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

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

Jul 15, 2023 26 likes •420 views

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.

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Premium sponsors:

DEBRA Members’ Weekend 2017

“First in EB”

Phase II trial of Rigosertib for RDEB SCC Andy South

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

Andy South

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  • 1. Cancer and how do we treat it?
  • 2. Rigosertib for RDEB Cancer

treatment

  • 3. Rigosertib Clinical Trial
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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

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What goes wrong in cancer?

Gius et al., 2007 Can Res 67: 7113-23

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What goes wrong in cancer?

Proliferation increases Differentiation decreases

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Gius et al., 2007 Can Res 67: 7113-23

Cancer Progression:

Increasing Mutation

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SCC Mutation:

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How do we treat cancer?

Proliferation increases Differentiation decreases Poison

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How do we treat cancer?

Proliferation increases Differentiation decreases Target the gene responsible for proliferation

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Targeted therapy works…

Wagle et al, 2011 J Clin Onc 29: 3085-3096

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…but has problems

Wagle et al, 2011 J Clin Onc 29: 3085-3096

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Tumor complexity represents significant barrier to cancer therapy:

A

B

C D

E

F

Tumor

Therapy A

B

C D

E

F

Genotype B

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RDEB tumors are not complex

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Recessive Dystrophic Epidermolysis Bullosa SCC

Mellerio et al, 2015

Currently there is no cure for RDEB SCC Standard of care for RDEB SCC is limited to surgery with wide local excision

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PLK1 is a therapeutic target in RDEB SCC

Watt et al., 2011 Oncogene

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PLK1 is a recognized cancer target

Talati et al., 2016 Crit. Rev. Onc/Hem.

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Increased PLK1 expression in RDEB SCC

Non-SCC RDEB Skin RDEB cSCC

Mw

(KDa)

150 100 75 55 37

PLK1 GAPDH PLK1 DAPI PLK1 DAPI

Normal RDEB SCC

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PLK1 siRNA reduces cSCC viability

***

SCCK NHK

Watt et al., 2011 Oncogene ***

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PLK1 inhibition reduces SCC viability

Watt et al., 2011 Oncogene *** ***

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

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Inhibitor Pharma Supplier PLK1 IC50 Clinical trial Delivery References BI 2536 Boehringer Ingelheim, Ingelheim, Germany Selleck Chemicals, Houston, TX IC50 0.83nM Phase II complete IV Steegmaier et al. Current Biology.2007 17(4):316-322 GW843682X GlaxoSmithKline, Middlesex, UK Tocris Biosciences, Bristol, UK IC50 2.2nM Lansing et al (2007) Mol.Cancer Ther. 6 450. GSK461364 GlaxoSmithKline, Middlesex, UK Selleck Chemicals, Houston, TX IC50 2.2nM EC50 <100nm in cell lines Phase I complete IV Sato Y et al. Bioorg Med Chem Lett. 2009 19(16):4673-8. TKM-080301 Tekmira Pharmaceuticals Corporation Phase I recruiting IV NMS-1286937 Nerviano Medical Sciences, Milano, Italy Active Biocehmical Co., Ltd. or Jihpharma Phase I recruiting Oral Beria et al., Presented at EORTC-NCI-AACR 2008; Geneva, Switzerland. BI 6727 Boehringer Ingelheim, Ingelheim, Germany Shanghai Sun-shine Chemical Technology Co., Ltd. Phase II recruiting IV Rudolph et al., Presented at EORTC-NCI-AACR Geneva, Switzerland, 2008. CYC-800 Cyclacel Ltd, Dundee, UK EC50 low nM range Oral AACR 2010 abstract TAK-960 Millennium Pharmaceuticals, Inc. Phase I recruiting Oral ON-01910 Onconova Therapeutic, Newtown, PA Selleck Chemicals, Houston, TX IC50 9nM EC50 50- 250nM Phase II recruiting IP Gumireddy K et al. Cancer

  • Cell. 2005 7(3):275-86.

HMN-214 Nippon Shinyaku Co. Ltd, Kyoto, Japan Selleck Chemicals, Houston, TX EC50 118nM Oral Tanaka H et al. Cancer

  • Res. 2003 63:6942-7

5-(5,6-Dimoxy-1H- benzi-1-yl)-3-[[4- (methylsulfonyl)phen yl]methoxy]-2-T. OTAVA Ltd, Toronto, Canada IC50 6.9nM ZK-Thiazolidinone (TAL) Bayer Schering Pharma AG N/A IC50 19nM Cell lines EC50 0.2- 1.3uM Santamaria et al (2007) Mol Biol Cell 18, 4024-4036 DAP-81 Rockefeller University, New York IC50 0.9nM Peters et al., Nat Chem Biol 2006;2:618–626.

PLK1 Inhibitor Screen

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Primary Breast Keratinocytes Primary Foreskin Keratinocytes Primary RDEB 85 Keratinocytes Primary RDEB 93 Keratinocytes RDEB 2 SCC Keratinocytes RDEB 3 SCC Keratinocytes RDEB 4 SCC Keratinocytes DMSO 0.01uM 0.1uM 1uM 10uM 100uM Rigosertib Concentration 48 hrs exposure

Rigosertib has specificity of three

  • rders magnitude
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Primary keratinocytes control 72 hrs Primary keratinocytes 1uM 72 hrs

Rigosertib has specificity of three

  • rders magnitude
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RDEB SCC keratinocytes 1uM 24 hrs RDEB SCC keratinocytes control 24 hrs

7/7 RDEB SCC keratinocyte populations are sensitive to rigosertib

Rigosertib has specificity of three

  • rders magnitude
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200 400 600 800 1000 1200 2 4 7 9 11 14 16 18 21 23 25

Tumour volume (mm3) Days

SCCRDEB16.4

PBS ON- 01910 BI2536

treatments

Control n=6 ON-01910 n=6 BI2536 n=2 Vehicle ON-01910

Rigosertib targets RDEB SCC in vivo

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“First in EB” phase II trial of rigosertib for treatment of RDEB SCC

Prof Jemima Mellerio Guys and St Thomas Hospital Prof Johann Bauer Paracelsus Medical University Salzburg

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Rigosertib

First described as a PLK1 inhibitor

Gumireddy et al., 2005 Can Cell

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Rigosertib

Now described as a RAS mimetic

Athuluri-Divakar et al., 2016

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HRAS is mutated in RDEB SCC

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Rigosertib: a phase III clinical stage anti-cancer agent

Clinicaltrials.gov

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Rigosertib can be taken orally (either pill or liquid)

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Aim: to recruit 6-10 patients over 3 years who are refractory to standard

  • f care

Anti-tumor activity of rigosertib Maximum tolerated dose

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

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

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

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Acknowledgements

Thomas Jefferson Evan Greenawalt Timothy Webster Rebecca Russell Velina Atanasova Joya Sahu Jouni Uitto

Sidney Kimmel Cancer Center Gold Goal Line award.

London John McGrath Salzburg Christina Gruber Monterrey Julio Salas-Alanis Sydney Dedee Murrell Singapore Birgit Lane Chapel Hill Jo-David Fine Freiberg Leena Bruckner- Tuderman Christina Has Colorado Anna Bruckner William Robinson Stanford Peter Marinkovich Heather Cohn Santiago Igancia Fuentes Francis Pallison Paris Alain Hovnanian Matthias Titeux Groningen Marcel Jonkman

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Premium sponsors:

DEBRA Members’ Weekend 2017

“First in EB”

Phase II trial of Rigosertib for RDEB SCC Andy South