Discussion of papers 3-4 and posters D-H, Session 1,
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Discussion of papers 3-4 and posters D-H, Session 1, CTOS, Prague, November 2012 Patrick Schöffski, Leuven, Belgium. Instructions received from Program C hair A. Gronchi. “... to discuss how presented data are going to change the landscape of sarcoma management today or tomorrow… ”.

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Instructions received from program c hair a gronchi

Discussion of papers 3-4 and posters D-H, Session 1, CTOS, Prague, November 2012Patrick Schöffski, Leuven, Belgium


Instructions received from program c hair a gronchi

Instructions received from Program Chair A. Gronchi

  • “...to discuss how presented data are going to change the landscape of sarcoma management today or tomorrow…”


Preclinical work

Preclinical work


Instructions received from program c hair a gronchi

ID 1436983, paper #3, p. 66Simultaneous autophagy induction and inhibition induces cell death through necroptosis in sarcomas that lack argininosuccinate synthetase 1 expressionPhilip A. Boone et al., St. Louis, USA


Instructions received from program c hair a gronchi

  • Conflict of interest of discussant:

    • None

  • Drug(s) tested:

    • Pegylated arginine delminase, an inhibitor of argininosuccinate synthase 1 (ASS 1), which is a key enzyme in the urea cycle

  • Experimental concept:

    • Study involving tissue samples, cell lines and xenografts using immunohistochemistry, assays for cell proliferation and cell death

  • Study aim(s):

    • To study the potential role of inhibition of ASS 1 in sarcoma models

    • Absence of ASS 1 associated with poor outcome in certain sarcomas

  • Key results:

    • ASS 1 not expressed in 85 % of sarcomas: promising

    • Arginine depletion by pegylated arginine delminase arrests cell cycle

    • Simultaneous autophagy induction and inhibition by chloroquin induces cell death through necroptosis in enzyme-negative sarcomas

  • Conclusions of authors:

    • Arginine depletion using pegylated arginine delminase may control tumor burden in sarcomas lacking ASS 1


Antiproliferative effects in mnng hos ass1 low osteosarcoma xenografts

Antiproliferative effects in MNNG/HOS ASS1 low osteosarcoma xenografts


Implications for the sarcoma community

Implications for the sarcoma community

  • New concept in sarcoma oncology: focusing on an absent molecular target

  • Clinical exploration of arginine depletion with pegylated arginine delminase +/- chloroquine (or related compounds that can be used in the clinic) warranted

  • Would suggest Phase 1 dose finding followed by disease-specific trial in ASS 1-negative bone and soft tissue sarcomas


Instructions received from program c hair a gronchi

ID 1408457 , paper #4, p. 66 Y box binding protein 1 (YB-1): a novel hypoxic response integrated factor steering sarcoma cell invasion & metastatic disseminationAmal Mohammad El-Naggar et al., Vancouver, Canada


Instructions received from program c hair a gronchi

  • Drug(s) tested:

    • None

  • Experimental concept:

    • Extensive preclinical study involving in vitro work, nude mice, zebrafish, genetically modified cells and various assays exploring cell motility and metastasis-promoting capacity of YB-1

  • Study aim(s):

    • To assess the potential role of YB-1 in sarcomas

    • YB-1 is a multifunctional cellular protein that mediates malignant transformation, cell migration and drug resistance, and is involved in epithelial-to-mesenchymal transition (EMT)

    • Key results:

    • YB-1 found to contribute to sarcoma cell motility (likely through its downstream mediator HIF1a), invasion and metastasis

  • Conclusions of authors:

    • YB-1 is a potential target for the treatment of metastatic sarcomas


Proposed mechanism for the interaction between yb 1 and hif1a

Proposed mechanism for the interaction between YB-1 and HIF1a

HIF1α Translation

VEGF & neovascularization

YB-1

Hypoxic Induction

(Cap-independent Mechanism?)

Tumor Progression

Metastatic Dissemination of sarcoma cells


Implications for the sarcoma community1

Implications for the sarcoma community

  • No immediate implications as it is unclear whether YB-1 is druggable with specific agents

  • Methodological challenge: clinical trial designs to assess anti-migratory or anti-metastatic capacity of new treatments are far from being optimal


Instructions received from program c hair a gronchi

ID 1436950, poster H, p. 69Trabectedin and PARP-1 inhibitors combination in preclinical models of bone and soft tissue sarcomaYmera Pignochino et al., Torino, Italy


Instructions received from program c hair a gronchi

  • Drug(s) tested:

    • Trabectedin, a DNA-minor groove binder

    • Olaparib and veliparib as PARP inhibitors

  • Experimental concept:

    • Preclinical study using cell lines of soft tissue and bone sarcomas, exploring the interaction between trabectedin and two PARP inhibitors

  • Study aim(s):

    • To demonstrate in vitro-synergism between the minor groove binder and olaparib/veliparib

  • Key results:

    • Trabectedin induces strong activation of PARP1 enzymatic activity in sarcoma cell lines

    • PARP1-inhibitors potentiate DNA damage induced by trabectedin

  • Conclusions of authors:

    • Trabectedinand PARP-inhibitors show synergistic anti-proliferative effects in sarcoma cell lines, with induction of cell cycle arrest and apoptosis


How does trabectedin interact with parp i

How does trabectedin interact with PARP-I?

3


Implications for the sarcoma community2

Implications for the sarcoma community

  • Would suggest a disease-specific Phase 1 study of trabectecin + PARP inhibitor (e.g. in sarcomas, breast cancer and ovarian cancer), involving sequential biopsies

  • Window-of-opportunity trial, e.g. in myxoid/ roundcell liposarcoma prior to surgery, with extensive pharmacodynamic tissue sampling

  • Bottleneck: availability of PARP-inhibitors


Clinical data

Clinical data


Instructions received from program c hair a gronchi

ID 1437492 , poster D, p. 67A phase II trial of novel anthracycline amrubicin in patients with advanced soft tissue sarcomaLaunce G. Gouw et al., Salt Lake City, USA


Instructions received from program c hair a gronchi

  • Drug(s) tested:

    • Amrubicin

  • Experimental concept:

    • Ongoing single-arm, open label Phase 2 trial in treatment-naive soft tissue sarcoma

  • Study aim(s):

    • Clinical: to study RR, PFS, safety and toxicity, OS

    • Translational: genomic and proteomic biomarkers

  • Key results:

    • AEs similar to experience with drug in other indications

    • No cardiotoxicity, no hematological toxicity

    • PR 25%, SD 58%, CBR 83%

    • Conclusions of authors:

    • Well-tolerated and encouraging activity in sarcoma

    • Further studies warranted as single-agent or in combination


Tumor shrinkage and waterfall plot response surrogate n 12

Tumor shrinkage and waterfall plot response surrogate (n=12)


Implications for the sarcoma community3

Implications for the sarcoma community

  • Randomized trial(s) required to assess the added value of this anthracyclin as compared to established treatment standard doxorubicin

  • Drug competes with a number of other innovative anthracyclin derivatives (non-cardiotoxic, tumor-activated, temperature-activated prodrugs...)

  • Non-inferiority trial comparing with doxorubicin will unlikely satisfy regulatory agencies and will not be the most attractive design for investigators

  • Drug qualifies for combination trials given its good safety profile, e.g. Phase 1 combo with palifosfamide


The benchmark eortc trial 62012

The benchmark: EORTC trial 62012

Overall survival (primary endpoint)

Response rate:

Doxorubicin 13.6 %

Progression-free survival:

Doxorubicin 4.6 mo

(95% CI 2.9 – 5.6)

Overall survival:

Doxorubicin 12.8 mo

(95.5 CI 10.5-14.3)

Survival at 1-year:

Doxorubicin 51 %

(95.5% CI 44-58)

HR = 0.83

(95.5% CI 0.67 – 1.03)

p = 0.076

Progression-free survival

HR = 0.74

(95% CI 0.60 – 0.90)

p = 0.003

Judson, Verweij, Gelderblom, Hartmann , Schöffski , Blay, deiTos, Marreaud , Litiere, van der Graaf, ESMO Vienna 2012


Instructions received from program c hair a gronchi

ID 1426644, poster G, p. 69Aldoxorubicin (INNO-206) is an active drug for the treatment of relapsed or refractory soft tissue sarcomasSant Chawla et al., Los Angeles, USA


Instructions received from program c hair a gronchi

  • Drug(s) tested:

    • Aldoxorubicin (INNO-206) is a prodrug of doxorubicin that binds to albumin through a specific linker

    • Active compound released due to the acidic environment of the tumor

  • Experimental concept:

    • Ongoing Phase 2 trial in sarcoma patients who failed prior chemo

    • Safety and efficacy of aldoxorubicin 350 mg/m2 (260 mg/m2 doxorubicin-equivalent) as single agent given i.v. q3w for up to 8 cycles

  • Study aim(s):

    • To explore the safety and efficacy of aldoxorubicin in previously treated sarcoma patients

  • Key results:

    • No relevant cardiotoxicity in patients exposed to high cumulative doses

    • Febrile neutropenia, sepsis and mucositis as SAEs

  • Conclusions of authors:

    • High cumulative doses can be administered even in anthracyclin-pretreated patients, with evidence of antitumor efficacy


Waterfall plot response surrogate n 13

Waterfall plot response surrogate (n=13)


Implications for the sarcoma community4

Implications for the sarcoma community

  • Randomized trial(s) required to assess the value of this anthracyclin as compared to doxorubicin in first line

  • Alternative strategy to explore the drug in patients progressing after previous response to doxorubicin

  • Drug competes with other innovative anthracyclin derivatives in the first line setting, and regulators will likely require more than a non-inferiority trial

  • In second line it would compete with trabectedin, pazopanib and a number of off label-treatments

  • Dose finding trial combining aldoxorubicin with palifosfamide to be considered as a strategic option


Instructions received from program c hair a gronchi

ID 1435530, poster E, p. 67TH-302 maintenance following TH-302 + doxorubicine induction: the results of a phase 2 studyKristen N. Ganjoo et al., Stanford, USA


Instructions received from program c hair a gronchi

  • Drug(s) tested:

    • Doxorubicin + TH-302, a prodrug of the DNA-crosslinking alkylator bromo-isophosphoramide mustard, that releases the active moeity under hypoxic conditions

  • Experimental concept:

    • Analysis of 48 patients who continued with maintenance TH-302 after having received up to 6 cycles of doxorubicin

  • Study aim(s)

    • To explore the role of TH-302 maintenance

  • Key results:

    • 53 % of patients entered maintenance period of Phase 2 trial after achieving CR, PR, SD, receiving TH-302 doses ranging between 300-167 mg days 1+8 q3w

    • 5 SDs converted to PR, 1 PR converted to CR during maintenance

  • Conclusions of authors:

    • Maintenance with TH-302 is well tolerated with limited hematological and manageable skin/mucosal toxicity; no cumulative toxicity during maintenance


Combining cytotoxic chemotherapy and hypoxia activated th 302

Combining cytotoxic chemotherapy and hypoxia-activated TH-302


Implications for the sarcoma community5

Implications for the sarcoma community

  • Supportive evidence for ongoing TH-CR-406/ SARC021 Phase 3 study comparing doxorubicin with doxorubicin/TH-302, which involves TH-302 maintenance (primary endpoint: overall survival)

  • Ongoing trial is performed in an increasingly competitive trial environment

    • EORTC 62012 comparing doxorubicin with doxorubicin/ifosfamide failed to meet OS endpoint

    • Phase 3 with doxorubicin vs. doxorubicin/palifosfamide already completed accrual (primary endpoint: PFS)


Instructions received from program c hair a gronchi

ID 1426542, poster F, p. 68Phase I trial of abexinostat and doxorubicine in patients with metastatic sarcomaEdwin Choy et al., Boston, USA


Instructions received from program c hair a gronchi

  • Drug(s) tested:

    • Doxorubicin and abexinostat (PCI-24781), a HDAC inhibitor with preclinical activity in sarcoma cell lines and xenografts

  • Experimental concept:

    • Phase 1b dose finding study of abexinostat combined with doxorubicin

  • Study aim(s):

    • To identify MTD, safety, tolerability, PK and PD of abexinostat when administered on days 1-5 with doxorubicin 75 mg/m2 on day 4 q3w (+/- G-CSF ) in patients with advanced sarcoma

  • Key results:

    • DLTs included grade 3 and 4 neuropenia without G-CSF grade 3 infection and grade 4 thrombocytopenia with G-CSF

    • In 17 participants evaluable for response there was 1 PR and 12 SD, and 7 patients continued >=5 cycles

  • Conclusions of authors:

    • Abexinostatcan be safely combined with full dose doxorubicin, toxicity is manageable with G-CSF support, clinical benefit seen


Most common aes in phase 1 trial combining abexinostat and doxorubicin

Most common AEs in Phase 1 trial combining abexinostat and doxorubicin


Implications for the sarcoma community6

Implications for the sarcoma community

  • Drug combination could be explored in a randomized Phase 2 study, with doxorubicin as the standard arm, involving maintenance with the HDAC inhibitor

  • Is the evidence for HDAC inhibition in sarcoma strong enough to embark on large, expensive trials?

  • If Phase 2 would generate a convincing efficacy signal the consecutive registration trial would have to be performed in an increasingly competitive environment

    • Outcome of Phase 3 with doxorubicin vs. doxorubicin/ palifosfamide likely reported at that point

    • Phase 3 trial doxorubicin vs. doxorubicin/Th-302 likely completed accrual at that point


Congratulations to all authors and sponsors of the presented work

Congratulations to all authors and sponsors of the presented work


Please show your real excitement for all the good work presented in session 1

Please show your real excitement for all the good work presented in Session 1 

Hypnosis conference


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