1. OvCa Clinical Trials Planning Meeting Orlando May 2009
GCIG
OvCa Clinical Trials Planning Meeting
Orlando May 2009

2. Efficient designs for Phase 11/111 Trials
Bad Phase 11 study design leads to missing effective treatments/misuse of resources in planning and execution of Phase III studies particularly when modest benefit aimed for.eg only 28% pos Phase III studies following Phase II
Randomised Phase II design allows for smaller patient numbers/incorporation of data from both arms into the subsequent Phase III eg GOG 182/ICON5....drop arms earlier
Size of benefit aimed for is critical to relevant design...three outcome design may reduce sample size 20-30% (but area of uncertainty)

3. Where to set the null bar?
Too low, go to Phase III too often and increases the sample size
Too high, do not go to Phase III often enough and miss a potential winner
Integrated randomised phase II/III design works well under the global null… E[N] and E[T] no larger than that of a randomized phase II study

4. What HAS changed in RECIST 1.1
Measuring tumor burden
10 targets
5 per organ
For response: 5 targets
(2 per organ)
Lymph node
Measure long axis as for other lesions.
Silent on normal size
Measure short axis.
Define normal size.
Progression definition
20% increase in sum
20% increase and at least
5 mm absolute increase
Non-measurable disease PD
“must be unequivocal”
Expanded definition to convey impact on overall burden of disease. Examples.
Confirmation of objective response
required
Required when response primary endpoint—but not otherwise
New lesions --
New section which includes comment on FDG PET interpretation

5. GCIG CA125 criteria Developed by GCIG to complement RECIST criteria
Response criteria1
For use in phase II studies in relapsed disease
Evaluable pts must have baseline CA125 > 2 x ULN
CA125 response: 50% decrease confirmed > 28 days
Date response = date of first 50% fall
Progression Criteria2
For use in front-line setting to complement objective PD
CA125 PD: Double of UNL (or nadir if > UNL) confirmed > 7 days
Date CA125 PD = date of first doubling
Date overall PD = earliest date of CA125 or objective PD
Exception: recent surgery or intraperitoneal procedure
Rustin GJ, et al: J Natl Cancer Inst :487-8
Vergote I, et al. J Natl Cancer Inst. 2000, 92:1534-5

6. CA125 PD definition
Does including CA125 as part of PD definition add value or just complexity?
Majority of pts with elevated CA125 have imaging and are found to have objective PD
i.e. would it be enough to measure CA125 routinely BUT to consider PD based on objective findings only? Main advantage: trial conduct simplified
Need data from other front-line trials which used GCIG definition PD to determine if value added by this composite endpoint

7. Phase II screening trials:
CA125 RR is usually higher than objective RR: does this mean anything?
Are drugs with CA125 responses but no objective responses “active”? Have any been identified and tested in phase III?
Is CA125 RR value added in drug development? (there is no doubt CA125 is useful in clinical management but that is another question)
Are other functional/molecular imaging endpoints of value?
Is non-progression rate (CR + PR + SD) more meaningful than response rate?
Need DATA to answer all these questions!

8. Phase III trials:
Although Baden Baden endpoint recommendations are symptom benefit or OS, PFS is often used in these trials as primary endpoint.
Does PFS prolongation of 1-2 mo have any “meaning” for patients in situation of recurrent disease if NOT accompanied by either OS or symptom improvement?
Is PFS a surrogate for OS in recurrent disease?

9. CONCLUSIONS
progression-free survival will become increasingly important endpoint as treatment options in recurrent disease increase
but ….. in the modern era of novel targeted therapies in ovarian cancer
do not assume that the same rules apply in assessment of disease progression, and more emphasis may need to be placed on RECIST, rather than CA125 changes

10. New Imaging Modalities
PET CT
Dynamic contrast enhanced CT (DCE-CT)
Dynamic contrast enhanced MRI (DCE MRI)
Nodal imaging...esp small nodes.
Ultrasmall superparamagnetic iron oxide (USPIO) MRI
Diffusion weighted imaging (DWI) MRI

11. PET-CT.. 30% Impact BUT WERE THEY APPROPRIATE?

12. Dynamic Contrast Enhanced MRI As a Biomarker
Correlates with pathologic prognostic indicators
Tumour grade, microvessel density, VEGF expression
Predict clinical response to therapy
Anti-VEGF antibody, tyrosine kinase inhibitor
Prospectively acquired DCE MRI databases
Neoadjuvant breast cancer
Recurrent glioblastoma

13. PET-CT in Recurrence n=532
PET-CT in Recurrence n=53
CT alone PET-CT
Sensitivity 92% %
Specificity 60% %
Kappa

14. New Agents Signalling Pathway interventions….eg P13 Kinase
XL47/ Perifosine/mTOR…..
E-Cadherin disruption
AZD0530 is a highly potent and selective, orally available, once-daily Src inhibitor....enhances taxane cell kill..
Acceptable side effect profile both as monotherapy and in combination with chemotherapy
OVERT I is the first randomised evaluation of the clinical benefit of Src inhibition in combo with CBP
Anti-angiogenics
VEG TRAP in highly pretreated
Bevacizumab data...leading to toxic antiangiogenic combinations...
Bevacizumab and m-TOR inhibitors eg everolimus under investigation

15. Ph II, nonrandomized; pts with persistent or recurrent EOC or PPC
NCT Identifier
Agent(s)
Study Design
NCT
Temsirolimus
Ph II, nonrandomized; pts with persistent or recurrent EOC or PPC
NCT
Temsirolimus + carboplatin/paclitaxel
Ph I, open label; in pts with advanced endometrial cancer, ovarian cancer
NCT
Temsirolimus + topotecan
Ph I, open label, nonrandomized; in pts with gynecologic malignancies..
NCT
Temsirolimus+
Doxil
Resistant solid Malignancies
NCT
Temirolimus+
docetaxel
Resistant solid malignancies 15

16. RESPONSE TO OLAPARIB BY PLATINUM-FREE INTERVAL
Total
Platinum sensitive
Platinum resistant
Platinum refractory
No. of evaluable patients 46 10 25 11
Responders by RECIST
13 (28%)
5 (50%)
8 (32%)
0 (0%)
Responders by GCIG CA125
18 (39%)
8 (80%)
2 (18%)
Responders by either RECIST or GCIG criteria
21 (46%)
11 (44%)
SD (> 4 cycles)
9 (15%)
1 (10%)
4 (16%)
1 (9%)
Median duration of response in weeks (range)
31 (10-96)
31 (16-96)
29 (10-84)
39 (27-51)

17. PARP Inhibitors in Clinical Trials..Phase I/II/III
Agent
Company
Strategy
Administration
AG014699
Pfizer
Combination* IV
KU59436
AstraZeneca-Kudos
Single
Oral
ABT-888
Abbott
BSI-201
BiPar
Combinations
INO-1001
Inotek-Genentech MK
Merck
Single agent and combination
GPI 21016
MGI Pharma

18. Clinical Impact of Genomic Characterization of Clear Cell Cancers
Remove clear cell tumors from ovarian cancer phase III trials….all genomically similar.
Create clear cell specific phase II trials.
Utilize understanding of molecular pathways of clear cell cancers from other organs to better treat ovarian cancer….eg HIF1 Pathway

19. Tumour microenvironment …the soil.
NEJM (2003) 348: 203
Nature Med (2004) 10: 942
PNAS (2005) 102:18538

20. Potential targets..
Cytokines eg
TNF-
IL-6
CCL2

21. Increase in Oncology Drugs
Pharmacogenomics (PGx)
Influence of Individual Genomic Polymorphisms on Drug Response
Personalized Medicine
Identify Risk for Toxicities..rising concerns….increased patient feedback
Identify Predictive Markers of Efficacy prior to drug release eg Tx and CYP2D6
Need to get blood in all Trials we do…

22. PFS (median follow up 29 m): OS (at 2 years): RR: similar
UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING Randomized PHASE III TC vs DDT+C in first-line AOC patients: a JGOG Study
Randomized phase III
T 180 mg/m2 + Carbo AUC 6 d1, q 3wk
T 80 mg/m2 d1,8,15 + Carbo AUC 6 d1, q3wk
Endpoint: PFS
n: 637 pts
PFS (median follow up 29 m):
17,1m vs 27,9m (p:0.0014) log-rank test
OS (at 2 years):
77,7% vs 83,6% (p:0.05)
RR: similar
Toxicity: Anemia G3-4 in weekly arm more freq
Isohishi S et al . ASCO 2008,Abstract-5506 (Oral)

23. UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING ONGOING STUDIES in front-line ovarian cancer
Group
Study Design Tmg/m2 n
Primary Objetive
Secondary Objetives
Status
Intergroup
MO22225 (OCTAVIA)
Phase II
T80 d1,8,15 q21
+ C AUC 6 q21 + Beva 7.5q21
180
PFS
ORR
RR Duration OS
Safety
Open in June 09
MITO-7
Phase III R C AUC6+ T175 vs
T60 d1,8,15, q21 C AUC 2 q 21
500
QoL
PFS,
Open

24. Epithelial Ovarian Cancer
GOG172 Trial
Epithelial Ovarian Cancer
Optimal Stages III
Randomization
Paclitaxel 135 mg/m2/24h IV D1
Cisplatin 75 mg/m2 IV D2
Q21, 6 Cycles
Paclitaxel 135 mg/m2/24h IV D1
Cisplatin 100 mg/m2 IP D2
Paclitaxel 60 mg/m2 IP D8
Q21, 6 Cycles

25. Planned Japanese IP Trial
Epithelial Ovarian Cancer
Stages II-IV
Excluding Clear Cell Carcinoma
Randomization
Paclitaxel 80 mg/m2 IV Weekly
Carboplatin AUC 6 IV
Q21, 6-8 Cycles
Paclitaxel 80 mg/m2 IV Weekly
Carboplatin AUC 6 IP
Q21, 6-8 Cycles
Primary Endpoint: PFS
Secondary Endpoint: OS, Toxicity, QOL

26. Optimal Debulked Stage III Epithelial Ovarian Cancer
Planned GOG Trial
Paclitaxel 175 mg/m2 IV
Carboplatin AUC 6 IV
Bevacizumab
Q21, 6-8 Cycles
Paclitaxel 175 mg/m2 IV
Carboplatin AUC 6 IP
Bevacizumab
Q21, 6-8 Cycles
Optimal Debulked Stage III
Epithelial Ovarian Cancer R A N D O M Z E
Paclitaxel 135 mg/m2 IV
Cisplatin 75 mg/m2 6 IP
Paclitaxel 60 mg/m2 IP D8
Bevacizumab
Q21, 6-8 Cycles

27. Initial Therapy of Ovarian Cancer: Controversial Areas
How can we best use targeted biologics with initial chemotherapy to improve outcome? ICON7/GOG218/Tarceva…?ICON8
Should consolidation therapy be offered to all ovarian cancer patients? SWOG9071/GOG 178
Should BRCA-associated cancers be treated differently…PARP Inhibitors with no BRCA mutation?
Should cost of treatment be an issue in designing clinical trials? Adding biologicals increases cost x10-20
Should access/eligibility be broadened to reflect the “real world” Comparative effectiveness research…

28. SURGICAL TRIALS AGO/OVAR OP3...lymphadenectomy vs
no lymphadenectomy in optimal debulked cases
DESKTOP 3...High AGO score...plat sensitive .....op vs no op (secondary debulk)

29. Rare Tumours Mucinous .. ..CT VS OXALI/ CAPE +-BEV
Sex Cord...CT vs BEP
... BEVACICZUMAB
Serous LMP....AZD 6244

30. But ….still many Questions !!
Impact of treatment on HRQOL
Which instruments do we use
How important is hope in decision making?
Would good palliative care achieve the same
Would palliative care be acceptable
How much time do patients spend in hospital as a result of toxicity
How many patients receive treatment within 30 days of death
Can we identify patients most likely to benefit

31. Questions What is the QOL of elderly ovarian cancer patients?
What type of impact does their “age” have on QOL and feasibility of surgery/chemotherapy?
Why is the elderly death rate so high (GOG 182, 158; ICON3)? And, what are the causes of death?
What is their trajectory of decline and what happens to QOL and needs?
What doses should we give?
PK differences?
What about >80?
Compared a retrospective cohort of ovarian cancer patients age >70 after opt. surgical procedure receiving IV carboplatin/paclitaxel as first line treatment
Lunney, J. R. et al. JAMA 2003
von Gruenigen et al. Cancer 2008

32. Partnering …Industry Perspective
What we Bring
Novel Molecules
Global Presence
Advocacy Links
Financial support
What we Need
Timeliness
Concept→PA→FPV
Regulatory Quality Data Collection
Cooperation with
CTR Requirements
Tissue for biological studies to predict response

33. Challenges Opportunities
Intellectual Property
(cf Alberts presentation)
Biomarker-Pt Segmentation
CONTRACTING
CoContractingntracting
Data
NDA
sNDA
Timeline(s)
Stakeholder dialogue
Safe harbor
Common Clauses
Streamlined
Optimized
Standardized/caBIG
Surrogate Endpoints (PFS -Ind/Review-EBM)
Curt G; McClellan M, Benner JS; Niederhuber JE
The Oncologist 2009 in press

34. Industry Group Industry-Cooperative group relationships sponsor
CAELYX - Module 2
Industry-Cooperative group relationships
Industry
Group
Late development (organ-specific phase II, combination trials)
sponsor
sponsor
Early development (phase I, early efficacy phase II, pivotal phase III for approval)

35. The good guys and the bad guys

36. Industry-Cooperative group relationships
What rules between industry and cooperative groups ?
ENGOT minimal requirement for Academic trials
What to share and how ? - one protocol - one data base (ownership, - one crf (e-crf) - monitoring , SOPs, SAEs flow - statistical analysis - IDSMB - publication policy

37. KEY ISSUES FROM HERE....

38. Trial design

39. Should each group take on a randomised Phase II and then expand to an Intergroup Stage III given the large number of new drugs?
Assessment of toxicity an important issue in such studies.

40. Response Assessment

41. CA125 PD definition
Does including CA125 as part of PD definition add value or just complexity?
Majority of pts with elevated CA125 have imaging and are found to have objective PD
i.e. would it be enough to measure CA125 routinely BUT to consider PD based on objective findings only? Main advantage: trial conduct simplified
Need data from other front-line trials which used GCIG definition PD to determine if value added by this composite endpoint

42. Phase III trials:
Although Baden Baden endpoint recommendations are symptom benefit or OS, PFS is often used in these trials as primary endpoint.
Does PFS prolongation of 1-2 mo have any “meaning” for patients in situation of recurrent disease if NOT accompanied by either OS or symptom improvement?
Is PFS a surrogate for OS in recurrent disease?

43. CONCLUSIONS
progression-free survival will become increasingly important endpoint as treatment options in recurrent disease increase
but ….. in the modern era of novel targeted therapies in ovarian cancer
do not assume that the same rules apply in assessment of disease progression, and more emphasis may need to be placed on RECIST, rather than CA125 changes

44. Imaging

45. OVCA and Radiology What modalities should we use? Pragmatic or ideal?
Can we expect investigators to have two different standards?
What should be the minimum? USG/CT/MRI?
How do we use PET-CT?..eg response?
Do we need centralised radiological review ?
Can we build radiological databases to include translational questions? Indeed if we can, should we?
Before embarking on the 2009 randomised Stage IIb study prior to ICON A 10 arm study, we need to establish what each group has available and feels is appropriate.
Liase with ACRIN

46. New Agents and Approaches

47. WHEN TO TEST NEW AGENTS AND APPROACHES
WHEN TO TEST NEW AGENTS AND APPROACHES? How to prioritise which pathway inhibitor to use?
What is the exact mechanism in vivo...how can we identify those tumours which will respond?
Will diet and exercise be as good?

48. Pharmacogenomics
All studies need to have blood collection built into the protocol.
Funding??

49. Separating the populations
Histology alone....eg clear cell,mucinous.
Are we ready to include homogenous histological groups only...eg G3 Serous....do we need arrays to identify first?
Are grade I serous tumours really like LMP tumours?
Why are we so behind breast cancer?

50. Initial therapy questions

51. Initial Therapy of Ovarian Cancer: Controversial Areas
How can we best use targeted biologics with initial chemotherapy to improve outcome? ICON7/GOG218…?ICON8
Dose dense?
Should consolidation therapy be offered to all ovarian cancer patients?
Does receiving consolidation therapy alter response to subsequent chemotherapy?
Should BRCA-associated cancers be treated differently?
Should cost of treatment be an issue in designing clinical trials?
Should access/eligibility be broadened to reflect the “real world”

52. Questions about the use of PARP inhibitors in ovarian cancer
Is there a role for PARP inhibitors in ovarian cancer patients without a BRCA mutation? Eg High grade serous…
Other defects in the homologous recombination pathway…approx 40% in ovca
Are platinum resistant patients likely to be PARP inhibition resistant?
Platinum plus PARP inhibitors?

53. Future Challenges Validation of prognostic and predictive biomarkers.
Larger numbers of carefully annotated specimens
FFPE technologies
Identification and validation of small molecule inhibitors targeting pathways
Integrated biomarkers will be mandated.
Molecular basis for resistance
Recurrent tumor biopsies should be a requirement in all GCIG studies…ascites as a surrogate?.
How do we get to the tumour micro-environment?

54. UNANSWERED QUESTIONS IN UPFRONT THERAPY Weekly Dosing
What is the standard weekly dose?
Which drugs should be administered in a weekly schedule
Only Taxane?
Taxane + carboplatin?
How to incorporate weekly dose as
i.p strategy?
biologic agents combination?
How best to determine the appropriate duration of weekly dose therapy?

55. IP Chemotherapy in Ovarian Cancer
Trial Endpoints to be Answered
Less Toxic Combinations
Can Carboplatin replace Cisplatin? NCIC….winner
Is Day 8 IP Paclitaxel required?
Efficacy Assessment
Is IP Carboplatin better than IV Carboplatin? Current study ..
Dose Day 8 IP Paclitaxel matter or Only Day 8 Paclitaxel (IV) matter?
New Approaches…
Adding Bevacizumab and testing the effect of day 8 Taxane

56. Neoadjuvant Chemotherapy
How to design trials incorporating both upfront surgery and IDS?
How to add new agents...ICON8 the answer?
Is there really a point in removing ‘normal’ organs?
How best to schedule surgery and bevacuzimab or weekly taxane?

57. Neoadjuvant Chemo
Can we develop a rational superiority trial incorporating neoadjuvant chemotherapy?
What info can we get using neoadjuvant chemo?...eg re-biopsy.
How to best determine extensive disease?
What is the best way to incorporate neoadjuvant chemotherapy into advanced age and poor performance populations?
What is the best timing for surgery in patients undergoing neoadjuvant chemotherapy (3 vs. 6 months)?
Which patients should not undergo surgical intervention?

58. Quality of Life

59. QOL issues
Do we need more instruments? Are Symptom Indices a surrogate?..’FOSI’ the answer?
PROMIS of use across all GCIG trials?
When in the illness do we assess QOL?
How important is hope in decision making?
Would good palliative care achieve the same?
Would palliative care be acceptable?
How much time do patients spend in hospital as a result of toxicity?
Does response translate into symptomatic benefit?
How many patients receive treatment within 30 days of death?
Can we identify patients most likely to benefit?

60. Questions
What is the QOL of elderly ovarian cancer patients? Are there cultural differences?
What type of impact does their “age” have on QOL and feasibility of surgery/chemotherapy?
Should neoadjuvant chemo be the standard of care?
Why is the elderly death rate so high (GOG 182, 158; ICON3)? And, what are the causes of death?
What is their trajectory of decline and what happens to QOL and needs?
What doses should we give?
Compared a retrospective cohort of ovarian cancer patients age >70 after opt. surgical procedure receiving IV carboplatin/paclitaxel as first line treatment
Lunney, J. R. et al. JAMA 2003
von Gruenigen et al. Cancer 2008

61. WHAT ABOUT THE PARTNERS?

62. Industry Issues

63. Communication Confidence and Transparency

64. Rules or guidelines with industry?