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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 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
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 HIF1α Translation VEGF & neovascularization YB-1 Hypoxic Induction (Cap-independent Mechanism?) Tumor Progression Metastatic Dissemination of sarcoma cells
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
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
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
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
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
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)
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 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 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: • 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 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
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
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
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)
ID 1426542, poster F, p. 68Phase I trial of abexinostat and doxorubicine in patients with metastatic sarcomaEdwin Choy et al., Boston, USA
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
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
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