discussion of papers 3-4 and posters d-h, session 1, ctos, prague, november 2012 patrick schöffski,...
TRANSCRIPT
Discussion of papers 3-4 and posters D-H, Session 1, CTOS, Prague,
November 2012
Patrick 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…”
Preclinical work
ID 1436983, paper #3, p. 66
Simultaneous autophagy induction and inhibition induces cell death through necroptosis in sarcomas that lack argininosuccinate synthetase 1 expression
Philip 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 dissemination
Amal 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
Tumor Progression
YB-1
Hypoxic Induction
HIF1α Translation VEGF & neovascularization
Metastatic Dissemination of sarcoma cells
(Cap-independent Mechanism?)
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. 69
Trabectedin and PARP-1 inhibitors combination in preclinical models of bone and soft tissue sarcoma
Ymera 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: – Trabectedin and PARP-inhibitors show synergistic anti-proliferative
effects in sarcoma cell lines, with induction of cell cycle arrest and apoptosis
3
How does trabectedin interact with PARP-I?
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
ID 1437492 , poster D, p. 67
A phase II trial of novel anthracycline amrubicin in patients with advanced soft tissue sarcoma
Launce 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)
1
23 4
5
67 8
9
1011 12-50
-40
-30
-20
-10
0
10
20
30
40
50
% c
hang
e
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
(years)
0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment188 228 113 54 29 19 14 9 2
184 227 130 64 30 20 13 7 3
Doxo
DxIf
Overall survival
(years)
0 1 2 3 4 5 6 7 8
0
10
20
30
40
50
60
70
80
90
100
O N Number of patients at risk : Treatment215 228 38 15 8 6 5 4 1
210 227 50 16 12 11 10 7 3
Doxo
DxIf
Progression free survival
HR = 0.83 (95.5% CI 0.67 – 1.03) p = 0.076
HR = 0.74 (95% CI 0.60 – 0.90) p = 0.003
Overall survival (primary endpoint)
Progression-free survival
Judson, Verweij, Gelderblom, Hartmann , Schöffski , Blay, dei Tos, Marreaud , Litiere, van der Graaf , ESMO Vienna 2012
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)
ID 1426644, poster G, p. 69
Aldoxorubicin (INNO-206) is an active drug for the treatment of relapsed or refractory soft tissue sarcomas
Sant 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
Waterfall plot response surrogate (n=13)
-60
-50
-40
-30
-20
-10
0
10
20
30
40
* Indicates prior therapy with doxorubicin, epirubicin or Doxil®
*
*
*
**
*
*
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. 67
TH-302 maintenance following TH-302 + doxorubicine induction: the results of a phase 2 study
Kristen 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. 68
Phase I trial of abexinostat and doxorubicine in patients with metastatic sarcoma
Edwin 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:
– Abexinostat can 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
Please show your real excitement for all the good work presented in Session 1
Hypnosis conference