The document discusses innovative clinical trial designs aimed at maximizing benefits in oncology, particularly through evidence-based medicine and integration of biological knowledge in drug development. It evaluates traditional and new methodologies, such as adaptive trials and basket trials, including their advantages and challenges, to accelerate drug development while ensuring safety and efficacy. The conclusion emphasizes the necessity of a robust infrastructure and collaboration among various stakeholders in clinical research to meet evolving healthcare needs.

1. Innovative Clinical Trial Designs:
How to maximize the benefit?
Emad Shash, MBBCh., MSc., MD.
Medical Oncology Department
National Cancer Institute
Cairo University

2. What are we going to discuss today!
Evidence
Based
Medicine
Resources
Utilization
Clinical
Research
Innovation
• How are we used to perform
clinical trials in Oncology?
• Does it fits in today’s needs?
• Integration of biology knowledge
in shaping drug development
• New Clinical trial designs “Can
they offer solution for
accelerating drug development?”
• The supporting infrastructure
role in clinical trial execution
Right Patient
Right
Treatment
Right Time
Cost
Effectiveness

3. Evolution Theory
Adaptation is always and should be according to Needs

4. Experimental design for Scurvy
“James Lind 1716-1794”
12 classical SCURVY
Sailors
Vinegar Diluted sulfuric acid Cider Sea Water Nutmeg & Garlic 2 Oranges & 1 Lemon
Normal diet +
supplementation
(6 experimental groups)

5. Phases of Clinical Trials
“what we are used to do”
Phase I
Drug given to 20-100
healthy volunteers
(although patients in some
cases)
Duration 1mth – 1 year
Cost $100K to $500K
Following studied here
• PK/PD
• Food interaction
• Safety
• Dose
escalation/MTD
• Safety
• Early evidence of
efficacy
Drug given to 100-500
patient volunteers
Duration 1 – 2 years
Cost $10M to $100M
Following studied here
• Efficacy
• Safety
• Establish dose for
Phase III
Drug given to 1000-5000
patient volunteers
Duration 3 – 4 years
Cost $10M to $500M
Following studied here
• Confirmation of
Efficacy
• Safety
Drug is launched in the
market. 1000’s of
patients
Many years
No specific amount
Additional post marketing
testing of patients for drug
• Safety & Efficacy
• Support use of the
approved indication
• Finding new therapeutic
opportunities
• Extended use to
different classes of
patients
• 1000s of patients
Phase II Phase III Phase IV

6. Stages of drug development
“Time & Money Consumption”
Source: “An Overview of the Drug Development Process”, by Ross Tonkens, M.D.
Phase I Phase IIIRESOURCES
≅15 Years
≅30 M – 700 M

7. Continuous Decline in Healthcare & Research Spending

8. What are we going to discuss today!
Evidence
Based
Medicine
Resources
Utilization
Clinical
Research
Innovation
• How are we used to perform clinical
trials in Oncology?
• Does it fit our today’s needs?
• Integration of biology knowledge in
shaping drug development
• New Clinical trial designs “Can they
offer solution for accelerating drug
development?”
• The supporting infrastructure role in
clinical trial execution

9. Molecularly Targeted therapy Versus
Conventional therapy
Patient
DrugBiomarker
Efficacy

10. Schwaederle M et al. JCO 2015
Better Biology Understanding & Treatment Outcome Optimization
Matching patients with drugs based on specific biomarkers
PubMed search
January 1, 2010,
and December 31,
2012
570
phase II single-
agent studies
32,149 patients

11. NSCLC Pathology: From Traditional View to more
sub-molecular categorization

12. Advanced NSCLC: Evolution of Treatment
2000 - 2006 2006 - 2009 2010 2011 – 2017……..
EGFR mutation
ALK rearrangement
K-ras mutation
B-raf, HER2 mutation
ROS1, RET
Immunotherapy
Non-Squamous
Squamous
Targeting an Oncogenic Driver
EGFR mutation
Non-Squamous
Squamous
Non-Squamous
Squamous
NSCLC
Targeting EGFRTreating according histologyNSCLC

13. Time elapsed from discovery to practice change

14. The biomarker and drug development cycle
Patients-industry-Drug
developers-
Translational researchers
Regulators
Payers
Analytical
validation
Clinical
validation
Clinical
utility
Market
access
Health
care
deliveryTR
Drug developers
Patients-Payers-Regulators-
Industry
Time & Money Consumption while patients are waiting!!

15. Can we accelerate time?
&
Still get the maximal benefit!

16. What are we going to discuss today!
Evidence
Based
Medicine
Resources
Utilization
Clinical
Research
Innovation
• How are we used to perform clinical
trials in Oncology?
• Does it fit in today’s needs?
• Integration of biology knowledge in
shaping drug development
• New Clinical trial designs “Can they
offer solution for accelerating drug
development?”
• The supporting infrastructure role in
clinical trial execution

17. Umbrella Trial
• Different targeted agents investigated in parallel in the same tumor
type and within independent cohorts of patients
• Defined by specific molecular aberrations that could predict
sensitivity to the investigational agent under assessment

18. Histology based clinical trial design
To evaluate multiple molecular aberrations

19. Le Tourneau et al. Lancet Oncol 2015
Paoletti et al. CCO 2015
Molecularly targeted therapy based on tumor molecular profiling versus
conventional therapy for advanced cancer (SHIVA) Trial: Proof-of-Concept

20. Le Tourneau et al. Lancet Oncol 2015
Molecularly targeted therapy based on tumor molecular profiling versus
conventional therapy for advanced cancer (SHIVA) Trial: Proof-of-Concept
Molecularly targeted agent group
(n=99)
Treatment at physician's choice
group (n=96)
Age (years) 61 (54–69) 63 (54–69)
Sex
Female 60 (61%) 69 (72%)
Male 39 (39%) 27 (28%)
Previous lines of treatment 3 (2–5) 3 (2–5)
Royal Marsden Hospital score
0 or 1 51 (52%) 48 (50%)
2 or 3 48 (48%) 48 (50%)
Molecular pathway altered
Hormone receptor pathway 40 (40%) 42 (44%)
PI3K/AKT/mTOR pathway 46 (46%) 43 (45%)
RAF/MEK pathway 13 (13%) 11 (11%)

21. Adapted from: Le Tourneau et al. Lancet Oncol 2015
Molecularly targeted therapy based on tumor molecular profiling versus
conventional therapy for advanced cancer (SHIVA) Trial: Proof-of-Concept
0 5 10 15 20 25
Breast adenocarcinoma
Colorectal cancer
Sarcoma
Adenocarcinoma of unknown primary
Non-adenoid cystic carcinoma salivary gland tumour
Neuroendocrine tumour
Cutaneous melanoma
Ependymoma
Germline tumour
Distribution By Tumor Type
Treatment at Physican Choice Moleculary Targeted Group
0
5
10
15
20
25
30
35
40
45
50
Hormone receptor pathway PI3K/AKT/mTOR pathway RAF/MEK pathway
Distribution By Molecular Abberation
Moleculary Targeted Group Physician Choice Group
Distribution of molecular alterations in the PI3K/AKT/mTOR pathway
Distribution of molecular alterations in the RAF/MEK pathway

22. Molecularly targeted therapy based on tumor molecular profiling versus
conventional therapy for advanced cancer (SHIVA) Trial: Proof-of-Concept
Le Tourneau et al. Lancet Oncol 2015
Progression-free survival Intent to
treat population
PI3K/AKT/mTOR pathway
RAF/MEK pathway

23. Molecularly targeted therapy based on tumor molecular profiling versus
conventional therapy for advanced cancer (SHIVA) Trial: Proof-of-Concept
Le Tourneau et al. Lancet Oncol 2015
Progression-free survival Intent to
treat population
PI3K/AKT/mTOR pathway
RAF/MEK pathway
• It is the first to test, with a randomized control, the idea of whether off-label use of commercial drugs for matched molecular
biomarkers confers a clinical benefit.
• The results suggest that off-label use of molecularly targeted agents in this manner should be restricted.
• Instead, patients should be encouraged to participate in well-designed next-generation clinical trials that use an iterative
and scientific approach to build on findings from trials such as SHIVA
• Irrespective of these limitations, SHIVA offers robust evidence for deficiencies in assigning therapy based on the various
loose associations between biomarkers and inhibitors that are often provided in commercial clinical diagnostic reports.

24. Basket Trial
• Histology-independent trial design
• Patients with cancers of different histology enrolled in the clinical trial
based on the presence of a specific molecular aberration

25. Histology-independent
aberration-specific clinical trial design

26. EXAMPLE: NCI MPACT BASKET TRIAL
KummarS, et al., ASCO Annual Meeting 2014 poster

27. CREATE EORTC TRIAL
• Six Cohorts of rare solid tumors and anaplastic large cell lymphoma
• ALK and/or MET alterations are considered to play a role of the carcinogenesis process of these tumors
Clinical trial information: NCT01524926

28. EORTC 90101 MET Driven (PRCC1 Cohort)
Schoffski et al. LBA AACR 2016

29. EORTC 90101 MET Driven (PRCC1 Cohort)
Schoffski et al. LBA AACR 2016

30. Basket of trials

31. BASKET TRIAL: PROS AND CONS
• Pros
• Determining potential tumor efficacy of a single targeted agent in different
cancer types with the same gene abnormality
• Cons
• Risk of overlooking the impact of tumor histology type. In fact, different
tumor responses by targeting the same mutation in several cancer types
could be observed. (e.g. BRAF in melanoma versus BRAF in colorectal cancer:
RR 50%-60% versus <5%)

32. ADAPTIVE TRIALS (1)
The principle of this trial is based on modifying parameters (dose,
sample size, drug, schedule …) of a clinical trial evaluating a treatment
in accord with observed outcomes in participants.

33. ADAPTIVE TRIALS (2)
Deepak et al. New Eng J Med 2016

34. ADAPTIVE TRIALS (3)
Deepak et al. New Eng J Med 2016

35. Park et al. New Eng J Med 2016
I-SPY 2
I-SPY 2 trial
Multicenter, adaptive phase 2 trial of neoadjuvant therapy
for:
• High risk clinical stage II or III breast cancer evaluated
multiple new agents added to standard chemotherapy
 To assess the effects on rates of pathological
complete response

36. Park et al. New Eng J Med 2016
Neratinib (HKI-272; Puma Biotechnology)
• an irreversible small-molecule inhibitor of the ErbB and the human
epidermal Growth factor receptor (HER) kinase family (epidermal
growth Factor receptor, HER2, and HER4)
• It has shown promising activity against HER2-positive metastatic
breast cancer.
• There is also evidence of preclinical activity against HER2negative
tumor cells

37. Probability Distributions for Selected
Biomarker Signatures
Park et al. New Eng J Med 2016
Eligible women were categorized according to
• 8 biomarker Subtypes on the basis of
• Human epidermal growth factor receptor 2 (HER2)
status
• Hormone-receptor status
• Risk according to a 70-geneprofile

38. Final Posterior and Predictive Probabilities of Neratinib
Efficacy with Regard to 10 Biomarker Signatures
* The status of high-risk category 2 on the 70-gene profile was determined with the use of the MammaPrint assay
Park et al. New Eng J Med 2016

39. Final Posterior and Predictive Probabilities of Neratinib
Efficacy with Regard to 10 Biomarker Signatures
* The status of high-risk category 2 on the 70-gene profile was determined with the use of the MammaPrint assay
Park et al. New Eng J Med 2016
• Neratinib reached the pre-specified efficacy threshold with regard to the
HER2-positive, hormone-receptor–negative signature
• Neratinib added to standard therapy was highly likely to result in higher
rates of pathological complete response than standard chemotherapy
with trastuzumab among patients with HER2-positive, hormone-
receptor–negative breast cancer.

40. ADAPTIVE TRIAL DESIGN: PROS AND CONS
• Pros
• Faster evaluation of the drug
• Modification of drug, dosage and sample size during the trial according to the
observed results
• Cons
• Practical difficulties during the performance of the trial
• The clinicians are not familiar with the essential statistical part of this
approach
• Active and dynamic follow-up of the trial is needed

41. WHAT ARE THE CHALLENGES OF THE NEW CLINICAL TRIAL
DESIGNS?
• To show significant benefit in overall survival
• Rapidly evolving and not validated technics in use for tumor
sequencing (NGS, circulating tumors cells, circulating tumor DNA…)
• High number of screened patients is needed
A strong infrastructure behind is needed to execute such trials with quality assurance

42. What are we going to discuss today!
Evidence
Based
Medicine
Resources
Utilization
Clinical
Research
Innovation
• How are we used to perform clinical
trials in Oncology?
• Does it fit our today’s needs?
• Integration of biology knowledge in
shaping drug development
• New Clinical trial designs “Can they
offer solution for accelerating drug
development?”
• The supporting infrastructure role in
clinical trial execution

43. The current fragmented approach of Drug & Biomarker
related Development
Screening
patients
Enrolling
patients
Collecting
tissue
Analyzing
tissue
Collecting
real-life data
Screening
patients
Enrolling
patients
Collecting
tissue
Analyzing
tissue
Collecting
real-life data
Screening
patients
Enrolling
patients
Collecting
tissue
Analyzing
tissue
Collecting
real-life data
Company A Company B Company C

44. QA/QC validated platforms & services
Collected data
Towards data-driven healthcare
Faster access
to effective care
Business risk reduction
Innovative
trial designs /
Trial access
Regulatory pathway
/
Market access
supported by
adaptive
licensing
Biomarker
analytical and
clinical
validation
Treatment guideline
development

45. QA/QC validated platforms & services
Collected data
Towards data-driven healthcare
Faster access
to effective care
Business risk reduction
Innovative
trial designs /
Trial access
Regulatory pathway
/
Market access
supported by
adaptive
licensing
Biomarker
analytical and
clinical
validation
Treatment guideline
development

46. • Clinical
infrastructure
• Quality
Assurance in
RT(QART)
• Imaging• Translational
Research Unit
• Biobank
Sample tool KEOSYS
platform
ORTA,
VISTA, Safe,
PRISMA
QART
VODCA
platform
EORTC Infrastructure as an “Example”
supporting new generation clinical trials

47. Conclusion
• We need to adapt in our trials according to the accelerating needs
• Networking between institutions to render molecular tumor board
accessible to the majority of centers and consequently to clinical trials and
new drugs
• More collaboration with pharmaceutical companies due to the need of
drugs (including off label drugs) with the different mechanisms of action to
be used in precision medicine at the right time for the patient
• Validation Role of biomarkers and/or molecular imaging in determining
mainly the negative predictive value of an evaluated drug
• We need the infrastructure that can support such complex trials

48. “In the long history of humankind (and animal kind, too) those who
learned to collaborate and improvise most effectively have
prevailed.”
Charles Darwin 1809-1882
Thank You