Phase Ib Study of the PI3K Inhibitor Taselisib (GDC-0032...
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Phase Ib Study of the PI3K Inhibitor Taselisib (GDC-0032) in Combination with Letrozole in Patients with Hormone Receptor-Positive Advanced Breast Cancer C. Saura, 1 J. Sachdev, 2 M. R. Patel, 3 A. Cervantes, 4 D. Juric, 5 J. R. Infante, 6 D. Richards, 7 S. Sanabria, 8 X. Lu, 8 J. Ware, 8 T. R. Wilson, 8 H. Parmar, 8 J. Y. Hsu, 8 M. Oliveira, 1 E. P. Winer, 9 D. D. Von Hoff, 2 J. Baselga, 10 I. E. Krop 9 1 Vall d’Hebron University Hospital, Vall d’Hebrón Institute of Oncology, Barcelona, Spain; 2 Virginia G. Piper Cancer Center/TGen, Scottsdale, AZ; 3 Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, FL; 4 Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain; 5 Massa- chusetts General Hospital Cancer Center, Boston, MA; 6 Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN; 7 Texas Oncology-Tyler, Tyler, TX; 8 Genentech, Inc., South San Francisco, CA; 9 Dana-Farber Cancer Institute, Boston, MA; 10 Memorial Sloan-Kettering Cancer Center, New York, NY BACKGROUND • Taselisib (GDC-0032) is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform (Ki = 0.29 nM) • Preclinically, taselisib has enhanced potency against PI3K alpha isoform (PIK3CA) mutant breast cancer cell lines that correlates with pathway knockdown and apoptosis superior to other PI3K inhibitors (Olivero et al., AACR 2013) • Taselisib Phase Ia data demonstrated confirmed partial responses in multiple patients with PIK3CA mutant breast cancer that was not observed in PIK3CA wildtype breast cancer patients (Juric et al., AACR 2013). Increased antitumor activity in PIK3CA mutant breast cancer patients was also observed in a Phase Ib study of fulvestrant in combination with taselisib (Juric et al., SABCS 2013). • Preclinical data show enhanced antitumor activity when taselisib is combined with letrozole in breast cancer xenograft models OBJECTIVES Primary Objectives • Evaluate the safety and tolerability of concomitant daily administration of taselisib and letrozole in postmenopausal female patients with locally advanced or metastatic hormone receptor-positive breast cancer Secondary and Exploratory Objectives • Evaluate the anti-tumor activity of taselisib in combination with letrozole • Assess the PK of taselisib and letrozole METHODS Study Design • A Phase Ib dose escalation study evaluating taselisib doses ranging from 6-9 mg QD capsules in combination with letrozole 2.5 mg orally on Days 1-28 in a modified 3+3 design. All data shown are based on a 30 July 2014 cut off date. Figure 1. Study Schema. Key Inclusion and Exclusion Criteria • Post-menopausal female with advanced or metastatic hormone receptor-positive breast cancer • Progression or recurrence on ≥ 1prior endocrine therapy in the metastatic setting • Evaluable or measurable disease per RECIST v1.1 • Eastern Cooperative Oncology Group performance status of 0 or 1 • Patients with diabetes requiring antihyperglycemic medication were excluded RESULTS • Data cutoff 30 Jul 2014 Table 1. Patient Baseline Characteristics. Demographics Taselisib 6 mg QD + Letrozole (n=20) Taselisib 9 mg QD + Letrozole (n=8) All Patients (N=28) Age in years, median (range) 64 (45-85) 60 (45-71) 62 (45-85) ECOG PS 0 1 9 (45%) 11 (55%) 4 (50%) 4 (50%) 13 (46%) 15 (54%) No. prior systemic therapies, median (range) 5 (3-9) 6 (4-12) 6 (3-12) Safety Table 2. Adverse Events Potentially Related to Taselisib Observed in ≥10% of All Patients, and All Grade ≥3 Events Potentially Related to Taselisib. Taselisib 6 mg QD + Letrozole (n=20) Taselisib 9 mg QD + Letrozole (n=8) All Patients (N=28) All Grades Grade ≥3 All Grades Grade ≥3 All Grades Grade ≥3 Any Adverse Event 19 (95%) 6 (30%) 7 (88%) 4 (50%) 26 (93%) 10 (36%) Diarrhea 14 (70%) 2 (10%) 5 (63%) 2 (25%) 19 (68%) 4 (14%) Stomatitis 9 (45%) 1 (5%) 2 (25%) - 11 (39%) 1 (4%) Nausea 7 (35%) - 3 (38%) - 10 (36%) - Fatigue 7 (35%) 1 (5%) 1 (13%) - 8 (29%) 1 (4%) Rash 5 (25%) 1 (5%) 3 (38%) - 8 (29%) 1 (4%) Decreased appetite 5 (25%) - 2 (25%) - 7 (25%) - Hyperglycemia 5 (25%) 1 (5%) 2 (25%) 1 (13%) 7 (25%) 2 (7%) Dysgeusia 3 (15%) - 3 (38%) - 6 (21%) - Mucosal inflammation 4 (20%) 2 (10%) 2 (25%) - 6 (21%) 2 (7%) Vomiting 5 (25%) - 1 (13%) - 6 (21%) - Dry skin 2 (5%) - 3 (38%) - 5 (18%) - Muscle spasms 3 (15%) - 2 (25%) - 5 (18%) - Asthenia 2 (10%) - 2 (25%) - 4 (14%) - Dry mouth 3 (15%) - 1 (13%) - 4 (14%) - Pruritis 1 (5%) - 3 (38%) - 4 (14%) - AST increase 1 (5%) - 2 (25%) 1 (13%) 3 (11%) 1 (4%) Amylase increase 1 (5%) 1 (5%) - - 1 (5%) 1 (4%) Alk. phos. increase - - 1 (13%) 1 (13%) 1 (4%) 1 (4%) GGT increase - - 1 (13%) 1 (13%) 1 (4%) 1 (4%) Hypokalemia 1 (5%) 1 (5%) - - 1 (4%) 1 (4%) Lipase increase 1 (5%) 1 (5%) - - 1 (4%) 1 (4%) • No Dose Limiting Toxicities were observed at either the 6 mg or 9 mg dose level • Dose expansion occurred at 6 mg dose level based upon observed antitumor activity at that dose level and long-term tolerability Pharmacokinetics • Plasma samples were collected at predose, 1, 2, 3, 4, 8, and 24 hr post-dose on Day 15 to characterize the PK of taselisib and letrozole • Taselisib plasma concentrations following 6 mg or 9 mg QD capsule dosing in combination with letrozole are within the 90% CI predicted by the population PK model in a majority of patients, suggesting no drug-drug interaction with letrozole (Figure 2) • Letrozole PK is comparable with historical data, suggesting no DDI with taselisib at 6 or 9 mg QD capsule Figure 2. Steady State Plasma Concentrations of Taselisib in Combination with Letrozole. Taselisib plasma concentration (μM) Taselisib 6 mg Taselisib 9 mg 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 4 8 12 16 20 24 Time (hr) Time (hr) 0 4 8 12 16 20 24 Dashed lines represent median and 90% CI from population pharmacokinetic prediction of taselisib as a single agent. The colors represent individual concentration-time-profiles for subjects in Cohort E at the 6 mg and 9 mg QD capsule dose. Clinical Activity/Efficacy Figure 3. Preliminary Data From 19 FDG-PET Evaluable Patients Shows a Partial Metabolic Response as Best Response in 12/19 (63%) Patients. 100 75 50 25 0 25 50 Mean SUVmax PIK3CA mutation 6 mg 9 mg Figure 4. Anti-Tumor Activity: Best Change in Target Lesions Based Upon Patients with RECIST Measurable Disease. Figure 5. Time on Study and Dose Received by Patients. Figure 6. Clinical Activity: cPR in ER+ PIK3CA-Mutant Breast Cancer. • Diagnosed with ER+, HER2-negative MBC in 2001. PIK3CA mutant (H1047L via plasma ctDNA) • Prior therapies: paclitaxel, anastrozole, exemestane, megestrol, fulvestrant, letrozole, capecitabine, nab-paclitaxel, eribulin, cisplatin, and irinotecan with disease progression prior to enrollment. • Patient was been treated with 6 mg QD taselisib + letrozole from Sept 2012 until subsequent disease progression in June 2013. Patient had cPR at Cycle 4 (RECIST -71%). Figure 7. Clinical activity: cPR in PIK3CA-Mutant Breast Cancer. • Diagnosed with Stage 2 ER+, HER2- negative breast CA in 2000. PIK3CA mutant (H1047R, archival tissue). • Prior therapies: Adjuvant chemotherapy followed by tamoxifen (5 yrs) and letrozole (5 yrs). Recurrence in 2011 and treatment with fulvestrant, nab-paclitaxel, capecitabine, epirubicin/ramucirumab, and NKTR-102 with disease progression prior to enrollment. • Patient was been treated with 9 mg QD taselisib + letrozole from Feb 2013 until disease progression in Aug 2013. Patient had had cPR at Cycle 4 (RECIST -76%). CONCLUSIONS • The combination of taselisib 6 mg QD (capsule) with letrozole is a well-tolerated regimen with promising preliminary activity in metastatic hormone receptor-positive breast cancer, especially in patients with PIK3CA mutant tumors. This is equivalent to 4 mg tablet dose level for taselisib based upon a separate clinical pharmacology study. Additional patients are being enrolled to test this letrozole/taselisib combination with the new tablet formulation. • No drug-drug interaction between taselisib and letrozole was observed • FDG-PET uptake reduction was observed in a large majority of patients treated at 6 mg and 9 mg • LORELEI: A Phase II neoadjuvant trial of taselisib with or without letrozole in postmenopausal women with ER+/HER2-negative early stage breast cancer is currently enrolling (NCT02273973). Trial is being presented at SABCS on Wed, Dec. 10th 5-7pm in Poster Session 1 (Halls A-B), Ongoing Clinical Trials 1 Targeted Therapies (OT1- 1-01). San Antonio Breast Cancer Symposium - December 9-13, 2014 This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute. PD5-2
Transcript of Phase Ib Study of the PI3K Inhibitor Taselisib (GDC-0032...
Phase Ib Study of the PI3K Inhibitor Taselisib (GDC-0032) in Combination with Letrozole in Patients with Hormone Receptor-Positive Advanced Breast CancerC. Saura,1 J. Sachdev,2 M. R. Patel,3 A. Cervantes,4 D. Juric,5 J. R. Infante,6 D. Richards,7 S. Sanabria,8 X. Lu,8 J. Ware,8 T. R. Wilson,8 H. Parmar,8 J. Y. Hsu,8 M. Oliveira,1 E. P. Winer,9 D. D. Von Hoff,2 J. Baselga,10 I. E. Krop9
1Vall d’Hebron University Hospital, Vall d’Hebrón Institute of Oncology, Barcelona, Spain; 2Virginia G. Piper Cancer Center/TGen, Scottsdale, AZ; 3Sarah Cannon Research Institute/Florida Cancer Specialists, Sarasota, FL; 4Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain; 5Massa-chusetts General Hospital Cancer Center, Boston, MA; 6Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN; 7Texas Oncology-Tyler, Tyler, TX; 8Genentech, Inc., South San Francisco, CA; 9Dana-Farber Cancer Institute, Boston, MA; 10Memorial Sloan-Kettering Cancer Center, New York, NY
BACKGROUND• Taselisib (GDC-0032) is an orally bioavailable, potent, and selective inhibitor of
Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform (Ki = 0.29 nM)
• Preclinically, taselisib has enhanced potency against PI3K alpha isoform (PIK3CA) mutant breast cancer cell lines that correlates with pathway knockdown and apoptosis superior to other PI3K inhibitors (Olivero et al., AACR 2013)
• Taselisib Phase Ia data demonstrated confirmed partial responses in multiple patients with PIK3CA mutant breast cancer that was not observed in PIK3CA wildtype breast cancer patients (Juric et al., AACR 2013). Increased antitumor activity in PIK3CA mutant breast cancer patients was also observed in a Phase Ib study of fulvestrant in combination with taselisib (Juric et al., SABCS 2013).
• Preclinical data show enhanced antitumor activity when taselisib is combined with letrozole in breast cancer xenograft models
OBJECTIVESPrimary Objectives• Evaluate the safety and tolerability of concomitant daily administration of taselisib
and letrozole in postmenopausal female patients with locally advanced or metastatic hormone receptor-positive breast cancer
Secondary and Exploratory Objectives• Evaluate the anti-tumor activity of taselisib in combination with letrozole• Assess the PK of taselisib and letrozole
METHODS
Study Design• A Phase Ib dose escalation study evaluating taselisib doses ranging from 6-9
mg QD capsules in combination with letrozole 2.5 mg orally on Days 1-28 in a modified 3+3 design. All data shown are based on a 30 July 2014 cut off date.
Figure 1. Study Schema.
Key Inclusion and Exclusion Criteria• Post-menopausal female with advanced or metastatic hormone receptor-positive
breast cancer• Progression or recurrence on ≥ 1prior endocrine therapy in the metastatic setting• Evaluable or measurable disease per RECIST v1.1• Eastern Cooperative Oncology Group performance status of 0 or 1• Patients with diabetes requiring antihyperglycemic medication were excluded
RESULTS• Data cutoff 30 Jul 2014
Table 1. Patient Baseline Characteristics.
DemographicsTaselisib 6 mg QD
+ Letrozole (n=20)
Taselisib 9 mg QD + Letrozole
(n=8)
All Patients (N=28)
Age in years, median (range) 64 (45-85) 60 (45-71) 62 (45-85)ECOG PS 0 1
9 (45%) 11 (55%)
4 (50%) 4 (50%)
13 (46%) 15 (54%)
No. prior systemic therapies, median (range) 5 (3-9) 6 (4-12) 6 (3-12)
SafetyTable2.AdverseEventsPotentiallyRelatedtoTaselisibObservedin≥10%ofAllPatients,andAllGrade≥3EventsPotentiallyRelatedtoTaselisib.
Taselisib 6 mg QD + Letrozole
(n=20)
Taselisib 9 mg QD + Letrozole
(n=8)
All Patients (N=28)
All Grades
Grade ≥3
All Grades
Grade ≥3
All Grades
Grade ≥3
Any Adverse Event 19 (95%) 6 (30%) 7 (88%) 4 (50%) 26 (93%) 10 (36%)Diarrhea 14 (70%) 2 (10%) 5 (63%) 2 (25%) 19 (68%) 4 (14%)Stomatitis 9 (45%) 1 (5%) 2 (25%) - 11 (39%) 1 (4%)Nausea 7 (35%) - 3 (38%) - 10 (36%) -Fatigue 7 (35%) 1 (5%) 1 (13%) - 8 (29%) 1 (4%)Rash 5 (25%) 1 (5%) 3 (38%) - 8 (29%) 1 (4%)Decreased appetite 5 (25%) - 2 (25%) - 7 (25%) -Hyperglycemia 5 (25%) 1 (5%) 2 (25%) 1 (13%) 7 (25%) 2 (7%)Dysgeusia 3 (15%) - 3 (38%) - 6 (21%) -Mucosal inflammation 4 (20%) 2 (10%) 2 (25%) - 6 (21%) 2 (7%)Vomiting 5 (25%) - 1 (13%) - 6 (21%) -Dry skin 2 (5%) - 3 (38%) - 5 (18%) -Muscle spasms 3 (15%) - 2 (25%) - 5 (18%) -Asthenia 2 (10%) - 2 (25%) - 4 (14%) -Dry mouth 3 (15%) - 1 (13%) - 4 (14%) -Pruritis 1 (5%) - 3 (38%) - 4 (14%) -AST increase 1 (5%) - 2 (25%) 1 (13%) 3 (11%) 1 (4%)Amylase increase 1 (5%) 1 (5%) - - 1 (5%) 1 (4%)Alk. phos. increase - - 1 (13%) 1 (13%) 1 (4%) 1 (4%)GGT increase - - 1 (13%) 1 (13%) 1 (4%) 1 (4%)Hypokalemia 1 (5%) 1 (5%) - - 1 (4%) 1 (4%)Lipase increase 1 (5%) 1 (5%) - - 1 (4%) 1 (4%)
• No Dose Limiting Toxicities were observed at either the 6 mg or 9 mg dose level• Dose expansion occurred at 6 mg dose level based upon observed antitumor
activity at that dose level and long-term tolerability
Pharmacokinetics• Plasma samples were collected at predose, 1, 2, 3, 4, 8, and 24 hr post-dose on
Day 15 to characterize the PK of taselisib and letrozole• Taselisib plasma concentrations following 6 mg or 9 mg QD capsule dosing in
combination with letrozole are within the 90% CI predicted by the population PK model in a majority of patients, suggesting no drug-drug interaction with letrozole (Figure 2)
• Letrozole PK is comparable with historical data, suggesting no DDI with taselisib at 6 or 9 mg QD capsule
Figure 2. Steady State Plasma Concentrations of Taselisib in Combination with Letrozole.
Tase
lisib
pla
sma
conc
entra
tion
(μM
)
Taselisib 6 mg Taselisib 9 mg0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.6
0.5
0.4
0.3
0.2
0.1
0.00 4 8 12 16 20 24
Time (hr)Time (hr)
0 4 8 12 16 20 24
Dashed lines represent median and 90% CI from population pharmacokinetic prediction of taselisib as a single agent. The colors represent individual concentration-time-profiles for subjects in Cohort E at the 6 mg and 9 mg QD capsule dose.
ClinicalActivity/EfficacyFigure 3. Preliminary Data From 19FDG-PET Evaluable Patients Shows a PartialMetabolicResponseasBestResponsein12/19(63%)Patients.
100
75
50
25
0
25
50
Mea
n S
UV
max
PIK3CA mutation 6 mg 9 mg
Figure 4. Anti-Tumor Activity: Best Change in Target Lesions Based Upon Patients with RECIST Measurable Disease.
Figure 5. Time on Study and Dose Received by Patients.
Figure 6. Clinical Activity: cPR in ER+ PIK3CA-Mutant Breast Cancer.
• Diagnosed with ER+, HER2-negative MBC in 2001. PIK3CA mutant (H1047L via plasma ctDNA)• Prior therapies: paclitaxel, anastrozole, exemestane, megestrol, fulvestrant, letrozole,
capecitabine, nab-paclitaxel, eribulin, cisplatin, and irinotecan with disease progression prior to enrollment.
• Patient was been treated with 6 mg QD taselisib + letrozole from Sept 2012 until subsequent disease progression in June 2013. Patient had cPR at Cycle 4 (RECIST -71%).
Figure 7. Clinical activity: cPR in PIK3CA-Mutant Breast Cancer.• Diagnosed with Stage 2 ER+, HER2-
negative breast CA in 2000. PIK3CA mutant (H1047R, archival tissue).
• Prior therapies: Adjuvant chemotherapy followed by tamoxifen (5 yrs) and letrozole (5 yrs). Recurrence in 2011 and treatment with fulvestrant, nab-paclitaxel, capecitabine, epirubicin/ramucirumab, and NKTR-102 with disease progression prior to enrollment.
• Patient was been treated with 9 mg QD taselisib + letrozole from Feb 2013 until disease progression in Aug 2013. Patient had had cPR at Cycle 4 (RECIST -76%).
CONCLUSIONS• The combination of taselisib 6 mg QD (capsule) with letrozole is a well-tolerated regimen with promising preliminary
activity in metastatic hormone receptor-positive breast cancer, especially in patients with PIK3CA mutant tumors. This is equivalent to 4 mg tablet dose level for taselisib based upon a separate clinical pharmacology study. Additional patients are being enrolled to test this letrozole/taselisib combination with the new tablet formulation.
• No drug-drug interaction between taselisib and letrozole was observed
• FDG-PET uptake reduction was observed in a large majority of patients treated at 6 mg and 9 mg
• LORELEI: A Phase II neoadjuvant trial of taselisib with or without letrozole in postmenopausal women with ER+/HER2-negative early stage breast cancer is currently enrolling (NCT02273973). Trial is being presented at SABCS on Wed, Dec. 10th 5-7pm in Poster Session 1 (Halls A-B), Ongoing Clinical Trials 1 Targeted Therapies (OT1- 1-01).
San Antonio Breast Cancer Symposium - December 9-13, 2014This presentation is the intellectual property of the author/presenter. Contact [email protected] for permission to reprint and/or distribute.
PD5-2
