Prostate Cancer Clinical Trial Overview: What is New? · What is a clinical trials? A clinical trial is one of the final stages of a long and careful cancer research process. Studies

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

Seed and Soil Hypothesis

Seed and Soil Hypothesis

Prostate Cancer Cells“Seeds”

Personalizing Treatment for Patients“New methods to evaluate the “Seed”

Leversha, M. A. et al. Clin Cancer Res 2009;15:2091-2097

Tumor Microenvironment“Soil”

Prostate Cancer Cells“Seeds”

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

Testosterone|DHT

Increased Androgen LevelProstate Cancer

Cell

Testosterone|DHT

Increased Androgen LevelProstate Cancer

Cell

Novel therapies

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

New Tumor Blood Vessels to the Cancer“Angiogenesis”

Prostate Cancer

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

Immune System

Immunotherapy

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

Personalizing Treatment for Patients“Seed and Soil”

Thank YouThank You

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

MLN2704

MLN591 Drug maytansinoid-1(aka J591) (DM1)

Tumor Localization: Bone (25 mg dose)

J591 Scan Bone Scan

Gene gun technologyGene gun technologyAnti-Tumor Immunity

zinc