OvCa Clinical Trials Planning Meeting
Orlando May 2009
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 2030% (but area of uncertainty)
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
RECIST 1.0
What HAS changed
in RECISTRECIST
1.1 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
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
1.
2.
Rustin GJ, et al: J Natl Cancer Inst. 2004 96:487-8
Vergote I, et al. J Natl Cancer Inst. 2000, 92:1534-5
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
 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!
 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?
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
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
PET-CT.. 30% Impact
BUT WERE THEY APPROPRIATE?
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
2
PET-CT in Recurrence n=53
CT alone
PET-CT
Sensitivity 92%
97%
Specificity 60%
80%
Kappa
0.29
0.63
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
NCT Identifier
Agent(s)
Study Design
NCT00429793
Temsirolimus
Ph II, nonrandomized; pts
with persistent or recurrent
EOC or PPC
NCT00408655
Temsirolimus +
Ph I, open label; in pts with
carboplatin/paclitaxel
advanced endometrial
cancer, ovarian cancer
NCT00523432
Temsirolimus +
topotecan
Ph I, open label,
nonrandomized; in pts with
gynecologic malignancies..
NCT00703170
Temsirolimus+
Doxil
Resistant solid
Malignancies
NCT00703625
Temirolimus+
docetaxel
Resistant solid
malignancies
RESPONSE TO OLAPARIB BY
PLATINUM-FREE INTERVAL
Total
Platinum
sensitive
Platinum
resistant
Platinum
refractory
46
10
25
11
Responders by RECIST
13 (28%)
5 (50%)
8 (32%)
0 (0%)
Responders by GCIG
CA125
18 (39%)
8 (80%)
8 (32%)
2 (18%)
Responders by either
RECIST or GCIG criteria
21 (46%)
8 (80%)
11 (44%)
2 (18%)
SD (> 4 cycles)
9 (15%)
1 (10%)
4 (16%)
1 (9%)
31 (10-96)
31 (16-96)
29 (10-84)
39 (27-51)
No. of evaluable patients
Median duration of
response in weeks
(range)
PARP Inhibitors in Clinical Trials..Phase I/II/III
Agent
Company
Strategy
Administration
AG014699
Pfizer
Combination*
KU59436
AstraZenecaKudos
Single
Oral
ABT-888
Abbott
Single
Oral
BSI-201
BiPar
Single
Combinations
IV
INO-1001
InotekGenentech
Combination*
IV
MK
Merck
Single agent and
combination
Oral
GPI 21016
MGI Pharma
Combination*
Oral
IV
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
Tumour microenvironment …the soil.
NEJM (2003) 348: 203
Nature Med (2004) 10: 942
PNAS (2005) 102:18538
Potential targets..
Cytokines eg
TNF-
IL-6
CCL2
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…
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)
UNANSWERED QUESTIONS IN UPFRONT THERAPY
WEEKLY DOSING
ONGOING STUDIES in front-line ovarian cancer
Group
Study Design
Tmg/m2
n
Primary
Objetive
Secondary Status
Objetives
Intergroup
Phase II
T80 d1,8,15 q21
+ C AUC 6 q21
+ Beva 7.5q21
180
PFS
ORR
Phase III R
C AUC6+ T175
vs
T60 d1,8,15, q21
C AUC 2 q 21
500
QoL
ORR
PFS,
OS
Safety
MO22225
(OCTAVIA)
MITO-7
Open in
RR Duration June 09
OS
Safety
Open
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
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
Planned GOG Trial
Optimal Debulked Stage III
Epithelial Ovarian Cancer
R
A
N
D
O
M
Z
E
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
Paclitaxel 135 mg/m2 IV
Cisplatin 75 mg/m2 6 IP
Paclitaxel 60 mg/m2 IP D8
Bevacizumab
Q21, 6-8 Cycles
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…
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)
Rare Tumours
 Mucinous .. ..CT VS OXALI/ CAPE +-BEV
 Sex Cord...CT vs BEP
... BEVACICZUMAB
Serous LMP....AZD 6244
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
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?
Lunney, J. R. et al. JAMA 2003
von Gruenigen et al. Cancer 2008
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
Challenges
Opportunities
Intellectual Property
(cf Alberts presentation)
Biomarker-Pt Segmentation
Stakeholder dialogue
Safe harbor
Common Clauses
CONTRACTING
CoContractingntracting
Data
NDA
sNDA
Timeline(s)
Streamlined
Optimized
Standardized/caBIG
Surrogate Endpoints
(PFS -
Ind/Review-EBM)
Curt G; McClellan M, Benner JS; Niederhuber JE
The Oncologist 2009 in press
Industry-Cooperative group relationships
Industry
Group
sponsor
sponsor
Early development
(phase I, early
efficacy phase II,
pivotal phase III for
approval)
Late development
(organ-specific
phase II,
combination
trials)
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
 KEY ISSUES FROM HERE....
 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.
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
 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?
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
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 10... A 10 arm study, we need to establish
what each group has available and feels is appropriate.
Liase with ACRIN
What is the exact mechanism in vivo...how can
we identify those tumours which will respond?
Will diet and exercise be as good?
Pharmacogenomics
 All studies need to have blood collection built into the
protocol.
 Funding??
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?
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”
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?
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?
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?
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
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?
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?
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?
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?
Lunney, J. R. et al. JAMA 2003
von Gruenigen et al. Cancer 2008
Rules or guidelines with industry?