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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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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…”



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


  • 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


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


  • 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 HIF1a

  • 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


ID HIF1a 1436950, poster H, p. 69Trabectedin and PARP-1 inhibitors combination in preclinical models of bone and soft tissue sarcomaYmera Pignochino et al., Torino, Italy


  • Drug(s) tested: HIF1a

    • 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 HIF1a does trabectedin interact with PARP-I?

3


Implications for the sarcoma community2
Implications for the sarcoma community HIF1a

  • 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



ID HIF1a 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


  • Drug(s) tested: HIF1a

    • 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



Implications for the sarcoma community3
Implications for the sarcoma community HIF1a

  • 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 HIF1a 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


ID HIF1a 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


  • Drug(s) tested: HIF1a

    • 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



Implications for the sarcoma community4
Implications for the sarcoma community HIF1a

  • 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


ID HIF1a 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


  • Drug(s) tested: HIF1a

    • 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



Implications for the sarcoma community5
Implications for the sarcoma community TH-302

  • 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)


ID TH-3021426542, poster F, p. 68Phase I trial of abexinostat and doxorubicine in patients with metastatic sarcomaEdwin Choy et al., Boston, USA


  • Drug(s) tested: TH-302

    • 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



Implications for the sarcoma community6
Implications for the sarcoma community doxorubicin

  • 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



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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