LET THE NEXT TREATMENT BE THE RIGHT TREATMENT
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Transcript of LET THE NEXT TREATMENT BE THE RIGHT TREATMENT
LET THE NEXT TREATMENTBE THE RIGHT TREATMENT
Personalized Ewing’s Sarcoma Case
Patient History (10yo)
• Was diagnosed at age 6 (2009) with Ewing’s Sarcoma of the scapula with bilateral pulmonary metastases. EWS-FLI1 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)
Personalized Ewing’s Sarcoma Case
Patient pulmonary tumor was resected on February 2012 and engrafted in immune-deficient mice in order to form a Personalized TumorGraft 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
TU
MO
RG
RA
FTPA
TIE
NT
FIRST ROUND
EXPANSION TREATMENT
RECOVERY
ENGRAFTMENTRESECTION
SURGERY
The TumorGraft Process
Preserve cancer cell heterogeneityRetain supporting microenvironment
Maintain Intrinsic Cross-Talk
Superior Pre-Clinical Model for Translational OncologyUltimate Model for Personalized Oncology
0 4 6 9 13 16 20 23 27 30 34 410
200
400
600
800
1000
1200
1400
1600
1800
2000 ControlGemcitabine/Docetaxel/PazopanibMithramycin APazopanibGemcitabineGemcitabine/Docetaxel/Be-vacizumab
Test Day
Tum
or V
olum
e (m
m3)
Patient Sample TumorGraft
Personalized Ewing’s Sarcoma Case
Group %TGI %TR
Gemcitabine/Docetaxel/Pazopanib 62 n/a
Gemcitabine/Docetaxel/Bevacizumab 122 64
Mithramycin A n/a n/a
Pazopanib 47 n/a
Gemcitabine 0 n/a
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
Personalized Ewing’s Sarcoma Case
37 patients
Sarcoma Experience
11 failed to grow
6 haven't proceeded to study16 successful clinical correlations
37
26
20
SOC drugs
Off-label drugs
Investigational drugs
Leiomyosarcoma
45yo male
Case Previous Treatment Avatar Treatment Response*gemcitabine/docetaxel
*doxorubicin/
ifosfamide
*gemcitabine/docetaxel/bevacizumab (PR, 9M)
*sorafenib/temozolomide (PR, 9M)
Chondrosarcoma
50yo male
*docetaxel/irinotecan/bevacizumab (PR, 9M)
Liposarcoma
56yo male
*CDK4 inhibitor
*JAK2 inhibitor
*ifosfamide (PR, 5M)
*regorafenib (PR, 7M)
Pleomorphic Undiff.
52yo female
*docetaxel/gemcitabine *doxorubicin (CR, >17M)
Ewing’s Sarcoma
9yo boy
*vincristine/doxorubicin/
cyclophosphamide *ifosfamide/etoposide
*irinotecan/temozolomide
*cyclophosphamide/topotecan
*docetaxel/gemcitabine/bevacizumab (PR, 8M)
Fibromyxoid Sarcoma
48yo male
*gemcitabine
*cyclophosphamide
*doxorubicin
*sorafenib
*temozolomide/irinotecan (PR, >6M)
Sarcoma Experience
Predictive Power of TumorGrafts
85 Drug Tests with Clinical Correlation
>90% Accuracy
Patient
Positive Negative Total
TumorGraftPositive 67 6 73
Negative 1 11 12 Total 68 16 85
• Clinical Sensitivity 67/68 = 98.5% • Clinical Specificity 11/16 = 68.8%
• PPV: 67/73 = 91.8% • NPV: 11/12 = 91.7%
Implantation Growth Study Treatment Outcome
Ovarian Validation Study – Target start December 2013 Sarcoma – Target start January 2014GI – Unknown Primary (UK) – in developmentLung Validation Study – in developmentBreast 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
Clinical Validation studies
• Doxorubicin• Ifosfamide• Doxorubicin + Ifosfamide• Gemcitabine + Docetaxel