OvCa Clinical Trials Planning Meeting Orlando May 2009 Slide 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)
Slide 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 Slide 4 What HAS
changed in RECIST 1.1 RECIST 1.0 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 endpointbut not otherwise New lesions -- New section which
includes comment on FDG PET interpretation Slide 5 GCIG CA125
criteria Developed by GCIG to complement RECIST criteria Response
criteria 1 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 Criteria 2 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.Rustin GJ, et al: J
Natl Cancer Inst. 2004 96:487-8 2.Vergote I, et al. J Natl Cancer
Inst. 2000, 92:1534-5 Slide 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 Slide 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! Slide 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? Slide
9 CONCLUSIONS but .. in the modern era of novel targeted therapies
in ovarian cancer progression-free survival will become
increasingly important endpoint as treatment options in recurrent
disease increase 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 Slide 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 Slide 11 PET-CT.. 30% Impact BUT WERE
THEY APPROPRIATE? Slide 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 Slide 13 2 PET-CT in Recurrence n=53 CT
alone PET-CT Sensitivity 92% 97% Specificity 60% 80% Kappa 0.29
0.63 Slide 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 Slide 15 NCT IdentifierAgent(s)Study
Design NCT00429793TemsirolimusPh II, nonrandomized; pts with
persistent or recurrent EOC or PPC NCT00408655Temsirolimus +
carboplatin/paclitaxel Ph I, open label; in pts with advanced
endometrial cancer, ovarian cancer NCT00523432Temsirolimus +
topotecan Ph I, open label, nonrandomized; in pts with gynecologic
malignancies.. NCT00703170Temsirolimus+ Doxil Resistant solid
Malignancies NCT00703625Temirolimus+ docetaxel Resistant solid
malignancies Slide 16 Total Platinum sensitive Platinum resistant
Platinum refractory No. of evaluable patients46102511 Responders by
RECIST13 (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%) Median duration of response in weeks (range) 31
(10-96)31 (16-96)29 (10-84)39 (27-51) RESPONSE TO OLAPARIB BY
PLATINUM-FREE INTERVAL Slide 17 PARP Inhibitors in Clinical
Trials..Phase I/II/III AgentCompanyStrategyAdministration
AG014699PfizerCombination*IV KU59436AstraZeneca- Kudos SingleOral
ABT-888AbbottSingleOral BSI-201BiParSingle Combinations IV
INO-1001Inotek- Genentech Combination*IV MKMerckSingle agent and
combination Oral GPI 21016MGI PharmaCombination*Oral Slide 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
Slide 19 Tumour microenvironment the soil. NEJM (2003) 348: 203
Nature Med (2004) 10: 942 PNAS (2005) 102:18538 Slide 20 Potential
targets.. Cytokines eg TNF- IL-6 CCL2 Slide 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 Slide 22 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) Slide 23
UNANSWERED QUESTIONS IN UPFRONT THERAPY WEEKLY DOSING ONGOING
STUDIES in front-line ovarian cancer GroupStudy Design Tmg/m2
nPrimary Objetive Secondary Objetives Status Intergroup MO22225
(OCTAVIA) Phase II T80 d1,8,15 q21 + C AUC 6 q21 + Beva 7.5q21
180PFSORR RR Duration OS Safety Open in June 09 MITO-7Phase III R C
AUC6+ T175 vs T60 d1,8,15, q21 C AUC 2 q 21 500QoLORR PFS, OS
Safety Open Slide 24 GOG172 Trial Epithelial Ovarian Cancer Optimal
Stages III 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 Randomization Slide 25
Planned Japanese IP Trial Epithelial Ovarian Cancer Stages II-IV
Excluding Clear Cell Carcinoma 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 Randomization Primary
Endpoint: PFS Secondary Endpoint: OS, Toxicity, QOL Slide 26
Planned GOG Trial Optimal Debulked Stage III Epithelial Ovarian
Cancer 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 RANDOMZERANDOMZE Paclitaxel 135 mg/m2
IV Cisplatin 75 mg/m2 6 IP Paclitaxel 60 mg/m2 IP D8 Bevacizumab
Q21, 6-8 Cycles Slide 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 differentlyPARP 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 Slide 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) Slide 29
Rare Tumours Mucinous....CT VS OXALI/ CAPE +-BEV Sex Cord...CT vs
BEP... BEVACICZUMAB Serous LMP....AZD 6244 Slide 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 Slide 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? Lunney, J. R. et al. JAMA 2003 von
Gruenigen et al. Cancer 2008 Slide 32 Partnering Industry
Perspective What we Bring Novel Molecules Global Presence Advocacy
Links Financial support What we Need Timeliness Concept PAFPV
Regulatory Quality Data Collection Cooperation with CTR
Requirements Tissue for biological studies to predict response
Slide 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 Slide 34 Industry-Cooperative group relationships sponsor
Industry Early development (phase I, early efficacy phase II,
pivotal phase III for approval)Group Late development
(organ-specific phase II, combination trials) sponsor Slide 35
Slide 36 Industry-Cooperative group relationships What to share and
how ? - one protocol - one data base (ownership, - one crf (e-crf)
- monitoring, SOPs, SAEs flow - statistical analysis - IDSMB -
publication policy What rules between industry and cooperative
groups ? ENGOT minimal requirement for Academic trials Slide 37 KEY
ISSUES FROM HERE.... Slide 38 Slide 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. Slide 40 Slide 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 Slide 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? Slide 43 CONCLUSIONS but .. in the modern era of
novel targeted therapies in ovarian cancer progression-free
survival will become increasingly important endpoint as treatment
options in recurrent disease increase 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 Slide 44
Slide 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
10... A 10 arm study, we need to establish what each group has
available and feels is appropriate. Liase with ACRIN Slide 46 Slide
47 What is the exact mechanism in vivo...how can we identify those
tumours which will respond? Will diet and exercise be as good?
Slide 48 Pharmacogenomics All studies need to have blood collection
built into the protocol. Funding?? Slide 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? Slide 50
Slide 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 Slide 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 pathwayapprox 40% in ovca
Are platinum resistant patients likely to be PARP inhibition
resistant? Platinum plus PARP inhibitors? Slide 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 studiesascites as a surrogate?. How do we
get to the tumour micro-environment? Slide 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? Slide 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 Slide 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? Slide 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? Slide 58 Slide
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?
Slide 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? Lunney, J. R.
et al. JAMA 2003 von Gruenigen et al. Cancer 2008 Slide 61 Slide 62
Slide 63 Slide 64 Rules or guidelines with industry?
