This document summarizes systemic treatment options for uveal melanoma including FDA-approved drugs and clinical trials. It discusses interferon alpha and pegylated interferon alpha as adjuvant therapies approved in the 1990s. It also discusses targeted therapies like vemurafenib approved in 2011 for BRAF V600E mutant melanomas, and immunotherapies like ipilimumab approved in 2011. Ongoing clinical trials exploring therapies targeting GNAQ/GNA11 mutations in uveal melanoma are summarized.
Richard Carvajal, MD presents Targeted Therapy for Uveal Melanoma and the Uveal Melanoma Clinical Research Landscape at the 2017 CURE OM Patient & Caregiver Symposium.
Maria Russell, MD, surgical oncologist at Winship Cancer Institute of Emory University presents Ocular Melanoma and Liver Metastases at the 2016 CURE OM Patient & Caregiver Symposium.
Mohammaed Khan, MD, PhD, DABR, radiation oncologist at Winship Cancer Institute of Emory University presents Localized Treatment for Metastatic Disease at the 2016 CURE OM Patient & Caregiver Symposium.
Richard Carvajal, MD presents Targeted Therapy for Uveal Melanoma and the Uveal Melanoma Clinical Research Landscape at the 2017 CURE OM Patient & Caregiver Symposium.
Maria Russell, MD, surgical oncologist at Winship Cancer Institute of Emory University presents Ocular Melanoma and Liver Metastases at the 2016 CURE OM Patient & Caregiver Symposium.
Mohammaed Khan, MD, PhD, DABR, radiation oncologist at Winship Cancer Institute of Emory University presents Localized Treatment for Metastatic Disease at the 2016 CURE OM Patient & Caregiver Symposium.
This deals with novel molecular findings and their implications in Ewings sarcoma. The role of dose dense and dose intense chemotherapy and role of high dose chemotherapy. Additionally it also deals with survivor ship issues
Presented by Sapna Patel, MD. Presented at the 2018 Eyes on a Cure: Patient & Caregiver Symposium, hosted by the Melanoma Research Foundation's CURE OM initiative.
advancements in the diagnostics help detect states like oligometastasis ,which can lead to selection of patients for local and MDT and prolong the time to adjuvant therapy, at present There is no consensus on the treatment of oligometastatic cancer and clinical trials can help in evidence formation.
Precision Oncology: Combining Orthotopic-PDX Models and MRI, Moving Research ...Scintica Instrumentation
Certis Oncology Solutions is a precision oncology and translational science company. It works directly with cancer patients and their oncologists to help determine the best therapies for individuals, and also partners with pharmaceutical companies to help develop the next generation of anticancer therapies. Certis’s approach to studying drug efficacy is rooted in orthotopic patient-derived xenograft (O-PDX) models. Because tumors are internal to the animal, they usually cannot be measured by calipers. Certis overcomes this challenge by using magnetic resonance imaging (MRI), employing the Aspect M3 Compact MRI to generate high-resolution 3D anatomical images to monitor anti-cancer therapies in real-time.
Topics that were discussed in this webinar :
- Overview of precision oncology and testing platforms
- Comparison on subcutaneous and orthotopic in vivo models
- Imaging modalities for pre-clinical in vivo studies
- Applications of MRI in precision oncology and preclinical in vivo pharmacology studies
Chris Bergstrom, MD in ocular oncology at Emory Eye Center in Atlanta, GA discusses the basics of ocular melanoma at the 2016 CURE OM Patient & Caregiver Symposium.
This deals with novel molecular findings and their implications in Ewings sarcoma. The role of dose dense and dose intense chemotherapy and role of high dose chemotherapy. Additionally it also deals with survivor ship issues
Presented by Sapna Patel, MD. Presented at the 2018 Eyes on a Cure: Patient & Caregiver Symposium, hosted by the Melanoma Research Foundation's CURE OM initiative.
advancements in the diagnostics help detect states like oligometastasis ,which can lead to selection of patients for local and MDT and prolong the time to adjuvant therapy, at present There is no consensus on the treatment of oligometastatic cancer and clinical trials can help in evidence formation.
Precision Oncology: Combining Orthotopic-PDX Models and MRI, Moving Research ...Scintica Instrumentation
Certis Oncology Solutions is a precision oncology and translational science company. It works directly with cancer patients and their oncologists to help determine the best therapies for individuals, and also partners with pharmaceutical companies to help develop the next generation of anticancer therapies. Certis’s approach to studying drug efficacy is rooted in orthotopic patient-derived xenograft (O-PDX) models. Because tumors are internal to the animal, they usually cannot be measured by calipers. Certis overcomes this challenge by using magnetic resonance imaging (MRI), employing the Aspect M3 Compact MRI to generate high-resolution 3D anatomical images to monitor anti-cancer therapies in real-time.
Topics that were discussed in this webinar :
- Overview of precision oncology and testing platforms
- Comparison on subcutaneous and orthotopic in vivo models
- Imaging modalities for pre-clinical in vivo studies
- Applications of MRI in precision oncology and preclinical in vivo pharmacology studies
Chris Bergstrom, MD in ocular oncology at Emory Eye Center in Atlanta, GA discusses the basics of ocular melanoma at the 2016 CURE OM Patient & Caregiver Symposium.
1) El espesor de la infiltración y la ulceración categorizan el T, más no el nivel e invasión. En T1 el índice mitótico.
2) El número de ganglios metastásicos y no su dimensión macroscopica, determinan el N
3) El sitio de metástasis y la presencia de DHL se usan en M
4) Los estadios I, II y III se estadian al superior cuando el melanoma esta ulcerado
5) Las metástasis satélite y en transito se estadian en IIIc
6) Se introduce el concepto de ganglio centinela en el estadiaje
Dana-Farber dermatologist Jennifer Lin, MD, discusses the latest research and treatment for melanoma.
This presentation was originally given as part of Dana-Farber's Tuesday Talks speaker series. In this talk, Lin provides an overview of melanoma, including recent research, progress and future goals.
Marlana Orloff, MD, from Thomas Jefferson University Hospital presents Understanding a Cluster of Uveal Melanoma Cases: Update from Huntersville, NC at the 2016 CURE OM Patient & Caregiver Symposium.
Dr. Patrick Hwu presents the latest information on immunotherapies for melanoma at the MRF's Patient Symposium at MD Anderson Cancer Center on January 31, 2015.
This downloadable slidedeck, presented in a regional grand rounds series, focuses on increasing awareness about current and emerging treatment options for patients with newly diagnosed and recurrent ovarian cancer.
Tonight’s speakers: Dr. Dan Sargent and Kim Ryan
Disclaimer: “This Report is not an official event of the 2012 Gastrointestinal Cancers Symposium. Not sponsored or endorsed by any of the cosponsoring organizations of the 2012 Gastrointestinal Cancers Symposium.”
Jonathan E. Rosenberg, MD, Hans Hammers, MD, PhD, and Ravi A. Madan, MD, prepared useful practice aids pertaining to genitourinary cancers for this CME activity titled "Strengthening Our Grip on Immuno-Oncology in Genitourinary Cancers: Understanding Science Through Stories." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2FAbCH0. CME credit will be available until March 21, 2019.
Gastric cancer
Second most common cancer-related death.
4th most common cancer
Korea, Japan, China, Taiwan high rates.
with 875,000 injured annually person in the world.
Palliative chemotherapy with:
Irinotecan and cisplatin.
Folic acid, 5-FU, and irinotecan (FOLFIRI).
Leucovorin, 5-FU, and oxaliplatin (FOLFOX).
Phase II studies evaluating irinotecan-based or oxaliplatin-based regimens demonstrate similar response rates
This slide deck has been created for clinician use in creating presentations detailing Colorectal Cancer Liver Metastases, the Selective Internal Radiation Therapy (SIRT) procedure available to treat this condition, supported by the clinical data that supports this treatment and and ongoing RCT trials to further document the success of this treatment. This information maybe used in its entirety or in sections, according to the material being presented and the audience to which it will be used. The sections included in this slide deck are as follows:
Colorectal Cancer Liver Metastases (mCRC)
Overview Selective Internal Radiation Therapy (SIRT)
Overview SIR-Spheres(r) microspheres
Clinical Data in mCRC Ongoing Level 1 RCT for mCRC in the liver
Surviving and Thriving with Gynecologic Cancer - 9.29.18Summit Health
Gynecologic Oncology and wellness experts from Summit Medical Group MD Anderson Cancer Center in a special "brunch and learn" survivorship event for ovarian, cervical and other gynecologic cancer survivors. Moderated by Dr. Darlene Gibbon, Medical Director of Gynecologic Oncology, speaker-led sessions will present the promise of immunotherapy in treating gynecologic cancer; managing Menopause and other symptoms; and complementary medicine topics for women, including Acupuncture, Nutrition and Yoga.
Naiyer Rizvi, MD, and Benny Weksler, MBA, MD, prepared useful Practice Aids pertaining to lung cancer for this CME/MOC/CE activity titled "The Evolving Role of Immunotherapy as a Component of Multimodal Therapy in Earlier Stages of Lung Cancer: Rationale, Current Evidence, Key Trials, and Implications for Multidisciplinary Care." For the full presentation, monograph, complete CME/MOC/CE information, and to apply for credit, please visit us at http://bit.ly/2KEjDL6. CME/MOC/CE credit will be available until December 5, 2019.
Similar to Systemic Treatments for Uveal Melanoma (20)
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
1. Patient
Education
Series
Systemic Treatment Options
for Uveal Melanoma
Do not download, distribute or copy
without the express permission of the Richard D. Carvajal, MD
Ocular Melanoma Foundation (OMF).
Memorial Sloan-Kettering Cancer Center
These materials are for educational
use only. No information provided
herein constitutes a medical
diagnosis, advice, or treatment.
Please consult a healthcare
professional for a specific
examination and evaluation of your
condition. Under no circumstances
shall OMF nor the authors listed
herein be held liable for anything that
may arise from anyone following any
advice, treatment, etc. included,
alluded to, or otherwise referenced to
herein.
2. Richard D. Carvajal, MD
Memorial Sloan-Kettering Cancer Center
Rich Carvajal is a medical oncologist with a special interest in the
treatment of melanoma and sarcoma. His research is focused on the
development of new targeted drugs and immunologic therapy against
these diseases, with the hope of attacking cancer cells while minimizing
damage caused to normal cells.
Education: MD, New York University School of Medicine
Residencies: University of Michigan Medical Center
Fellowships: Memorial Sloan-Kettering Cancer Center
Board Certifications: Internal Medicine, Medical Oncology, Hematology
Clinical Expertise: Melanoma; Sarcoma
Appointments for New Patients: 646-497-9067
Phone: 646-888-4161
Patient
Education
Series
3. Systemic Treatment Options
for Uveal Melanoma
Richard D. Carvajal, M.D.
Assistant Attending Physician
Melanoma/Sarcoma Service
Memorial Sloan‐Kettering Cancer Center
4. Who is a Cancer Survivor?
“An individual is considered a cancer survivor from the
time of diagnosis through the balance of his or her life.
Family members, friends, and caregivers are also
impacted by the survivorship experience and are
therefore included in this definition.”
-National Coalition for Cancer Survivorship
Consolidation
Initial Long-Term
Active Therapy Therapy/
Diagnosis Survivorship
Observation
Twombly R. J Natl Cancer Inst. 2004.
Mullan F. N Engl J Med. 1985.
5. Topics
1. What is uveal melanoma?
2. What FDA approved treatment options are available
for this disease?
3. What clinical trials are currently available specifically
for patients with uveal melanoma?
4. How do I find and participate in a clinical trial?
6. Ocular Melanoma
• Uveal Tract
– >95% of ocular
melanomas
• Conjunctiva
– <4% of ocular
melanomas
• Orbit/Eyelid
– <1% of ocular
melanomas
7. Uveal Melanoma
The most common primary eye cancer in adults
Represents 5% of all melanomas
Biologically distinct from skin melanoma
Plaque brachytherapy (radiation treatment) or enucleation
(surgery) is effective in eliminating the disease in the eye
Once it has spread from the eye, treatment is challenging
8. Timeline for FDA Approved Drugs
for the Adjuvant Treatment of Melanoma
1994 2011
PEG IFN approved
for Stage II/III
Melanoma
HD IFN approved
for Stage II/III
Melanoma
9. Interferon-
• Approved in 1994 based on results of ECOG 1684
• Administered 20 MU/m2 IV, 5 days/week x 4 weeks, then 10 MU/m2 SC,
TIW x 11 months
• With a median f/u of 7 years,
ECOG 1684 demonstrated:
– 9% survival benefit at 5
years
– Prolongation in median
survival from 2.8 to 3.8
years
Relapse-free survival Overall survival
10. ECOG 1690: High Dose vs Low P = 0.05 for HD
P = 0.17 for LD
Dose vs Observation
Relapse-free survival
P = NS
Overall survival
Kirkwood et al. JCO 18:2444, 2000
11. Adjuvant Interferon in Uveal Melanoma
Enrolled 121 patients with high risk ocular melanoma (118 PBI; 3 enucleation)
Age > 65, tumor diameter > 15mm, ciliary body involvement, extrascleral
extension
Treated with 3 MIU IFN-alfa-2a subq 3 times/week x 2 years
Compared with historical controls matched for age, tumor diameter, gender,
survival time from primary tx to initiation of adjuvant tx
Lane et al. Ophthalmology. Volume 117, Issue 9, September 2010.
12. Adjuvant Uveal Melanoma Trials
(03/2012)
Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID
mRNA Transfected Dendritic Cell Radboud University,
II NCT00929019
Vaccination Netherlands
DTIC & Interferon Alfa‐2b II Cleveland Clinic NCT01100528
San Diego Pacific Onc &
Sunitinib, Tamoxifen, and Cisplatin II NCT00489944
Hematology
Challenges of developing effective adjuvant trials:
What treatments should be tested?
Which patients should be enrolled onto the study?
What defines a “positive” study?
How many patients are required to prove that a
treatment is effective?
www.clinicaltrials.gov
13. www.clinicaltrials.gov
• A service of the US National Institutes of Health
• Offers up-to-date information on federally and privately
supported clinical trials for a wide range of diseases and
conditions.
• Currently contains 116,889 trials* sponsored by the
National Institutes of Health, other federal agencies, and
private industry.
• Studies listed in the database are conducted in all 50
States and in 178 countries*
(* - as of November 2011)
14. Timeline for FDA Approved Drugs
for Melanoma
2011
1975 1994 1998 2011 2011
DTIC approved Aldesleukin (IL2) PEG IFN approved
for Stage IV approved for for Stage II/III
Melanoma Stage IV Melanoma Melanoma
HD IFN approved
for Stage II/III
Vemurafenib
Melanoma
Ipilimumab
15. Vemurafenib inhibits BRAFV600E Kinase
RTK
RAS
40-60% of melanomas BRAFV600E
RAF
ATP VEMURAFENIB
(PLX4032, RO5185426)
MEK
ATP
ERK
Cellular
Proliferation
16. Vemurafenib
Screening
960 mg po bid
(N=337)
BRAFV600E mutation
Randomization
Stratification
• Stage N=675
• ECOG PS (0 vs 1) Dacarbazine
• LDH level (↑ vs nl)
• Geographic region 1000 mg/m2 iv q3w
(N=338)
Courtesy of P Chapman
17. Maximal tumor shrinkage by individual patient
(RECIST 1.1)
>100
Vemurafenib
Percent change from baseline in sum of tumor diameters
CR: 0.9% PR: 47.5%
50 ORR: 48.4%
0
-50
-100
>100 Dacarbazine
CR: 0% PR: 5.5%
50
ORR: 5.5%
0
-50
-100
Courtesy of P Chapman
19. Differential Sensitivity of Uveal Melanoma Cell Lines
to PLX4720 by Mutational Status
Ambrosini et al. AACR 2010, abstr 5035.
20. Ipilimumab: Mechanism of Action
T-cell T-cell T-cell
activation inhibition potentiation
CTLA4
T cell T cell T cell
CD28 CD28 CTLA4
CTLA4
TCR TCR TCR
B7 IPILIMUMAB
MHC B7 MHC MHC B7 blocks
CTLA-4
APC APC APC
21. MDX010-20: Study Design
Ipilimumab + gp100 (N=403)
R
A
Pre-treated N
Metastatic D
Melanoma Ipilimumab + placebo (N=137)
(N=676)
O
M
I
Z
E gp100 + placebo (N=136)
Courtesy of S O’Day
22. Kaplan-Meier Analysis of Survival
Ipi + gp100 (A)
Ipi alone (B)
gp100 alone (C)
Ipilimumab Alone versus GP100 Alone
HR 0.66
Median OS 10.1 vs 6.4 months
P value 0.003
1 2 3 4
Years
Survival Rate Ipi + gp100 N=403 Ipi + pbo gp100 + pbo
N=137 N=136
1 year 44% 46% 25%
2 year 22% 24% 14%
Courtesy of Steven O’Day
23. Efficacy of Ipilimumab in Uveal Melanoma
Week 1: n = 13
Week 12: n = 9
2 SD; 7 POD
Week 24: n = 5
3 SD; 2 POD
Week 36: n = 3
1 SD; 2 POD
Danielli et al. Cancer Immunol Immunother. 2011.
24. Response to Systemic Therapy
Author Study n RR OS/PFS
Homsi et al, 2010 Phase 2 Docosahexaenoic 22 4% 9.8 mo OS
acid-Paclitaxel (1/22)
Penel et al, 2008 Phase 2 Imatinib 10 0% 10.8 mo OS
Schmittel et al, Phase 2 Gem/Treosulfan vs 48 2% 2-3 mo PFS
2006 Treosulfan (1/48)
Oneill et al, 2006 Phase 2 DTIC/Treosulfan 15 0% 3 mo PFS
Schmittel et al, Phase 2 17 0% 3 mo PFS
2005 Gem/Cis/Treosulfan
Schmidt-Hieber et Phase 2 Bendamustine 9 0% NR
al, 2004
Bedikian et al, Phase 2 Temozolomide 14 0% 1.8 mo TTP
2004
Kivelä et al, 2003 Phase 2 BOLD + IFN 22 0% 1.9 mo PFS
157 1.3%
2/157
25. More than one disease…
Gnaq/11
4%
"Wild-type"
28%
BRAF
45%
KIT Melanoma
3%
NRAS
20%
27. Gq/11 Mutations are Frequent
in Primary UM Samples
GNAQ Exon 5
Q209P
Onken et al, 2008 49% 33%
(33/67)
Q209L
Van Raamsdonk et al, 2008 46%
67%
(22/48)
GNAQ Ex 4 GNAQ Ex 5 GNA11 Ex 4 GNA11 Ex 5
Blue Nevi 1.0% 54.7% 1.0% 6.5%
(1/96) (76/139) (1/96) (9/139)
Primary UM 2.8% 44.8% 2.1% 31.9%
(4/145) (73/163) (3/145) (52/163)
Metastatic 5.9% 21.7% 5.9% 56.5%
UM (1/17) (5/23) (1/17) (13/23)
Onken et al. Investigative Ophthalmology and Visual Science, 2008.
Van Raamsdonk et al. Nature, 2008.
Van Raamsdonk et al. NEJM, 2010.
28. The Gα
Pathway
Gα Gα PLCβ
Gβγ
GTP
GDP
DAG
PIP2
GNAQ Q209L PKC
IP3
P Raf Raf
Akt
P MEK MEK
P ERK ERK
mTOR
Tumor growth
and proliferation
29. Differential Sensitivity of Uveal Melanoma Cell Lines
to AZD6244 by Mutational Status
Ambrosini et al. AACR 2010, abstr 5035.
30. A Randomized Phase II Trial of Temozolomide versus
AZD6244 in Patients with Metastatic Uveal Melanoma
(NCI#8443)
Part A Temozolomide Cross‐over to
AZD6244 Allowed
TMZ/DTIC Naïve (n = 60) at Progression
Metastatic Uveal
Melanoma Stratification by:
AZD6244 1. Mutation status
(n = 60) 2. M1a/b vs M1c
3. Prior therapy (0 vs ≥1)
TMZ (n) AZD6244 (n) TOTAL (n)
Gnaq/11 Mut At least 40 At least 40 At least 80
Gnaq/11 Wt Up to 20 Up to 20 Up to 40
Probability is 80% that this design will detect a treatment
difference at a one-sided 10% significance level if the
true PFS hazard ratio is 0.6 in the Gq/11 mutant only
population AND the overall population
31. Phase I Study of AEB071 in UM
• Includes a dose‐escalation portion and a 25 patient dose expansion
cohort at the MTD
– Starting dose 300 mg BID
– Dose escalation using an adaptive Bayesian logistical regression model
• Pre‐ and day 15 biopsies in all patients
• Primary Endpoint: Estimate the MTD, safety/tolerability
• Secondary Endpoints: Overall response rate, PFS, TTP, PK
• Exploratory Endpoints: pMARCKS, correlation of PK/PD
• Participating Centers: 1. MSKCC (PI: Gary K. Schwartz)
2. DFCI (PI: Stephen F. Hodi)
3. Institut Curie (Sophie Piperno‐Neumann)
4. Leiden Univ (H.W. Kapitejin)
32. Major Oncogenic Events in Uveal Melanoma
45% Gnaq mutations
30% Gna11 mutations
60% PTEN loss
70% IGF1R expression
80% MET expression
100% SSTR expression
85% KIT expression
85% ERK activation
Patel M et al. Clin Cancer Res 2011;17:2087-2100
33. Metastatic Uveal Melanoma Trials
(03/2012)
Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID
AEB071 I Novartis NCT01430416
Sorafenib (STREAM Trial) II Essen, Germany NCT01377025
Sunitinib vs DTIC II Clatterbridge Centre, UK NCT01551459
Alberta Health Sciences,
CP‐675,206 II NCT01034787
Canada
Liposomal vincristine (Marqibo) II Talon Therapeutics, Inc NCT00506142
Genasense, Carboplatin & Paclitaxel II MD Anderson NCT01200342
SOM230 & RAD001 II Memorial Sloan‐Kettering NCT01252251
Cixutumumab (A12) II MD Anderson NCT01413191
AZD6244 versus Temozolomide II Memorial Sloan‐Kettering NCT01143402
Paclitaxel Albumin‐Stabilized
II Ohio State NCT00738361
Nanoparticle Formulation
Temozolomide & Bevacizumab II Institut Curie, Paris, France NCT01217398
STA‐9090 II Dana‐Farber NCT01200238
SAHA II Memorial Sloan‐Kettering pending
www.clinicaltrials.gov
34. Uveal Melanoma Liver Targeted Trials
(03/2012)
Rational for Liver-Directed Therapy:
1. Liver is 1st site of metastasis in >60% of cases and may be the dominant
site of disease
2. Currently available systemic treatments have limited effectiveness
3. Regional tx allows dose escalation to the cancer-bearing organ while
minimizing systemic exposure/toxicity via separation of the regional and
systemic circulation
4. Based on its unique vascular anatomy, the liver is a favorable site for
regional therapy (established tumors in liver derive the majority of blood
flow from the arterial tree - tumors: 100% versus normal liver: 25%)
Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID
SIR‐Spheres® 90Y Microspheres II Thomas Jefferson NCT01473004
IV versus Hepatic Arterial Infusion of
III EORTC NCT00110123
Fotemustine
Liver Transplantation II Oslo University NCT01311466
www.clinicaltrials.gov
35. A Phase-III Random Assignment Trial Comparing Percutaneous Hepatic
Perfusion with Melphalan (PHP-mel) to Standard of Care for Patients with
Hepatic Metastases from Metastatic Ocular or Cutaneous Melanoma
H
E
P
A
PHP Arm T
R Follow-up
(n= 44) I
A
C
N
Melanoma D
Metastatic P
O Cross over to PHP
R
to Liver M (n=27, 55%)
O
(n = 93) I
G
Z
R
E
E
BAC Arm S Follow-up
1:1 (n = 49) S
I
Total Accrual: 93 patients O
(PHP: 44, BAC: 49, Crossover: 27) N
43. Outline
1. What is uveal melanoma?
2. What FDA approved treatment options are available
for this disease?
3. What clinical trials are currently available specifically
for patients with uveal melanoma?
4. How do I find and participate in a clinical trial?
44. Summary
• Uveal melanoma is a distinct disease entity from cutaneous
melanoma, with a unique biology and response pattern to
systemic therapy
• Currently available treatments for cutaneous melanoma have
limited efficacy in uveal melanoma (although further
investigation of ipilimumab in uveal melanoma is warranted)
• Hepatic directed therapy has activity in liver metastases from
uveal melanoma but the role of this treatment in uveal
melanoma must be further defined
• Emerging insights into the biology of uveal melanoma have
led to the development of a series of clinical trials which hold
promise for positive clinical impact in this disease
• Patient participation in clinical trials, both in the adjuvant and
metastatic setting, remains critical to the successful
development of effective treatments
45. Uveal Melanoma Resources
• AIM at Melanoma
– http://www.aimatmelanoma.org/en/
• Melanoma International Foundation
– www.melanomainternational.org
• Melanoma Research Foundation: Cure OM
– http://www.melanoma.org
• Ocular Melanoma Foundation
– http://www.ocularmelanoma.org
• Melanoma Research Alliance
– http://www.melanomaresearchalliance.org
• National Cancer Institute
– http://www.cancer.gov/cancertopics/pdq/treatment/intraocularmelanoma/Patient/page1