include:– A new formulation of BEZ235 with improved bioavailability and
PK properties– Combination treatment with HER2 or MEK-targeted therapies
Acknowledgments• Patients and their families • BEZ235 Clinical Study Team
• Sponsor-Novartis
Sarah Cannon Research InstituteJohanna BendellSuzanne Jones
Nevada Cancer Institute
Vall d’Hebron University HospitalFrancesco Atzori
Gemma SalaJavier Cortes
Virtual ScopicsS Mahmood
MD Anderson Cancer CenterFaye Johnson
George BlumenscheinJustina Price
Back-up slides
BEZ235 Phase I: Patient disposition
Status* N=59
n (%)
On treatment 5 (9%)
Discontinued due to disease progression 46 (78%)
Discontinued due to AE 6 (10%)
Discontinued at the discretion of the treating physician
1 (2%)
Withdrew consent 1 (2%)
*Cut-off date March 2, 2009.
1 2
540
Tim
e (D
ays
)
0
60
120
180
240
300
380
420
480
600
660
720
3 4 5 6 7 8 9 10 11
TTP at last prior therapy
TTP on BEZ235 treatment according to local review
PIK3CA: wild-type (WT), mutant (MUT)PTEN: high, medium, lowPTEN: wild-type (WT), mutant (MUT)
WTHighMUT
MUTMediumMUT
MediumMUT Medium
WTHighWT
WT
WT MUTLowWT
MUTLowWT
WTMediumMUT
WTHighWT
Fas
t 40
0 m
g/d
Fas
t 40
0 m
g/d
Fas
t 40
0 m
g/d
Fed
300
mg
/d
Fed
400
mg
/d
Fas
t 25
mg
/d
Fas
t 50
mg
/d
Fas
t 50
mg
/d
Fas
t 10
0 m
g/d
Fed
100
mg
/d
UNK
BEZ235 Phase I: comparison of TTP for patients with SD for ≥4 months
Patientsa
Fas
t 40
0 m
g/d
aAs per data cutoff March 2009TTP, time to progression; UNK, unknown