Prostate Cancer Clinical Trial Overview: What is New? · What is a clinical trials? A clinical...
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Prostate Cancer Clinical Trial Prostate Cancer Clinical Trial Overview:Overview:
What is New?What is New?Wm. Kevin Kelly, DO
Associate Professor of Medicine and SurgeryYale University
Yale University School of Medicine
What is a clinical trials?
A clinical trial is one of the final stages of a long and careful cancer research process. Studies are done with cancer patients to find out whether promising approaches to cancer prevention, diagnosis, and treatment are safe and effective.
Clinical trials are research studies in which people help doctors find ways to improve health and cancer care. Each study tries to answer scientific questions and to find better ways to prevent, diagnose, or treat cancer.
Why are there clinical trials?
What are the different types of clinical trials?
1. Treatment Trials2. Prevention Trials3. Screening Trials4. Quality of Life Trials
What are the phases of clinical trials?
1. Phase I2. Phase II3. Phase III4. Phase IV
Accrual to Clinical Trials in US
“3-10% with newly diagnosed cancer patients are treated on clinical trials”
17α hydrolase/17, 20 lyase inhibitor AbirateroneAnti-angiogenic/immunomodulatory CC4047,Lenalidomide, thalidomideAnti-CTLA4 antibody IpilimumabAnti-Il-6 antibody CNTO 95Anti-insulin-like GFR antibody IMC-A12Anti-integrin anti-body CNTO 95Anti-PSMA immunoconjugate MLN2704, 177 Lu-J591Anti-prostate stem cell antibody AGS-PSCAAnti-VEGF BevacizumabCytotoxic agent ABT-751, abraxane, E7389, GMO-paclitaxel,
Irofulven, Paclitaxel poliglumex, Pemtrexed, Trabectin, Vinfluvine, Epothilones, Satraplatin
EGFR antibodies\TKI Pertuzumab, Cetuximab, Erlotinib, Gefitnib, Lapatinib
GMP phospodiesterase inhibitor ExisulindHSP-90 inhibitor 17-AAGHDACi LBH589, Romidepsin, Valproic acid,
Vorinostat, BelinostatIntegrin receptor antagonist CilengitideM-TOR inhibitor RAD-001Multi-targeted TKI Sunitinib, Sorafenib, CEP 701Pro-apoptotic agent AT-101Proteosome Inhibitor BortezomibSignal Transduction inhibitor PCK-3145Survivin suppressant YM155
Novel Agents in CRPCClass of agent Agent
Personalizing Treatment for Patients“New methods to evaluate the “Seed”
Leversha, M. A. et al. Clin Cancer Res 2009;15:2091-2097
Increased intra-tumoral Testosterone in Advanced Prostate Cancer
Testosterone and dihydrotestosterone occur in recurrent prostate cancer at sufficient levels to activate the androgen receptor.
Mohler et al., Clin Cancer Res. 10(2):440-8, 2004
Abiraterone Acetate (CB7630)
• CYP17 is key to androgenic steroid synthesis
• Oral, selective inhibitor of CYP17 – one enzyme, dual function– 17α –hydroxylase – C17,20 -lyase
• Inhibits testosterone production in testis, adrenal glands and prostate
3β-Acetoxy-17-(3-pyridyl)androsta-5,16-diene
MW = 391.55
Activity of Abiraterone in patients that the tumors growing despite treatment with multiple
hormone therapies:Maximum Decline in PSAMaximum Decline in PSA
Ryan et al Proc ASCO 2007
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.
Antitumor Activity of MDV3100 in a Phase 1-2 Study of Castration-Resistant Prostate
MDV3100
Scher et al. ASCO 2009
Patients that failed hormone therapy PSA Change from Baseline- MDV3100
Chemotherapy‐Naïve (N=65) Post‐Chemotherapy (N=75)
62% (40/65)>50%
Decline
51% (38/75)>50%
Decline
VEGF: The Key Mediator to New Blood Vessel Growth
(Angiogenesis)
Binding and activation of VEGF receptor
Environmental factors
(Hypoxia, pH)Growth factors(EGF, bFGF, PDGF, IGF-1, IL-1α, IL-6)
HIF-1α
Genes involved in tumorigenesis
(p53, p73, src, ras, vHL, Bcr-Abl)
PP
PP
ANGIOGENESIS
ProliferationSurvival Migration
Endothelial cellactivation
VEGF
Docetaxel
Avastin™ (bevacizumab)• Recombinant humanized
monoclonal IgG1 antibody1
• Recognizes all isoforms of VEGF2
• Estimated half-life is approximately 20 days (range, 11-50 days)1
• Approved for the use in multiple cancers
• Improves survival in many cancer
1. Avastin™ (Avastin) PI. February 2004.2. Presta et al. Cancer Res. 1997;57:4593.
Opgenorth TJ, et al. J Pharmacol Exp Ther. 1996 Feb;276(2):473-81.Carducci MA, et al. J Clin Oncol. 2002 Apr 15;20(8):2171-80. Nelson JB, Carducci MA. BJU Int. 2000 Apr;85 Suppl 2:45-8.Nelson, Prostate J 1999;1:126.
Orally bioavailableOnce daily dosing1800 x more selective for ETA than ETB
Atrasentan: A Selective Endothelin-A Receptor Antagonist (important for tumors to grow in the bone)
Targeting the Tumor and Its “Soil”
AngiogenesisInhibitors-Bevacizumab
Microtubules
G2
G1S
Cell Death
Docetaxel
Endothelium-AAtrasentan OR
Tumor (seed)
Micro-environment (soil)
Immunotherapy“Vaccine”
• Sipuleucel-T (Provenge)• G-VAX• Prostvac-VF-Tricom
Turns on the Immune system• CTLA-4 (Ipilimumab)• Anti-PD-1
Provenge: Overall Survival: Provenge: Overall Survival: Primary Endpoint IntentPrimary Endpoint Intent--toto--Treat PopulationTreat Population
0 6 12 18 24 30 36 42 48 54 60 660
25
50
75
100
Perc
ent S
urvi
val
Survival (Months)
P = 0.032 (Cox model)HR = 0.775 [95% CI: 0.614, 0.979]
Median Survival Benefit = 4.1 Mos.
Sipuleucel-T (n = 341)Median Survival: 25.8 Mos.
Placebo (n = 171)Median Survival: 21.7 Mos.
AUA 2009
Tri-com vaccine: Overall Survival
Kantoff et al; ASCO 2009: Abstract #5013
PROSTVAC-VF (PV) comprises 2 recombinant viral vectors (Vaccinia and Fowlpox), each encoding transgenes for prostate specific antigen (PSA) and 3 immune costimulatory molecules (B7.1, ICAM-1, and LFA3: TRICOM).
VITAL-2: G-VAX trial: Survival
GVAX/docetaxel: 67 deathsMedian OS 12.2 m
Pred/docetaxel: 47 deathsMedian OS 14.1 m
HR 1.7 (95% CI: 1.15, 2.53) P = 0.0076
Small et al., ASCO GU Symposium 2009; Abst 7
(GVAX: 2 lines of whole prostate tumor cells modified to constantly produce GM-CSF)
Blocking CTLA-4 Increases Immune Responses
CD28MHC
TCR
T cell CTLA-4
APC
1. Co-stimulation via CD28 ligation transduces T cell activating signals
MHC
TCR
Anti-CTLA4 mAb (MDX-010)
CD28
T cell
CTLA-4
APC
T cell Activation
3. Blocking CTLA-4 ligation enhances T cell responses
MHC
TCR
T cell
APC
CD28
CTLA-4
T cell Inactivation
B7
2. CTLA-4 ligation on activated T cells down-regulates T cell responses
B7B7
T cell Activation
FTI (BMS 214662)
AKT
PI3K
NF-kB
Bad BCL-2
ER
Altered Gene
Expression
Ansamycins (17-AAG)TK Inhibitors (ZD1839,OSI774)Mono Abs (C225, Herceptin, 2c4)
PTEN
Antisense (G3139)
Grb2/Shc
Sos
Ras
Raf
MEK
MAPK
Src
PD98059
PD173855/PD179483)
mTOR Rapamycin, CCI- 779
Cyclin D/CDK4
LY294002
SERM3
Novel Prostate Therapies
Proteasome inhibitors (PS341)
Ansamycins
AR Casodex
Flavopiridol
HDAC inhibitors (SAHA)Vit D, Retinoids
Tubulin(Epothilone B)
PSMA AbVaccine B\T cellsDendritic
M
G2
S
G2
GU Clinical Research Program Clinical Trial Status
Localized ProstateCancer
Rising PSA
Non-CastrateMetastatic
CastrateMetastatic
High Risk Disease:•PH III: CALGB 90203: AD + Doc + RP vs RP •RTOG 0521: AD + XRT +/- Docetaxel )
High Risk Disease:•PH II AD + Bevac.Low\Inter. Risk DiseasePhenoxodiol
First Line •Ph III CALGB 902022nd Line•Phenoxodiol•COU-AA-302•Lu-J591 + Keto
1st Line•Ph III: Doc +/- Aflibercept.•PH II Docetaxel + metronic cytoxan 2nd line•Mito + IMC-A12 or IMC- 1121 •MDV31003rd Line therapy•Lu-J591 + Docetaxel•Anti-PD-1
Protocol being writtenProtocol written-pending receiptProtocol written-pending submissionProtocol under Institution reviewProtocol activated 9/30/09
Nanoparticles for Diagnosis and Therapy
Adaptor
Biodegradable polymer
Targeting or transport elements
Encapsulated agents
Protective transport elementsEndosomal disruption element or sensitizer or adjuvant
Protection during transport (PEG)
Targeting ligands (such as anti-PMSA)
Encapsulated agent (such as HDACi or siRNA)
Encapsulated adjuvant or sensitizer
Transport enhancer (such as cell penetrating peptide)
100-400 nm
Features of technology:•Constructed entirely from FDA-approved materials•Versatility:
•Encapsulate agents of any type or size•Encapsulate multiple agents•Surface modification, through high density surface attachment sites•Proven in multiple animal models, in oral and injected dosages
Saltzman and Hoimes
Targets for Prostate Cancer Therapy
Cell Growth Motility Survival Proliferation Angiogenesis
PP
PP
PDK1,2Growth Factor
Signaling
Gene Transcription DNA Replication and Repair
1
6 3
5
8
9
1011
2Plasma Membrane
Nuclear Membrane
127
4
7
71. Growth factors2. Growth factor
receptors3. Adaptor proteins4. Docking
proteins/binding proteins
5. Guanine nucleotide exchange factors
6. Phosphatases and phospholipases
7. Signaling kinases8. Ribosomes9. Transcription
factors10. Histones11. DNA12. Microtubules
Microtubule Dynamics
RNA Translation
Normal cellETB receptorspredominateNEP activeET-1 degraded
Cancer cellETA receptor expressionETB receptor expressionNEP activity
Normal cell
Cancer cell
ET-1 Pathway Dysregulation in Cancer
NEP
ETA receptor
ET-1
NEP Neutral endopeptidase 24.11
NEP
ETB receptor