antitumor activity of mdv3100 in a phase 1-2 study of castration-resistant prostate cancer h. i....
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Antitumor Activity of MDV3100 in a Phase 1-2 Study of Castration-Resistant
Prostate Cancer
H. I. Scher, T. Beer, C. Higano, M. Taplin, E. Efstathiou, A. Anand, D. Hung, M. Hirmand, M. Fleisher, C. Sawyers
Memorial Sloan-Kettering Cancer Center, New York, NY; Oregon Health and Science University, Portland, OR; University of Washington, Seattle, WA; Dana Farber Cancer Institute, Boston, MA; M.D. Anderson
Cancer Center, Houston, TX; Medivation, San Francisco, CA; and the
Prostate Cancer Clinical Trials Consortium
Disclosure Information Antitumor Activity of MDV3100 in a Phase 1-2 Study of Castration-Resistant Prostate Cancer
Howard I. Scher, M.D.
I have the following financial relationships to disclose:
Consultant for: Medivation (uncompensated)
Grant/Research support from: MedivationVeridex
I will discuss the following off label use and/or investigational use in my presentation:
MDV3100
The Development Landscape For Systemic TherapiesIn Prostate Cancer
Castration resistant:Docetaxel
Deaths From Disease
Diagnoses
Rising PSA
3Clinical
Metastases:Castrate1st Line
DocetaxelStandard
2Clinical
Metastases:Castrate
Pre-
ClinicallyLocalizedDisease
1Rising PSA:
Castrate
ClinicalMetastases:
Non-Castrate
4Clinical
Metastases:Castrate
Post-No Standard
With detectable metastases:deaths from cancer exceed
that from other causes
28,660186, 320
Non-CastrateAndrogen depletion
/blockade (bicalutamide)
Primary Tumors Castration Resistant
Scher et al. Endocrine-RelatedCancer 11:2004;459
Androgen Receptor Overexpression is Frequent in Castration Resistant Tumors and is a Target for Therapy
Increased AR proteinAR mRNA overexpressionIncreased AR DNA copy numberIncreased androgen synthesis
o
MDV3100 A Second-Generation Antiandrogen
1. Engineered for activity in prostate cancer cells that overexpress the androgen receptor (AR).
2. Binds the AR more potently than bicalutamide.
3. Unlike bicalutamide, MDV3100 inhibits nuclear translocation of the AR and its binding to DNA.
4. Induces apoptosis in prostate cancer cells.
Ligand
1. AR Binding Affinity• DHT ~ 5nM• Bicalutamide ~160 nM• MDV3100 ~35 nM
2. Nuclear Import• DHT: ++++• Bicalutamide: ++++• MDV3100: ++
3. DNA Binding• DHT: ++++• Bicalutamide: ++• MDV3100: -
4. Coactivator recruitment• DHT: ++++• Bicalutamide: ++• MDV3100: -
The Effects of MDV3100 on the Androgen Receptor Are Distinct from Bicalutamide
1
2
Chen, Clegg and Scher
3
4
DNA
POL II
HS
P 9
0
LB
D
HD
DBD
NTD
MDV3100 Is Active Against Bicalutamide Resistant Cell Lines and Xenografts with Overexpressed AR,
And Inhibits AR Nuclear Translocation
Tran et. al. Science [Epub April 9, 2009]
Phase 1-2 Multicenter Trial in CRPC (Prostate Cancer Clinical Trials Consortium)
1. Determine safety
2. Determine pharmacokinetics (PK)
3. Assess antitumor activity: Prostate-specific antigen (PSA) Soft tissue
Bone
4. Exploratory:
Circulating tumor cells
PET: FDG - 18-fluorodeoxyglucose FDHT - 18-fluorodihydrotestosterone
Key Inclusion Criteria
1. Pathologic confirmation of adenocarcinoma of prostate
2. Serum testosterone level <50 ng/dL
3. Progressive disease defined as one or more of:
• 3 rising PSA levels; screening PSA >2 ng/mL
• RECIST
• Two or more new lesions on bone scan
4. No more than 2 prior chemotherapy regimens, at least one of which contained docetaxel
Rising PSAClinicallyLocalizedDisease
MDV3100 Was Evaluated in Pre- and Post-Chemotherapy Treated Patients
1Rising PSA:
Castrate
ClinicalMetastases:
Non-Castrate
3Clinical
Metastases:Castrate1st Line
DocetaxelStandard
2Clinical
Metastases:Castrate
Pre-
4Clinical
Metastases:Castrate
Post-No Standard
“TYPICAL” “ATYPICAL”
Trial Design
SingleDose6 days
Continuous DosingAssess Monthly;Q3 Month Imaging
Long-TermDosingIndefinite
Cohort 1
SingleDose6 days
Continuous DosingAssess Monthly;Q3 Month Imaging
Long-TermDosingIndefinite
Cohort 2After 28Day Safety
Subsequent Dose Levels
Cohort expansion at > 60 mg/day12 pre- and 12 post-chemotherapy Post-chemotherapy only at > 480 mg/day
Demographics/Prior Therapy (N=140)
Med. (range)AGE (years) 68 (44–93)
PSA (ng/mL) 50 (2–2,159)
N (%)PRIOR HORMONE THERAPY 140 (100%)
1 line 32 (23%)2 lines 42 (30%)>3 lines 66 (47%)
CHEMOTHERAPY 75 (54%)
Distribution of Disease (N=140)
Soft tissueSoft tissue 92 (66%) 92 (66%)
Evaluable by PCWG2 59 (42%)
BoneBone 109 (78%)109 (78%)
Rising PSA only:Rising PSA only: 7 7 (5%)(5%)
No detectable metastases:No detectable metastases:
(Bone and soft tissue disease = 68)
Dose Expansions Allowed Rapid Enrollment of 140 Patients Across Dose Levels
Dose (mg/day) Pre-Chemotherapy
Post-Chemotherapy
Total
30 3 - 3
60 15 12 27
150 15 13 28
240 17 12 29
360 15 13 28
480 - 22 22
600 - 3 3
TOTAL 65 75 140
MDV3100 Was Generally Well-Tolerated
Possibly Related Grade 2/3 Adverse Events in >2 Patients
Adverse Event All Doses
(N = 140)
<240 mg/day
(N = 60)
G2 G3 G2 G3
Fatigue
Nausea
Anorexia
Seizure
29 (21%)
11 ( 8%)
4 ( 3%)
12 (9%)
3 (2%)
8 (13%)
2 ( 3%)
3 (5%)
1. Only one subject discontinued treatment due to fatigue which coincided with disease progression
2. There were 2 witnessed seizures (1 each at 600 and 360 mg/day) and a possible unwitnessed seizure (at 480 mg/day). Both patients with witnessed seizures were taking concomitant medications
that can cause seizure3. MTD determined to be 240 mg/day; patients at higher doses were lowered to 240 mg/day
1. Report PSA changes using waterfall plots.2. Assess changes in soft tissue that a 2 cm or greater at baseline.3. Eliminate “overall response” as an outcome measure.4. Focus more on “time to event”, i.e. the treatment is no longer working.
Waterfall Plot of Best Percent PSA Change from Baseline
Chemotherapy-Naïve (N=65) Post-Chemotherapy (N=75)
62% (40/65)
>50% Decline
51% (38/75)
>50% Decline
Radiographic Changes in Soft Tissue (N=59) and in Bone (N=109)
Chemotherapy-Naïve Patients (N=65)
Post-Chemotherapy Patients (N=75)
Soft Tissue* (Best Response)
Partial Response
Stable Disease
N=25
36% (9/25)
44% (11/25)
N=34
12% (4/34)
53% (18/34)
Bone Scan (Week 12)
Stable Disease
N=41
63% (26/41)
N=68
51% (35/68)
*59 patients with evaluable soft tissue disease as defined by PCWG2 consensusJ Clin Oncol 2008.
Time to PSA Progression For Pre-and Post-Chemotherapy Treated Patients
Pre (Not reached)
Post (186 days)
Time to Radiographic Progression in Pre- and Post-Chemotherapy Treated Patients
Pre (Not yet reached)
Post (201 days)
Exploratory Biomarker Analyses
1. Circulating Tumor Cells:
Enumeration (CellSearch™ - Veridex, LLC)
AR FISH
AR mutations
2. Positron Emission Tomography:
FDHT - 18-fluorodihydrotesterone
FDG - 18-fluorodeoxyglucose
Circulating Tumor Cell Number is Prognostic for Survival and the Conversion From an Unfavorable (> 5) to a
Favorable (< 5) Count Predicts for an Improved Survival
De Bono Clin Cancer Res; 14:6304, 2008
De Bono, Scher, Montgomery et al. Clin Cancer Res (2008)
Pre- and Post-Treatment CTC Number (N=128/140)
*12 patients with no baseline and/or follow-up CTC count
Total (N=128/140)
Pre-Chemotherapy (N=60/65)
Post-Chemotherapy (N=68/75)
Favorable to Favorable 91% (70/77) 91% (40/44) 91% (30/33)
Favorable to Unfavorable 9% (7/77) 9% (4/44) 9% (3/33)
Unfavorable to Favorable
49% (25/51) 75% (12/16) 37% (13/35)
Unfavorable to Unfavorable
51% (26/51) 25% (4/16) 63% (22/35)
Favorable < 5 CTCs/7.5 ml Unfavorable ≥ 5 CTCs/7.5 ml
PRE- and POST-MDV3100 PET Imaging of Biopsy Proven Metastatic Disease in a Lymph Node
SUV=~
PRE
SUV=3.3 SUV = 8.3
FDHTFDG
POST
SUV = <2SUV = <2AR expression in tumor (IHC)
18F-DHT
Changes In FDG and FDHT Uptake in Tumor by PET and PSA Were Generally Concordant
1. 24* Patients had FDG/FDHT Scans performed at Baseline
2. SUVMaxsum = sum of the hottest SUVs (up to 5 lesions)
SUV Max Decrease from Baseline at 4 Weeks
N=22
SUV Max Decrease from Baseline at 12 Weeks
N=21
FDG 17 (73%) 17 (81%)
FDHT 22 (100%) 21 (100%)
Summary and Conclusions1. MDV3100 is a second-generation antiandrogen engineered for activity in cells that
overexpress AR, unique from bicalutamide.
2. The drug is active in CRPC both before and after chemotherapy as shown by:
declines in PSA, imaging, CTC conversion rates, and PET
3. MDV3100 is generally well-tolerated
4. A Phase 3 placebo-controlled survival trial in post-docetaxel CRPC patients is beginning this year
Dose selected to be 240 mg/day based upon: Significant anti-tumor effects plateau at this dose Few side effects Benefit:risk ratio
AFFIRMAFFIRM
Phase 3 Registration Trial of MDV3100 in Post-Chemotherapy CRPC Patients
R
MDV3100 – 240 mg QD
Placebo QD
2
1
Primary Endpoint:25% survival increase (12 to 15 months)Sample size: ~1170 (780 and 390)Statistics: 85% Power; p=0.05, two-sidedBiomarkers: CTC enumeration and profiling with outcome
Department of Defense Prostate Cancer Clinical Trials Consortium
Prostate Cancer Foundation
Acknowledgments
Daniel Danila
Michael Morris
Susan Slovin
David Solit
Ethan Basch
Aseem Anand
Julie Shelkey
Kin Tse
Ryan Stephenson
Martin Fleisher
Margaret Leversha
Mike Kosczuika
Rita Espinosa-
Gonzalez
Charles Sawyers
Michael Jung
Samedi Ouk
Derek Welsbie
Charlie Chen
Yu Chen
Uma Gopalan
Victor Reuter
Larry Schwartz
Steven Solomon
Steven Larson
Neeta Pandit-Taskar
Heiko Schoder
Peter Smith Jones
OHSU
Tom Beer
Joshi Alumkal
Chris Ryan
Erin LaMaye
U Washington
Celestia Higano
Bruce Montgomery
Evan Y. Yu
MDACC
Christopher Logothetis
Eleni Efstathiou
DFCIMary-Ellen Taplin
Medivation
David Hung
Lynn Seely
Mohammad Hirmand
Beth Spencer
Veridex
Robert McCormack