DEBRA Members Weekend 2017 First in EB Phase II trial of Rigosertib - PowerPoint PPT Presentation

DEBRA Members’ Weekend 2017 “First in EB” Phase II trial of Rigosertib for RDEB SCC Andy South Premium sponsors:

"First in EB" Phase II trial of Rigosertib for RDEB SCC Andy South

1. Cancer and how do we treat it? 2. Rigosertib for RDEB Cancer treatment 3. Rigosertib Clinical Trial

Overall SCC Survival (5yr) Skin SCC: >99% Esophagus SCC: ~15% Head and Neck SCC: 50-60% Lung SCC: 55-65% Cervix SCC: ~70% Bladder SCC: 28-33% RDEB SCC: LOW

What goes wrong in cancer? Gius et al., 2007 Can Res 67: 7113-23

What goes wrong in cancer? Differentiation Proliferation decreases increases

Cancer Progression: Increasing Mutation Gius et al., 2007 Can Res 67: 7113-23

SCC Mutation:

How do we treat cancer? Differentiation Proliferation decreases increases Poison

How do we treat cancer? Differentiation Proliferation decreases increases Target the gene responsible for proliferation

Targeted therapy works… Wagle et al, 2011 J Clin Onc 29: 3085-3096

…but has problems Wagle et al, 2011 J Clin Onc 29: 3085-3096

Tumor complexity represents significant barrier to cancer therapy: Therapy A B B A E E F F C C D D Genotype B Tumor

RDEB tumors are not complex

Recessive Dystrophic Epidermolysis Bullosa SCC Currently there is no cure for RDEB SCC Standard of care for RDEB SCC is limited to surgery with wide local excision Mellerio et al, 2015

PLK1 is a therapeutic target in RDEB SCC Watt et al., 2011 Oncogene

PLK1 is a recognized cancer target Talati et al., 2016 Crit. Rev. Onc/Hem.

Increased PLK1 expression in RDEB SCC RDEB Mw Normal SCC (KDa) RDEB cSCC 150 100 75 PLK1 55 37 GAPDH Non-SCC RDEB Skin PLK1 DAPI PLK1 DAPI

PLK1 siRNA reduces cSCC viability *** *** SCCK NHK Watt et al., 2011 Oncogene

PLK1 inhibition reduces SCC viability *** *** Watt et al., 2011 Oncogene

2012 Debra funded project: Screen commercially available PLK1 inhibitors for RDEB SCC specificity

PLK1 Inhibitor Screen Inhibitor Pharma Supplier PLK1 IC50 Clinical Delivery References trial BI 2536 Boehringer Ingelheim, Selleck Chemicals, IC50 0.83nM Phase II IV Steegmaier et al. Current Ingelheim, Germany Houston, TX complete Biology.2007 17(4):316-322 GW843682X GlaxoSmithKline, Tocris Biosciences, IC50 2.2nM Lansing et al (2007) Middlesex, UK Bristol, UK Mol.Cancer Ther. 6 450. GSK461364 GlaxoSmithKline, Selleck Chemicals, IC50 2.2nM Phase I IV Sato Y et al. Bioorg Med Middlesex, UK Houston, TX EC50 <100nm complete Chem Lett. 2009 in cell lines 19(16):4673-8. TKM-080301 Tekmira Phase I IV Pharmaceuticals recruiting Corporation NMS-1286937 Nerviano Medical Active Biocehmical Phase I Oral Beria et al., Presented at Sciences, Milano, Italy Co., Ltd. or Jihpharma recruiting EORTC-NCI-AACR 2008; Geneva, Switzerland. BI 6727 Boehringer Ingelheim, Shanghai Sun-shine Phase II IV Rudolph et al., Presented at Ingelheim, Germany Chemical Technology recruiting EORTC-NCI-AACR Co., Ltd. Geneva, Switzerland, 2008. CYC-800 Cyclacel Ltd, Dundee, EC50 low nM Oral AACR 2010 abstract UK range TAK-960 Millennium Phase I Oral Pharmaceuticals, Inc. recruiting ON-01910 Onconova Therapeutic, Selleck Chemicals, IC50 9nM Phase II IP Gumireddy K et al. Cancer Newtown, PA Houston, TX EC50 50- recruiting Cell. 2005 7(3):275-86. 250nM HMN-214 Nippon Shinyaku Co. Selleck Chemicals, EC50 118nM Oral Tanaka H et al. Cancer Ltd, Kyoto, Japan Houston, TX Res. 2003 63:6942-7 5-(5,6-Dimoxy-1 H - OTAVA Ltd, Toronto, IC50 6.9nM benzi-1-yl)-3-[[4- Canada (methylsulfonyl)phen yl]methoxy]-2-T. ZK-Thiazolidinone Bayer N/A IC50 19nM Santamaria et al (2007) Mol (TAL) Schering Pharma AG Cell lines Biol Cell EC50 0.2- 18, 4024-4036 1.3uM DAP-81 Rockefeller University, IC50 0.9nM Peters et al., Nat Chem Biol New York 2006;2:618–626.

Rigosertib has specificity of three orders magnitude Rigosertib Concentration 48 hrs exposure DMSO 0.01uM 0.1uM 1uM 10uM 100uM Primary Foreskin Keratinocytes Primary Breast Keratinocytes Primary RDEB 85 Keratinocytes Primary RDEB 93 Keratinocytes RDEB 2 SCC Keratinocytes RDEB 3 SCC Keratinocytes RDEB 4 SCC Keratinocytes

Rigosertib has specificity of three orders magnitude Primary keratinocytes Primary keratinocytes 1uM 72 hrs control 72 hrs

Rigosertib has specificity of three orders magnitude RDEB SCC keratinocytes RDEB SCC keratinocytes control 24 hrs 1uM 24 hrs 7/7 RDEB SCC keratinocyte populations are sensitive to rigosertib

Rigosertib targets RDEB SCC in vivo SCCRDEB16.4 1200 Vehicle 1000 Tumour volume (mm3) treatments 800 600 PBS Control n=6 ON-01910 n=6 ON- 400 01910 ON-01910 BI2536 n=2 BI2536 200 0 0 2 4 7 9 11 14 16 18 21 23 25 Days

“First in EB” phase II trial of rigosertib for treatment of RDEB SCC Prof Johann Bauer Prof Jemima Mellerio Paracelsus Medical University Salzburg Guys and St Thomas Hospital

Rigosertib First described as a PLK1 inhibitor Gumireddy et al., 2005 Can Cell

Rigosertib Now described as a RAS mimetic Athuluri-Divakar et al., 2016

HRAS is mutated in RDEB SCC

Rigosertib: a phase III clinical stage anti-cancer agent Clinicaltrials.gov

Rigosertib can be taken orally (either pill or liquid)

Aim: to recruit 6-10 patients over 3 years who are refractory to standard of care Anti-tumor activity of rigosertib Maximum tolerated dose

How does the trial work? Patient with late stage cancer is given the option of joining the trial

How does the trial work? Oral dose, either capsule or liquid formulation 2 weeks on 1 week off, outpatient visit every 3 weeks

How does the trial work? Every 3 cycles tumor is measured Biomarker analysis done to match tumor with response

Acknowledgements London Colorado John McGrath Anna Bruckner William Robinson Salzburg Christina Gruber Stanford Peter Marinkovich Monterrey Heather Cohn Julio Salas-Alanis Santiago Sydney Igancia Fuentes Dedee Murrell Francis Pallison Singapore Paris Birgit Lane Alain Hovnanian Chapel Hill Thomas Jefferson Matthias Titeux Jo-David Fine Evan Greenawalt Groningen Freiberg Timothy Webster Marcel Jonkman Leena Bruckner- Rebecca Russell Tuderman Velina Atanasova Christina Has Joya Sahu Sidney Kimmel Cancer Center Gold Goal Line award. Jouni Uitto

DEBRA Members’ Weekend 2017 “First in EB” Phase II trial of Rigosertib for RDEB SCC Andy South Premium sponsors: