LET THE NEXT TREATMENT BE THE RIGHT TREATMENT

Personalized Ewing’s Sarcoma Case

Personalized Ewing’s Sarcoma Case Patient History (10 yo) • • Was diagnosed at age 6 (2009) with Ewing’s Sarcoma of the scapula with bilateral pulmonary metastases. EWS-FLI 1 fusion gene rearrangement was confirmed Initial therapy consisted of high dose vincristine, doxorubicin and cyclophosphamide alternating with ifosfamide and etoposide • Scapulectomy revealed predominantly viable residual tumor (2010) • Consolidative whole lung-irradiation was followed by a completion of 6 cycles of maintenance therapy using irinotecan and temozolomide (2011) • Recurrent pulmonary metastases were developed and resected following 7 cycles of cyclophosphamide and topotecan therapy (2012) Patient pulmonary tumor was resected on February 2012 and engrafted in immunedeficient mice in order to form a Personalized Tumor. Graft model Rapid disease progression occurred during continued treatment with cyclophosphamide and topotecan followed by further aggressive progression over one month during treatment on a phase I trial

The Tumor. Graft Process RECOVERY FIRST ROUND TUMORGRAFT PATIENT SURGERY RESECTION ENGRAFTMENT EXPANSION Preserve cancer cell heterogeneity Retain supporting microenvironment Maintain Intrinsic Cross-Talk Superior Pre-Clinical Model for Translational Oncology Ultimate Model for Personalized Oncology TREATMENT

Personalized Ewing’s Sarcoma Case Patient Sample Tumor. Graft 2000 Control Gemcitabine/Docetaxel/Pazopanib Mithramycin A Pazopanib Gemcitabine/Docetaxel/Bevacizumab 1800 Group %TGI %TR Gemcitabine/Docetaxel/Pazopanib 62 n/a Gemcitabine/Docetaxel/Bevacizumab 122 64 Mithramycin A n/a Tumor Volume (mm 3) 1600 1400 1200 1000 800 600 400 200 0 0 Pazopanib 47 n/a Gemcitabine 0 n/a 4 6 9 13 16 20 Test Day 23 27 30 34 41

Personalized Ewing’s Sarcoma Case December 5, 2012 March 20, 2013 • In December 2012 the patient commenced treatment with the combination of gemcitabine+docetaxel+bevacizumab • Initially suffered from acral dermatitis (treated locally) • Scans performed at 6 weeks demonstrated clear clinical benefit (PR) • Treatment continued and further tumor reduction was observed for a duration of 9 months Metastasis December 5 January 21 % Reduction Left lung upper lobe 2. 1 x 1. 3 1. 8 x 1. 2 21 Left lung lower lobe 3. 8 x 2. 8 2. 9 x 1. 8 51 Left lung lower lobe 3. 8 x 3. 1 2. 9 x 1. 9 53 Pleura / Pericardium 2. 6 x 1. 1 2. 2 x 0. 4 70 Mediastinum node 5. 1 x 4. 1 3. 7 x 2. 3 59

Sarcoma Experience 37 patients 11 failed to grow 37 26 16 successful clinical correlations 6 haven't proceeded to study 20 SOC drugs Off-label drugs Investigational drugs

Sarcoma Experience Case Previous Treatment Avatar Treatment Response Leiomyosarcoma *gemcitabine/docetaxel/bevacizumab (PR, 9 M) 45 yo male *doxorubicin/ifosfamide *sorafenib/temozolomide (PR, 9 M) *docetaxel/irinotecan/bevacizumab (PR, 9 M) Chondrosarcoma 50 yo male Liposarcoma *CDK 4 inhibitor *ifosfamide (PR, 5 M) 56 yo male *JAK 2 inhibitor *regorafenib (PR, 7 M) Pleomorphic Undiff. *docetaxel/gemcitabine *doxorubicin (CR, >17 M) Ewing’s Sarcoma *vincristine/doxorubicin/cyclophosphamide *docetaxel/gemcitabine/bevacizumab (PR, 8 M) 9 yo boy *ifosfamide/etoposide 52 yo female *irinotecan/temozolomide *cyclophosphamide/topotecan Fibromyxoid Sarcoma *gemcitabine 48 yo male *cyclophosphamide *doxorubicin *sorafenib *temozolomide/irinotecan (PR, >6 M)

Predictive Power of Tumor. Grafts 85 Drug Tests with Clinical Correlation Tumor. Graft Implantation Positive Negative Total Positive 67 6 73 Negative 1 11 12 Total 68 16 85 • Clinical Sensitivity • Clinical Specificity • PPV: • NPV: Patient 67/68 = 98. 5% 11/16 = 68. 8% 67/73 = 91. 8% 11/12 = 91. 7% Growth Study Treatment Outcome >90% Accuracy

Clinical Validation studies Ovarian Validation Study – Target start December 2013 Sarcoma – Target start January 2014 GI – Unknown Primary (UK) – in development Lung Validation Study – in development Breast Validation Study – in development • • • Phase II Trial Investigator-initiated Newly diagnosed patients First line therapy Standard cytotoxic Monotherapy and combination Primary objective – response rate Secondary objective - PFS Doxorubicin Ifosfamide Doxorubicin + Ifosfamide Gemcitabine + Docetaxel