First-in-man Phase I study of the oral dual PI3K and mTORC1/2 inhibitor BEZ235 in patients with advanced solid tumors

1
First-in-man Phase I study of the oral dual PI3K
and mTORC1/2 inhibitor BEZ235 in patients with
advanced solid tumors

• Howard 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 dHebron 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
2
Disclosures
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
AG Novartis Pharma AG is the study sponsor
Study investigators
3
BEZ235 inhibits the PI3K signaling pathway
PI3K
BKM120
BEZ235
PIP3
PTEN
PDK1
Akt
TORC2
Tuberin
BEZ235
Rheb
TORC1
S6K
4EBP1
S6
4
BEZ235 Orally available potent dual inhibitor of
PI3K and mTORC1/2
N

• 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

O
N
N
N
N
Enzyme IC50 nM/L
Class I PI3K p110a 4.0 2
Class I PI3K P110a-H1047R 4.6 0.8
Class I PI3K P110a-E545K 5.7 1.0
Class I PI3K p110ß 75 45
Class I PI3K p110d 7 6
Class I PI3K p110? 5 4
mTOR mTOR 20.7
Panel of 18 other protein kinases Panel of 18 other protein kinases gt10,000
Maira et al. Mol Cancer Ther 20087185163 Serra
et al. Cancer Res 200868802230
5
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 Events ADA, American Diabetes Association
6
BEZ235 Phase I Study design
Single-agent dose-escalation Oral, once-daily
BEZ235 28-day cycle (N24)
MTD / safety expansion arm in patients with
alterations in PIK3CA/PTEN Oral, once-daily
BEZ235 28-day cycle
Declaration of MTDa
Fasted, mg/day
10
25
50
400
300
100
200
Fed, mg/day
300
400
1100
700
Combination with trastuzumab dose escalation arm
in patients with HER2 mBC with a PIK3CA
activating mutation

• 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

• Special safety assessments
• Fasting plasma glucose
• 2-hour plasma glucose during a 75 g fasting OGTT
• Hemoglobin A1C

aDefined as the drug dosage expected to cause a
medically unacceptable DLT in gt33 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
7
BEZ235 Phase I Patient characteristics
Characteristic N59
Median age, years (range) 55 (2981)
lt65 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 (018)
Patients with gt3 prior regimens 30 (51)
Primary tumor type N59
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 aOne patient each (1.7) kidney, adrenal, pleural, choroid, gallbladder, pararenal
Cut-off date March 2, 2009
8
BEZ235 Phase I Retrospective analysis of tumor
mutation status
N59 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 lt 40) 10 (20)
Protein level medium (H-score 40-90) 12 (24)
Protein level high (H-score gt90) 26 (51)
Tumors with PI3K pathway activation (any PIK3CA/PTEN alterations) 19 (37)
a Population enrichment was not employed. Samples
available for 51/ 59 patients, some analyses
incomplete due to sample quantity or
quality bSNaPshot genotyping, exons 9 and
20 cGenomic DNA sequencing of PTEN exons 1-9,
Semiquantitative IHC
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BEZ235 Phase I Dose escalation

• 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 gt7 consecutive days or
  febrile neutropenia
• Grade 3 thrombocytopenia for gt7 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

Schedule Dose (mg) Patients Exposure (wks) Exposure (wks)
Schedule Dose (mg) Patients gt4 gt12
Fasted 10 3 2 0
Fasted 25 6 6 3
Fasted 50 4 4 4
Fasted 100 6 5 1
Fasted 200 5 4 2
Fasted 300 6 5 0
Fasted 400 11 8 5
Fed 300 6 5 3
Fed 400 3 3 1
Fed 700 5 5 2
Fed 1100 4 1 1
All 59 48 (81) 21 (36)
aAs per ADA guidelines.
10
BEZ235 Phase I AEs in gt20 of patients,
regardless of causality
Fasting, dose in mg Fasting, dose in mg Fasting, dose in mg Fasting, dose in mg Fasting, dose in mg Fasting, dose in mg Fasting, dose in mg Fed, dose in mg Fed, dose in mg Fed, dose in mg Fed, dose in mg
10 n3 25 n6 50 n4 100 n6 200 n5 300 n6 400 n11 300 n6 400 n3 700 n5 1100 n4 All n59 n ()
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)

• AE incidence was similar in both schedules
• Gastrointestinal disorders 70
• General disorders 66
• Hematologic disorders 18

11
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

12
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 17 hrs
• Apparent t½ from 114.5 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

Individual AUC values
Day 28
Day 8
Day 1
Partial response, Max AUC0-24
Partial response, Min AUC0-24
13
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

Time (hours post dose)
Increase relative to 10-25 mg dose 50100 mg 40 increase 200400 mg 53 increase
Increase relative to Day 1 52 Day 8 56 Day 28
14
BEZ235 Phase I BEZ235 decreases tumor
phospho-S6 and Ki-67 levels
BEZ235 50 mg/dayCycle 1, Day 28
Baseline
Tumor tissue from a patient with esophageal
cancer with staining for P-S6
Decrease
P-S6 (H-score) 240 120 50
Ki-67 ( cells) 15 2 87
15
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

16
BEZ235 Phase I Clinical PR in a patient with ER
HER2 normal breast cancer

BL
C1D28
C2D28
CT
18FDG-PET
BEZ235 1100 mg/day
BL, Baseline C, Cycle D, Day
17
BEZ235 Phase I comparison of TTP for patients
with SD for 4 months
720
TTP at last prior therapy
660
TTP on BEZ235 treatment according to local review
A
600
540
A
480
A
420
Time (Days)
380
300
N
240
A
N
A
A
180
120
Fast 400 mg/d
Fed 300 mg/d
Fed 400 mg/d
Fast 25 mg/d
Fast 50 mg/d
Fed 100 mg/d
Fast 400 mg/d
Fast 400 mg/d
Fast 400 mg/d
Fast 50 mg/d
Fast 100 mg/d
60
UNK
0
1
2
3
4
5
6
7
8
9
10
11
Patientsa
aAs per data cutoff March 2009
A,Tumor PI3K pathway alteration (PIK3CA / PTEN
mutation, low/null PTEN expression) N, No
identified PI3K pathway alterations
TTP, time to progression UNK, unknown
18
BEZ235 Phase I reduction in tumor burden as per
CT
50
40
Colorectal
Esophageal
Breast
Colorectal
Ovarian
Melanoma
Breast
Breast
Lung
Breast
Breast
Breast
Breast
Neuroendocrine
Prostate
Breast
Breast
Mesothelioma
30
20
10
Best percent change from baseline in SLD
(measurable lesions)
0
10
20
30
Colorectal
Adrenal
Lung
Lung
Synovial sarcoma
Breast
Colorectal
Esophagus
Colorectal
Colorectal
Cholangiocarcinoma
Nasopharyngeal
Melanoma
Colorectal
Colorectal
Melanoma
Endometrial
40
50

• 18 out of 35 evaluable patients had tumor
  shrinkage as per central review

19
BEZ235 Phase I tumor metabolic response as per
18FDG-PETa
60
40
Breast
Breast
Cholangiocarcinoma
Mesothelioma
Colorectal
Lung
Colorectal
Breast
Renal
Esophageal
Breast
Pancreatic
Breast
Breast
Sarcoma
Breast
Lung
Melanoma
20
Percent change in sSUVmax Baseline C1D28
0
20
Colorectal
Melanoma
Colorectal
Colorectal
Colorectal
Breast
Colorectal
Colorectal
Colorectal
Ovarian
Colorectal
Adrenal
Breast
Lung
Endometrial
Breast
Lung
Colorectal
Breast
40
60

• 18 out of 37 patients demonstrated a detectable
  decrease in tumor 18FDG-uptake as per central
  review

aEnd of Cycle 1
C, Cycle D, Day
20
BEZ235 Phase I correlation between single-lesion
responses by CT and PET
10300 mg dose group 10 patients with comparable
lesions
4001100 mg dose group 8 patients with
comparable lesions
1.0
y0.1756x - 0.0563R20.0086
y1.3549x 0.0822R20.4474
0.8
0.6
No correlation
Significant correlation
0.4
change in sSUVmax
0.2
0
0.2
0.4
0.6
0.8
1.0
1.0
-0.5
0
0.5
1.0
change in SLD

• Correlation between CT and PET responses at 400
  mg/day BEZ235 suggests clinically active exposure
  levels have been achieved

21
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 4001100 mg/day
• Dose-dependent effects on plasma C-peptide
• Decrease in tumor phospho-S6
• Correlation between CT and PET response

22
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

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Acknowledgments

• Patients and their families

• BEZ235 Clinical Study Team
• Sponsor-Novartis

Nevada Cancer Institute
Sarah Cannon Research Institute Johanna
Bendell Suzanne Jones
MD Anderson Cancer Center Faye Johnson George
Blumenschein Justina Price
Vall dHebron University Hospital Francesco
Atzori Gemma Sala Javier Cortes
Virtual Scopics S Mahmood
24
Back-up slides
25
BEZ235 Phase I Patient disposition
Status N59
Status 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.
26
BEZ235 Phase I comparison of TTP for patients
with SD for 4 months
720
PIK3CA wild-type (WT), mutant (MUT)PTEN high,
medium, low PTEN wild-type (WT), mutant (MUT)
660
WTMedium MUT
600
MUTLowWT
540
MUTMediumMUT
480
420
Time (Days)
380
WTHighWT
300
WT WT
WTHighWT
MUTLowWT
WTHighMUT
240
MediumMUT
Medium
180
120
Fast 400 mg/d
Fast 400 mg/d
Fast 400 mg/d
Fast 400 mg/d
Fed 300 mg/d
Fed 400 mg/d
Fast 25 mg/d
Fast 50 mg/d
Fast 50 mg/d
Fast 100 mg/d
Fed 100 mg/d
60
UNK
0
1
2
3
4
5
6
7
8
9
10
11
Patientsa
TTP at last prior therapy
TTP on BEZ235 treatment according to local review
aAs per data cutoff March 2009
TTP, time to progression UNK, unknown