Transcript First-in-man Phase I study of the oral PI3K inhibitor

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
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
1Sarah
Abstract #3005
Disclosures
Howard Burris
Jordi Rodon
Sunil Sharma
Roy Herbst
Josep Tabernero
Jeffrey Infante
Jose Baselga
Study investigators
Antonio Silva, David Demanse, and Wolfgang Hackl
are employees of Novartis Pharma AG
Novartis Pharma AG is the study sponsor
BEZ235 inhibits the PI3K signaling
pathway
BEZ235
PI3K
PTEN
TORC2
PIP3
Akt
PDK1
Tuberin
BEZ235
Rheb
TORC1
S6K
S6
4EBP1
BKM120
BEZ235: Orally available potent dual
inhibitor of PI3K and mTORC1/2
N
• Potent, specific, oral PI3K and
mTORC1/2 inhibitor
O
N
N
N
• Broad antiproliferative effect
across different tumor types
N
• Pro-apoptotic effect in PI3Kpathway activated tumor
models
• Antiangiogenic
Class I PI3K
Enzyme
IC50 nM/L
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
Panel of 18 other protein kinases
20.7
>10,000
Maira et al. Mol Cancer Ther 2008;7:1851–63
Serra et al. Cancer Res 2008;68:8022–30
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
BEZ235 Phase I: Study design
Single-agent dose-escalation
Oral, once-daily BEZ235
28-day cycle (N≥24)
Declaration
of MTDa
Fasted, mg/day
Fed, mg/day
MTD / safety expansion arm
in patients with alterations
in PIK3CA/PTEN
Oral, once-daily BEZ235
28-day cycle
Combination with trastuzumab dose escalation
arm in patients with HER2+ mBC with a PIK3CA
activating mutation
• Special safety assessments:
• 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
aDefined
− Fasting plasma glucose
− 2-hour plasma glucose during a 75 g
fasting OGTT
− Hemoglobin A1C
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
BEZ235 Phase I: Patient characteristics
Characteristic
Median age, years
(range)
<65 years (%)
N=59
55 (29–81)
47 (80%)
Primary tumor type
N=59
Colorectal
14 (24%)
Breast
13 (22%)
Lung
5 (9%)
Male / Female
20 (34%) / 39 (66%)
Ovarian
4 (7%)
WHO PS, 0/1
29 (49%) / 30 (51%)
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%)
Prior antineoplastic
therapy
56 (95%)
Median number of
regimens (range)
3 (0–18)
Patients with
>3 prior regimens
30 (51%)
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
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)
a Population
19 (37%)
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
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 >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
Schedule
Fasted
Fed
Exposure (wks)
>4
>12
Dose
(mg)
Patients
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
300
6
5
3
400
3
3
1
700
1100
All
5
4
59
5
2
1
1
48 (81%) 21 (36%)
aAs
per ADA guidelines.
BEZ235 Phase I: AEs in >20% of patients,
regardless of causality
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=59
n (%)
3
6
2
6
5
5
11
6
3
5
4
56 (95)
Fatigue/
Asthenia
2
1
2
4
3
5
2
3
3
Diarrhea
1
2
3
4
2
4
1
4
2
23 (39)
2
2
2
3
3
1
2
3
1
20 (34)
1
2
1
1
3
2
4
1
17 (29)
1
3
1
12 (20)
Total events
Nausea
1
Vomiting
1
1
Anemia
2
2
•
1
1
1
25 (42)
AE incidence was similar in both schedules
– Gastrointestinal disorders: 70%
– General disorders: 66%
– Hematologic disorders: 18%
BEZ235 Phase I: most common AEs
suspected to be related to study drug
Preferred Term, 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
– High intra- and inter-patient
variability
10000
BEZ235 exposure
(AUC0-24 - ng.h/mL)
• Non-proportional increase in
systemic exposure and Cmax
across all doses
• 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
1000
100
10
1
10
50
100
500 1000
Dose (mg)
Individual AUC values
Day 1
Day 8
Day 28
Partial response, Max AUC0-24
Partial response, Min AUC0-24
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
50–100 mg
Number of patients = 8
10–25 mg
Number of patients = 9
30
200–400 mg
Number of patients = 28
C-peptide (ng/ml)
25
20
15
10
Observations at Day 1
Observations at Day 8
Observations at Day 28
5
0
0
1
2
3
4
0
1
2
3
4
0
1
2
3
4
Time (hours post dose)
Increase relative to 10-25 mg
dose
Increase relative to Day 1
50–100 mg
40% increase
200–400 mg
53% increase
52% Day 8
56% Day 28
BEZ235 Phase I: BEZ235 decreases
tumor phospho-S6 and Ki-67 levels
BEZ235 50 mg/day
Cycle 1, Day 28
Baseline
Tumor tissue from a patient with esophageal cancer with staining for P-S6
P-S6 (H-score)
Ki-67 (% cells+)
240
15
120
2
% Decrease
50%
87%
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
BEZ235 Phase I: Clinical PR in a patient
with ER+ HER2 normal breast cancer
C1D28
C2D28
18FDG-PET
CT
BL
BEZ235 1100 mg/day
BL, Baseline; C, Cycle; D, Day
BEZ235 Phase I: comparison of TTP for
patients with SD for ≥4 months
720
TTP at last prior therapy
TTP on BEZ235 treatment
according to local review
660
600
A
540
A
A
420
380
300
1
2
3
4
5
6
Patientsa
7
8
aAs
Fast 100 mg/d
Fast 50 mg/d
UNK
Fast 50 mg/d
Fast 25 mg/d
Fed 400 mg/d
Fast 400 mg/d
0
Fast 400 mg/d
60
Fast 400 mg/d
120
N
A
9
10
Fed 100 mg/d
A
A
180
N
Fed 300 mg/d
240
Fast 400 mg/d
Time (Days)
480
11
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
Best percent change from baseline
in SLD (measurable lesions)
–10
–20
–30
–40
Colorectal
Esophagus
Adrenal
Breast
Lung
Melanoma
Endometrial
Colorectal
Lung
Melanoma
Colorectal
Colorectal
Colorectal
Colorectal
Cholangiocarcinoma
Nasopharyngeal
–50
Synovial sarcoma
30
20
10
40
0
• 18 out of 35 evaluable patients had tumor shrinkage as per central
review
Breast
Lung
Melanoma
Breast
Neuroendocrine
Breast
Breast
Breast
Breast
Prostate
Breast
Ovarian
Esophageal
Breast
Mesothelioma
Colorectal
Colorectal
Breast
BEZ235 Phase I: reduction in tumor
burden as per CT
50
Percent change in sSUVmax
Baseline – C1D28
–20
–40
Colorectal
Melanoma
Colorectal
Colorectal
Colorectal
Breast
Colorectal
Colorectal
Colorectal
Ovarian
Colorectal
Adrenal
Breast
Lung
Endometrial
Breast
Lung
Colorectal
Breast
60
40
20
Pancreatic
Breast
Breast
Sarcoma
Breast
Lung
Melanoma
Colorectal
Breast
Renal
Esophageal
Breast
Mesothelioma
Colorectal
Lung
Breast
Breast
Cholangiocarcinoma
BEZ235 Phase I: tumor metabolic
response as per 18FDG-PETa
0
–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
BEZ235 Phase I: correlation between
single-lesion responses by CT and PET
10–300 mg dose group
10 patients with comparable lesions
1.0
1.0
y=0.1756x - 0.0563
R2=0.0086
0.8
% change in sSUVmax
400–1100 mg dose group
8 patients with comparable lesions
0.6
No correlation
0.4
y=1.3549x + 0.0822
R2=0.4474
0.8
0.6
0.4
Significant correlation
0.2
0.2
0
0
–0.2
–0.2
–0.4
–0.4
–0.6
–0.6
–0.8
–0.8
–1.0
–1.0
–1.0
–1.0 –0.8 –0.6 –0.4 –0.2
-0.5
0
0.5
1.0
0
0.2 0.4 0.6 0.8 1.0
% change in SLD
• Correlation between CT and PET responses
at ≥400 mg/day BEZ235 suggests clinically
active exposure levels have been achieved
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 Institute
Johanna Bendell
Suzanne Jones
Nevada Cancer Institute
Vall d’Hebron University Hospital
Francesco Atzori
Gemma Sala
Javier Cortes
MD Anderson Cancer Center
Faye Johnson
George Blumenschein
Justina Price
Virtual Scopics
S Mahmood
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.
BEZ235 Phase I: comparison of TTP for
patients with SD for ≥4 months
720
660
600
PIK3CA: wild-type (WT), mutant (MUT)
PTEN: high, medium, low
PTEN: wild-type (WT), mutant (MUT)
WT
Medium
MUT
MUT
Low
WT
540
MUT
Medium
MUT
420
380
1
2
3
4
5
6
7
8
Patientsa
TTP, time to progression; UNK, unknown
9
10
Fed 100 mg/d
Fast 100 mg/d
UNK
Fast 50 mg/d
Fast 25 mg/d
Fed 400 mg/d
0
Fast 400 mg/d
60
Fast 400 mg/d
120
WT
High
WT
MUT
Low
WT
WT
Medium
Fast 400 mg/d
180
Medium
MUT
Fed 300 mg/d
WT
High
MUT
240
WT
Fast 50 mg/d
WT
High
WT
300
Fast 400 mg/d
Time (Days)
480
11
TTP at last prior therapy
TTP on BEZ235 treatment
according to local review
aAs
per data cutoff March 2009