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Widening the Net: The Role of Combination Therapy in Cancer
Heather DiBenedetto, MS RAC
Global Head of Clinical Operations
Translational Clinical Oncology, Novartis
July 15, 2015
Topics for Discussion
Why is cancer different?
What is combination therapy?
Study Design
Regulatory submission
Sponsor considerations
What is next?
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Why is Cancer Different? It is far from one disease
Ca
nce
r Breast
Luminal A Different
mutations
Luminal B Different
mutations
TNBC/Basal Different
mutations
Her2 Different
mutations
Lung
Melanoma
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New Therapy ‘A’
0
20
40
60
80
100
120
Pretreatment 2 cycles 4 cycles 6 cycles
Patient A
Patient B
Patient C
Patient D
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New Therapy ‘A’ After 10 cycles
0
20
40
60
80
100
120
Patient A
Patient B
Patient C
Patient D
Time of Relapse
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Tum
or
Volu
me
Combination Therapy
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When drugs with different
effects are combined, each drug
can be used at its optimal dose,
without intolerable side effects.
For some cancers, the best
approach is a combination of
surgery, radiation therapy, and
chemotherapy.*
*Definition of Combination Drug Therapy-The Merck Manuals
Promise of Combination Oncology Trials
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Cancer trial of drug combination yields 'spectacular' results The Guardian, June 13 2015
Clinical trial analysis
suggests drug
combination may be
highly effective in
recurrent ovarian
cancer NIH, June 2014
Study: Combination Therapy Could Revolutionize Cancer Treatment Voice of America, June 2013
Exploring the
Pathway: The
RAS/RAF/ME
K/ERK
Pathway in
Cancer:
Combination
Therapies and
Overcoming
Feedback ASCO Daily News, May 31 2015
Combination Effective in Advanced Melanoma; Cost Questions Raised
ASCO Daily News, May 31 2015
Is Cancer smarter than us?
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No
problem-
easy
escape
Escape Mechanisms
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ABC pathway
1. Drug blocks
downstream
effect
2. Escape
mechanism
used and
function
restored
Combination Therapy ‘A’ + ‘B’ After 12 cycles
0
20
40
60
80
100
120
Patient A
Patient B
Patient C
Patient D
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Combination Therapy in Melanoma
DiBenedetto/ Arena Oncology Conference/Day 2/July 2015 11
Royal Marsden patient Vicky Brown’s CT scan before treatment (left) and 12 weeks after initial treatment. Photograph: Royal
Marsden
Study Design in Drug Combination Therapy
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One size does not fit all-small molecule, biologics, immunotherapy
Novel agent + Novel agent
Novel agent + ‘Standard of Care’
Novel agent + approved agent in a new indication
Study Design in Drug Combination Therapy
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What data already exists for the compounds?
Dose escalation
• Both agents vs. anchor agent
• Information from single agent
• Overlapping risks= Low starting dose
• Dosing
Single Agent Combination in same study
Signal seeking Multiple arms
Crossover
Randomization
Sponsor Considerations in Combinations
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More complexity
• Clinical documents
• Consistency across program
• More frequent updates, amendments
• Risk document
• Drug/Drug interactions
• More conmed exclusions
• More assessments
• Increased monitoring
• Drug Supply and comliance
• Naming conventions
• System limitations
Protocol
ICF
Patient
Information
Drug Diary
Patient Considerations in Combinations
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Making a complex study work on a patient level
• Informed consent form
• Sample collection
• Safety, PK, biomarker
• Blood, Skin, Tumor, Hair, Urine
• Drug administration
• Dose strength, pill color, patient kits
• Patient Tools
• Appointment reminders, drug diary, instructions, calendar
• Assessment schedule
• Long days, multiple visits to clinic
Looking to the future
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Genetic tumor profiling for all patients
Combinations earlier in treatment
More immunotherapy
Understanding resistance mechanisms and adaptive responses
Quest to CURE cancer and not just slow it
Heather DiBenedetto [email protected]
The messages in this presentation represent my own opinion and not necessarily that of Novartis