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Andrew J. Wagner1, Johanna C. Bendell2, Jeffrey A. Morgan1, James Butrynski1, Suzanne George1, George D. Demetri1, Jill Fredrickson3, Jill Spoerke3, Doris Apt3, Jennifer Lauchle3, Gordon Jayson4, Johann S. de Bono5, Howard A. Burris2, Jean-Charles Soria6
1Dana-Farber Cancer Institute, Boston, MA, USA2Sarah Cannon Research Institute, Nashville, TN, USA3Exploratory Clinical Development, Genentech Inc., South San Francisco, CA, USA4The Christie NHS Foundation Trust, Manchester, UK5Royal Marsden Hospital and Institute of Cancer Research, Sutton, UK6Institut de Cancerologie Gustave Roussy, Villejuif, France
Tolerability and anti-tumor activity of the PI3K/mTOR inhibitor GDC-0980
in patients with GIST and other sarcomas on two Phase I studies
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2
GDC-0980, a Potent PI3K/mTOR Inhibitor
The PI3K-PTEN-AKT-mTOR signaling pathway is dysregulated in multiple cancers
Multiple mechanisms in GIST and other sarcomas
– Activation of RTKs, RAS, PI3K– Loss of PTEN, NF1, TSC1/2
Kinase Isoform IC50
p110α 4.8 nM
p110β 26.8 nM
p110γ 13.8 nM
p110δ 6.7 nM
mTOR Ki 17.3 nM
GDC-0980 is a potent, selective, oral inhibitor of Class I PI3 and mTOR kinases
Anti-tumor activity demonstrated in several cancer xenograft models
Wallin JJ, et al. Mol Cancer Ther. 2011; 10:2426-36
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3
Study Design QD Dosing Schedule
Screening
D1
Cycle 1: DLT Assessment (D1-35) Cycle 2
D8 D28 D36D15
FDG-PET
D22 D50
PK PK
D64D56
TumorAssess.
TumorAssess.
PIK3CA, PTEN status
FDG-PET
Tumor
Assessment
Study Objectives: Safety, PK, PD, Anti-tumor activity
Tumor Type Patients (n=115)
GDC-0980 Dose - Schedule
Escalation: All Tumor TypesExpansion: All Tumor Types
5659
2 to 70 mg - QD 21d and 28d30 mg and 40 mg - QD 28d (RP2D)
Sarcoma 11 2 to 40 mg - QD 21d and 28d•5 pts at RP2D
GIST 11 2 to 70 mg - QD 21d and 28d•4 pts at RP2DAssessments
FDG-PET
4
4
Study Design QW Dosing Schedule
Assessments
Study Objectives: Safety, PK, PD, Anti-tumor activity
D-28 D29D22D15D8D1 D43D36 D50 D57
2 x DCE-MRIBiopsyFDG-PETTumor Assessment
DCE-MRI
Biopsy FDG-PET
Tumor Assessment Tumor Assess.FDG-PET
Screening Cycle 1: DLT Assessment Cycle 2
Tumor Type Patients GDC-0980 Dose
All Tumor Types 38 6 to 200 mg
Sarcoma 7 4 pts at 25 to100 mg 3 pts at 150 mg
GIST 6 2 pts at 6 mg4 pts at 150 or 200 mg
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5
Safety and Tolerability QD Schedule
Schedule Dose (mg)
DLTs (n)
DLTs / significant SAEs
21d 2 0/3 -
4 0/3 -
8 0/3 -
16 0/3 -
32 0/7 -
50 0/6 G5 colitis (n=1)
70 2/8 G3 RashG4 HyperglycemiaG3 sympt. Hyperglyc.G2, G3 pneumonitis (1 each)
40 0/4 -
28d 40 0/14 G3, G5 pneumonitis (1 each)
50 0/5 -
Dose Escalation Expansion RP2DDrug-related Grade > 3 AEs
40 mg (n=50) Stg. 1 and 2
Any AE 26 (52%)
Hyperglycemia 9 (18%)
Rash 4 (8%)
Diarrhea 5 (10%)
Fatigue 2 (4%)
Abnormal LFTs 4 (8%)
Pneumonia *^ 4*^ (8%)
Pneumonitis ^ 4^ (8%)
Mucosal inflammation 3 (6%)
Colitis 0 (0%)
Nausea 1 (2%)
Stomatitis 2 (4%)
• incl. 2 pts with Pneumonocystis jiroveci Pneumonia • ^ Gr 5 AEs: Pneumonitis, Pneumonitis/Pneumonia, Pneumonocystis jiroveci Pneumonia (1 pt each)
Additional Gr ≥3 AEs observed at 40 mg QD in 1 patient each: Alopecia, asthenia, dehydration, dry skin, hyperbilirubinaemia, hypoxia, leucocytoclastic vasculitis, lymphopenia, vomiting
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Safety and Tolerability QW Schedule
DLT Assessment
Dose (mg)
DLTs (n)
DLTs
6 0/6 -
12 0/5 -
25 0/3 -
50 0/4 -
100 0/3 -
150 1/11 G3 Hyperglycemia*
200 1/6 G3 Hyperglycemia*
Drug-related Grade > 3 AEs
150 mg(n=11)
200 mg(n=6)
Hyperglycemia 4 (36.4) 6* (100%)
Dysgeusia 1 (9.1%) -
No Grade ≥3 AE at doses of 6 – 100 mg QW
Adverse Events
* Includes one event of symptomatic Grade 4 hyperglycemia
* defined as a repeated episode of fasting G3 HG that occurred after initiation of oral anti-hyperglycemic therapy
7
7PK Profile and PI3K Pathway InhibitionQD Schedule
# PIK3CA mutant
• Dose-proportional increases in AUC and Cmax, half-life of 6-18 hours
• Decreases in pAKT in PRP of ≥ 90% observed at GDC-0980 doses ≥ 16 mg
• FDG-PET pathway inhibition observed in ~50% pts at RP2D (30 mg, 40 mg)
PK Profile
pAKT in platelet-rich plasma
Best overall FDG-PET response40 mg Cohort
#
# ##
## #
#
PR # # #
#
% M
ean
Ch
ange
SU
Vm
ax
8
8PK Profile and PI3K Pathway InhibitionQW Schedule
Dose-proportional increases in AUC and Cmax, half-life of 8-15 hours
PK Profile PD on Pre-Postdose Biopsies
Robust pathway modulation for both PI3K and mTOR downstream readouts
pS
6 H
-Sco
re
Pa
tho
log
y S
core
Pa
tho
log
y S
core
12 m
g25
mg
50 m
g
pS6 pPRAS40pAKT
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9
Time on Study Sarcoma Patients
QD Schedule
QW Schedule
PEComa
Chondrosarcoma
Metastatic Diffuse-Type Giant Cell Tumor (PVNS)
Soft Tissue Sarcoma
Extraskeletal Myxoid Chondrosarcoma
Leiomyosarcoma
Soft Tissue Sarcoma
Leiomyosarcoma
Angiosarcoma
Myxofibrosarcoma
Alveolar Rhabdomyosarcoma
Solitary Fibrous Tumor
Solitary Fibrous Tumor
Bone Sarcoma
Synovial Sarcoma
Chondrosarcoma
Epithelioid Sarcoma
Leiomyosarcoma
Median ToS2.6m
(1.0-18.1m)
Median ToS 2.9 m
(1.0-11.2m)
PTEN loss
PTEN loss
PTEN loss
PTEN loss
10
10
Tumor Response Sarcoma Patients
QD Schedule QW Schedule
PT
EN
loss
PT
EN
loss
PT
EN
loss
PT
EN
loss
11
11
Time on Study GIST Patients
QD Schedule
QW Schedule
Median ToS 3.5 m
(1.0-9.9m)
Median ToS 1.4 (0.1-13.9)
SDH-deficient
PDGFRA mutant
Exon 9 mutant
12
12
Tumor Response GIST Patients
QD Schedule QW Schedule
13
13Conclusions: Dual PI3K/mTOR Inhibitor GDC-0980
Safety and Tolerability– Generally well tolerated with manageable toxicities on QD and QW
schedule PK/PD
– Favorable PK profile
– Evidence of target modulation at or below recommended Phase II
doses
Activity– Prolonged disease control observed for rare sarcoma and GIST
patients Status Further evaluation in the Phase Ib (QD schedule) and other Phase
II studies (endometrial, renal cell carcinoma) ongoing. Further study in GIST and selected sarcomas needed
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14
Acknowledgements
We thank the patients who participated in the study and their families
We thank the study teams from the participating sites:Dana-Farber Cancer Institute, Boston, MA, USASarah Cannon Research Institute, Nashville, TN, USARoyal Marsden Hospital and Institute of Cancer Research, Sutton, UKThe Christie NHS Foundation Trust, Manchester, UKInstitut de Cancerologie Gustave Roussy, Villejuif, France
We thank the contributors from Genentech Inc:Biostatistics: Ru-Fang YehPharmacology: Joseph R. Ware, Gillian SmelickBiomarker: Mark Lackner, Hartmut Koeppen, Yibing Yan