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Targeted Therapy for Uveal Melanoma and the Uveal Melanoma Clinical Research Landscape
Richard D. Carvajal, M.D.Director, Experimental Therapeutics
Director, Melanoma ServiceAssociate Professor of Medicine
Columbia University Medical Center
Critical Gaps in the UM Field
Epidemiology Primary Therapy
Adjuvant Therapy Surveillance
Management of Advanced
Disease
Surveillance strategies
Risk stratification
Liver-directed & systemic tx
Risk factors
International Uveal Melanoma Natural History StudySpecific Aim 1: To document clinical outcomes of patients with uveal melanoma, adjusting for known prognostic risk factors as well as other baseline demographic and clinical factors, including therapies, in order to provide benchmark endpoints for the development of novel therapies for this disease.
Specific Aim 2: To inform critical outstanding questions in the field unlikely to be answered by well-designed prospective clinical trials regarding risk stratification, radiographic surveillance, and optimal patient selection for liver-directed as opposed to systemic therapies.
Specific Aim 3: To develop a virtual uveal melanoma tumor repository that can be utilized by investigators to develop or confirm hypotheses related to tumor biology and to facilitate drug development.
Participating Centers: Cleveland Clinic Foundation
Columbia University Medical CenterDana-Farber Cancer Institute
Duke University Medical CenterEmory University
Ohio State UniversityMassachusetts Eye and Ear
Massachusetts General HospitalMemorial Sloan Kettering Cancer Center
Mt. Sinai Medical CenterNYU Medical Center
Northwestern UniversityOregon Health Sciences University
University of California San FranciscoUniversity of Cincinnati
University of Miami Medical CenterUniversity of North CarolinaUniversity of Texas HoustonThomas Jefferson University
Vanderbilt University
CUMC UM Natural History Program: Participating Centers
• US National Cancer Institute
• European Organization for Research and Treatment of Cancer
• Cancer Research UK
• National Institute for Health Research Cancer Research Network
• Institut National Du Cancer
• National Cancer Institute of Canada Clinical Trials Group
Parallel International Natural History Efforts
UK/Europe Australia
Lead Investigator Joseph Sacco Anthony Joshua
Coordinating Organization Liverpool Clinical Trials Unit Garvan Institute of Medical
Research
Platform MACRO Save Sight Registry
Number of Centers 10 TBD
Critical Gaps in the UM Field
Epidemiology Primary Therapy
Adjuvant Therapy Surveillance
Management of Advanced
Disease
Vision preserving therapy for
primary disease
Surveillance strategies
Risk stratification
Effective tx in adjuvant setting
Effective tx in metastatic setting
Liver-directed & systemic tx
Risk factors
Compartmentalization of Biomedical Research
http://www.urmc.rochester.edu/ctsi/information/what-we-do.cfm
Bench to Bedside Translation: Laboratory
to Human
cMET and HGF is Overexpressed in Uveal Melanoma• Uveal melanomas overexpress c-MET in 60% - 86% of cases• Activating mutations or genetic amplifications of c-MET are uncommon• HGF/c-MET pathway activation is associated with inferior clinical outcomes
Surriga et al. Mol Cancer Ther 2013.
cMET Inhibition with Crizotinib Results in Decreased Cell Migration
Surriga et al. Mol Cancer Ther 2013.
Crizotinib Reduces Development of Uveal Melanoma Metastasis
Surriga et al. Mol Cancer Ther 2013.
Phase II Trial of Adjuvant Crizotinib in High-Risk Uveal Melanoma Following Definitive Therapy
Active Therapy Observation Follow-upo 48 weeks (12 four-week cycles)
of crizotinib 250 mg PO BIDo Routine bloodwork and physical
examination every 4 weeks o Imaging studies every 12 weeks.
o Patients who have distant disease recurrence during follow-up will then be contacted every 3 months (+/-2 weeks) to obtain vital status for at least 32 months from the start of active therapy.
o Imaging studies every 12 weeks until distant disease recurrence, withdrawal of patient consent, or study closure.
Primary Endpoint o Distant relapse free survival
Secondary Endpointso Overall survival, Disease specific survivalo Quality of life
Adjuvant Trials for Uveal MelanomaAgent(s) Phase Sponsor/Lead Center Clinicaltrials.gov ID
DTIC + Interferon* II Cleveland Clinic NCT01100528
Ipilimumab* I/II MDACC NCT01585194
Cisplatin, Tamoxifen + Sunitinib II San Diego Pacific Oncology NCT00489944
Fotemustine IV vs Observation III Institut Curie EudraCT Number 2008-005691-27
Dendritic Cell Vaccination * I/II Radboud University NCT00929019
Crizotinib II CUMC NCT02223819
Sunitinib vs Valproic Acid II Jefferson NCT02068586
Prophylactic Liver RT * II UCLA NCT02336763
(as of 1/27/2017)(* - accrual held/complete)
Oncogenic Drivers In Melanoma Subtypes
CutaneousTCGA
(n = 333)
ConjunctivalGreiwank et al
(n = 78)
MucosalSheng et al(n = 284)
Uveal (Primary)
TCGA(n = 80)
Uveal(Metastatic)
Piperno-Neumann et al
(n = 75)
BRAF 52% 29% 13% 0% 1%NRAS 28% 18% 8% 0% 1%NF1 14% NR NR 0% 1%KIT 7% 0 – 7% * 7% 0% NR
GNAQ 2% 0% 5% 50% 63%GNA11 3% 0% 5% 46% 33%
Akbani et al. Cell 2015; Sheng et al. Eur J Cancer 2016; Omholt et al. Clin Cancer Res 2011; Piperno-Neumann et al, ASCO 2014; Griewank KG et al. Clin Cancer Res 2013* Beadline et al, Clin Cancer Res 2008; Wallander et al. Mod Pathol 2011.
A Subway Map of Cancer Pathways
http://www.nature.com/nrc/poster/subpathways/index.html
MEK Inhibition has Clinical Activity in Uveal Melanoma
Ambrosini et al. Clin Cancer Res, 2012; Patel et al. CCR 2011; Carvajal et al. JAMA. 2014.
Selumetinib
Carvajal et al, Society for Melanoma Research, 2015.
No Improvement Observed with Selumetinib/DTIC vs Placebo/ DTICDTIC/Placebo vs DTIC/SelumetinibTMZ vs Selumetinib
PFS
RR
Carvajal et al, JAMA 2014Carvajal et al, SMR 2015
14% Response Rate(n = 5/49)
3% Response Rate(n = 3/97)
mPFS: 2.8 vs 1.8 months
Strategies to Improve MEK Inhibition Efficacy
2. Vertical Pathway Blockade 3. Dual Pathway Blockade
1. Optimizing Single Agent MEK Inhibition• Might other MEK inhibitors be more effective?• Are there alternative dosing schedules that can
improve efficacy?
• Can we block the MAPK pathway at multiple levels to improve outcomes?
• Can we block other parallel growth pathways to improve outcomes?
A A BMEK Inhibitor
Drug XMEK Inhibitor
Drug Y
Pharmacodynamic activity of selumetinib predicts radiographic
response in advanced uveal melanoma (abstract #8598)
Richard D. Carvajal1, Grazia Ambrosini1, Jedd D. Wolchok1, Paul B. Chapman1, Mark A. Dickson1, Sandra P. D'Angelo1, Mark J. Bluth2, Daniel
Paucar1, Anne Fusco1, David Bohr1, Ruth Ann Roman1, Mary Montefusco1, L. Austin Doyle5, Brian Marr3, David H. Abramson3, Joanne F. Chou4, Katherine Panageas4, Gary K.
Schwartz1
Departments of Medicine1, Radiology2, Ophthalmic Oncology3 and Epidemiology & Biostatistics4; Memorial Sloan-Kettering Cancer Center ; National Cancer Institute5
ASCO 2012
Clinical Benefit*n = 6
No Clinical Benefitn = 12 p
Median pERK (IQR) -81.4%(-58%, -96%)
-26.6% (11%, -60%) 0.04
Median CyclinD1 (IQR) -80.5% (-64%, -92%)
-63.7% (10%, -82%) 0.38
(* Clinical benefit defined as a RECIST response or SD > 16 weeks)
Sustained pathway inhibition is associated with improved clinical outcome
Multi-Center Phase I Study of Intermittent Dosing of the MEK Inhibitor, Selumetinib, in Patients with Advanced Uveal Melanoma not Previously
Treated with a MEK Inhibitor
Hypothesis: Intermittent dosing will enhance the tolerability of selumetinib, permit the use of higher drug doses, achieve greater pERK inhibition, and lead to greater anti-tumor effects
Specific Aims• To identify the spectrum of toxicities and the maximum tolerated dose
of selumetinib when administered on an intermittent dosing schedule;• To assess the efficacy of selumetinib in uveal melanoma when dosed
intermittently; and,• To use serial tumor biopsies to evaluate for changes in degree of
MAPK pathway inhibition at various dosing time points, and correlate these results with pharmacokinetic and clinical outcomes.
Resistant tumors emerge more rapidly under continuous dosing with vemurafenibTumor growth controlled on intermittent schedule with no resistance emerging
Resistance emerged in all mice
| AACR 2013 | Das Thakur
4 weeks on / 2 weeks off - No evidence of resistance
0200400600800
1,0001,200
59 79 99 119 139 159 179 199
Tum
or V
olum
e m
m3
Days Post Treatment
Intermittent dosing 15mg/kg Vemurafenib
0200400600800
1,0001,200
23 43 63 83 103 123 143 163 183Tum
or V
olum
e m
m3
Days
Continuous dosing 15mg/kg Vemurafenib
Start dose
Start doseStop dose
0 20 40 60 80 100 120 140 160 180 200
0 20 40 60 80 100 120 140 160 180 20021 Das Thakur et al. Nature. 2013.
Phase I Study of Intermittent Dosing of Selumetinib in Metastatic UM
Key Inclusion:• Metastatic or unresectable UM• ECOG ≤ 2• Measurable disease• No prior MEK, RAS, RAF inhibitor therapy
• Stats: Estimated ~28 subjects enrolled using TITE-CRM method• Primary endpoint: MTD and RP2D dose of intermittent selumetinib in UM
Dose Level Selumetinib Dose1 100mg BID2 125mg BID3 150mg BID4 175mg BID5 200mg BID6 225mg BID
C1W1 C1W2 C1W3 C1W4
3d ON 3d ON 3d ON 3d ON
Baseline Biopsy
On Tx Biopsy Off-TxBiopsy
POD Biopsy (optional)
4d OFF 4d OFF 4d OFF 4d OFF
Assess target inhibition and
Feedback activation
Assess for reversal of feedback
Assess for mechanismsof resistance
1 cycle = 4 weeks
PIP2
BYL719
PIP3
mTOR
GPCR
GDPINACTIVE
Ga
GTP
GNAQ/11Mutant
ACTIVE
Ga
CELL GROWTH
PI3K
PTEN
Akt
AEB071
MEKP
ERK P
PPKC
PRAF
NFkB
P
PLC
GSK2141795
SelumetinibTrametinib
PYAP
YAP
Rho Rac
Trio
LATS
YAPTEAD
Verteporfin
Inactive
ActiveAmot
YAPAmot
G-ActinHippo signaling
F-Actin
The Gα Pathway LXS196
Binimetinib
Molecularly Targeted Trials for Uveal MelanomaPathway Agent Phase Sponsor/Lead Center Clinicaltrials.gov ID
PKC/MEK
AEB071 + BYL719 I CUMC NCT02273219Intermittent Selumetinib I CUMC NCT02768766Binimetinib + AEB071 * I/II Novartis NCT01801358
LXS196 I Novartis NCT02601378
EpigeneticVorinostat II NCI/CUMC NCT01587352PLX51107 II CUMC pending
OtherSorafenib (STREAM Trial) * II Essen, Germany NCT01377025
Cabozantinib versus TMZ/DTIC II NCI/Alliance NCT01835145
Liver Directed Sorafenib + Radioembolization I Centre Hospitalier
Universitaire Vaudois NCT01893099
(as of 1/27/2017)(* - accrual held/complete)
• A number of abnormally expressed genes that distinguish between class 1 and 2 are known to be epigenetically regulated:
– Histone acetylation PHLDA1 , GSTM3, SPP1, ENDRB, and BTG1
– Micro RNAs PDCD4– Hypermethylation TIMP3, p16INK3a, 29
LZTS1
• Gene Set Enrichment Analysis and Connectivity mapping demonstrates that histone deacetylase inhibitors are predicted to shift class 21
Genes that Define Class 2 UM are Epigenetically Regulated
Landreville S et al. Clin Cancer Res 2012;18:408-416
“Reversal” of BAP1 Phenotype with HDACi
Landreville S et al. Clin Cancer Res 2012;18:408-416Harbour et al. Science 2010
Metastatic Uveal MelanomaAge ≥ 18ECOG 0-2Measurable Disease RESIST 1.1 Any # prior treatmentsTissue for GNAQ/GNA11/BAP1 typingAdequate End organ Function
Eligibility
Vorinostat300mg PO BID 3 of 7 days each week1 cycle = 4 weeks
Pre-Rx Evaluation 10 pts mandatory Bx
Treatment Evaluation
Week 2 paired Bx for 10 patients
-Toxicity by CTCAE 4.0 q 4 wk-Disease Assessment q 8 wk
(i.e. CT-CAP or MRI)
Phase II Trial of Vorinostat in Uveal Melanoma
Primary Endpoint: ORR (5% vs 20%)Secondary Endpoints: OS, PFS, Toxicity
Two Stage Design: 1/18 required to expand to 2nd stage; 3/32 to support 20% response rate (alpha and beta both 0 .1)
Conclusions• Uveal melanoma is a unique biological and clinical subset of melanoma that
require therapeutic considerations distinct from those required for cutaneous disease
• Emerging insights into the biology of uveal melanoma have led to the development of a series of novel immunological and targeted therapies which hold promise for improving the outcomes for patients with advanced disease
• Patient participation in clinical trials, both in the adjuvant and metastatic setting, remains the standard of care and is critical to the successful development of effective therapies for this challenging disease
Immunotherapy Trials for Uveal MelanomaAgent Phase Sponsor/Lead Center Clinicaltrials.gov ID
Pembrolizumab II Vanderbilt NCT02359851Ipilimumab/Nivolumab II MDACC NCT01585194
Ipilimumab/Nivolumab II Grupo Español Multidisciplinar de Melanoma NCT02626962
Ipilimumab + Radioembolization * I Case Comprehensive Cancer Center NCT01730157
Ipilimumab/Nivolumab + Radioembolization Feasibility California Pacific Medical Center
Research Institute NCT02913417
Glembatumumab Vedotin II NCI/MDACC NCT02363283
Tumor Infiltrating Lymphocytes II NCI NCT01814046
IMCgp100 I Immunocore NCT02570308
(* - accrual held/complete) (as of 1/27/2017)
Liver Targeted Trials for Uveal MelanomaAgent Phase Sponsor/Lead Center Clinicaltrials.gov ID
SIR-Spheres II Thomas Jefferson NCT01473004Liver Transplantation * II Oslo University NCT01311466
Isolated Hepatic Perfusion vs Best Alternative Care (SCANDIUM) III Sahlgrenska University NCT01785316
Sorafenib + SirSpheres I Centre Hospitalier Universitaire Vaudois NCT01893099
Ipilimumab/Radioembolization * 0 Case Comprehensive Cancer Center NCT01730157
SIR-Spheres, Ipilimumab and Nivolumab I California Pacific Medical Center Research Institute NCT02913417
SIR-Spheres vs Chemoembolization II Charite University, Berlin, Germany NCT02936388
Percutaneous Hepatic Perfusion vs Best Alternative Care (FOCUS) III Delcath Systems, Inc NCT02678572
(as of 1/27/2017)(* - accrual held/complete)
Bench to Bedside Translational Science
Schwartz Laboratory
• Grazia AmbrosiniMEK targetingBET targeting
• Oliver SurrigacMET targeting
• Elgilda Musi PKC targeting
Clinical TeamResearch Manager • Sarah DeNoble Regulatory Coordinator• Danielle Lacey Research Nurses• Amanda Carter• Shahnaz Singh Research Coordinators• Latoya Stewart• Lauren Taiclet
