Download especially for phase III trials

Clinical Trials in Colon
Cancer – the promise for
better outcomes
Mital Patel MD
Gastrointestinal Medical Oncologist
November 12, 2016
Primer on Clinical Trials
Definition, types, advantages and challenges
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What are Cancer Clinical Trials?
The NIH Definition:
“A research study in which one or more human subjects are prospectively assigned to one or
more interventions (which may include placebo or other control) to evaluate the effects of
those interventions on health-related biomedical or behavioral outcomes.”
The common (old) definition:
Clinical trials are research studies that involve volunteers used to advance science. Many
clinical trials study new cancer treatments.
The current definition: (especially for phase III trials)
(Treatment) Clinical trials are treatment options which are delivered in a research setting (and
hence monitored rigorously) which have the potential to benefit the patient, provide early
access to groundbreaking therapies, improve quality of life and…advance science.
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Phases of Trials
Years
3-6mo
upto 2 yrs
1-4yrs
Preclinical
Animal studies
Cell Lines
Phase I
All tumors
Safety
Dose finding
Administration
Maybe efficacy
Phase II
Efficacy
More safety data
Phase III
Randomized
Is it better than
standard?
Is this difference
real?
Side effects
Phase IV
Effects in the real
world
Long term side
effects
Danger signals
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Phases of Trials: efforts to accelerate
Years
3-6mo
upto 2 yrs
1-4yrs
years
Preclinical
Animal studies
Cell Lines
Phase I
All tumors
Phase II
Phase III
Safety
Cancer specific
Dose finding
Efficacy
Administration
Randomized
More safety
data
Is it better than
standard?
Maybe efficacy
Cohort
expansion
Randomized
Phase IV
Effects in the
real world
Is this difference Long term side
Larger numbers real?
effects
Side effects
Danger signals
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Types of Cancer Clinical Trials
• Cancer Prevention trials
• Screening trials
• Diagnosis trials
• Cancer Treatment trials
• Quality of life trials
• Comparative effectiveness / Cost effectiveness
• GENOMIC trials
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Genomically oriented trials (Not genetic)
BASKET TRIALS
UMBRELLA TRIALS
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Benefits of participating in cancer clinical trials
Direct
• Potentially better treatment
• Access to new medications
• Improvement in quality of life
Indirect
• Regulatory necessity
• Advancing science
• Benefit to other patients
• The value proposition
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Advantages: potentially better treatment
Continuation of bevacizumab after first progression in metastatic
colorectal cancer (ML18147): a randomized phase 3 trial
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Advantages: Access to newer treatments
•
Recruitment of patients :April, 2009 to
February, 2012
•
Recruitment of patients from October
2008 to February 2012
•
Phase 1 study published in June 2012
in the same edition
•
Phase 1 study published in June 2012
in the same edition
•
Then phase II, then phase III
•
Then phase II, then phase III
•
FDA approval (Keytruda)
•
FDA approval (Opdivo)
– Melanoma: 2014
– Melanoma: 2014
– Lung: 2015
– Kidney and Lung: 2015
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Advantages: improvement in quality of life
• TAS-102 vs placebo
• It slowed down the decline in
causing weakness and debility
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Advantages: Regulatory
• Phase III trials compare treatments to standard of care.
• For new drugs to be approved by U.S. Food and Drug
Administration
• They also must be done before new surgical or radiation
therapy methods are regularly included with cancer treatment.
• Participation in clinical trials – better survival.
• They remain Category 1 recommendation for most national
cancer guidelines.
FDA approved drugs in colorectal cancers
Chemotherapy
Antibodies
Oral targeted molecules
5- Fluorouracil
Panitumumab (Vectibix)
Regorafenib (Stivarga)
Irinotecan (Camptosar)
Cetuximab (Erbitux)
Oxaliplatin (Eloxatin)
Capecitabine (Xeloda)
Bevacizumab (Avastin)
Lonsurf (TAS102)
Ziv-Aflibercept (Zaltrap)
Ramucirumab (Cyramza)
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Strong network
Organizational
• ASCO:
• AACR
• National organizations:
– Colon Cancer Alliance
– American Cancer Society
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National priority
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But its not all good…..
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Low participation in oncology clinical trials
• California Cancer Registry 2001-2008
– < 1%
– Al-Refaie et al. Annals Surgery 2011
• NCI-Sponsored Coop Group Trials Enrollment 1996-2002
– 1.7% of incident cancer cases enrolled
– Lower in racial/ethnic minorities, older patients
– Murthy et al. JAMA 2004
• NCI Comprehensive Cancer Centers 2013
– 12% median
– http://cancercenters.cancer.gov/DT/DT3
Key influences in participation in clinical trials
Patient
Physician
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Key influences in participation in clinical trials
Patient
Families
Physician
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Key influences in participation in clinical trials
Patient
Healthcare
Physician
systems
Families
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Key influences in participation in clinical trials
Patient
Insurance
Healthcare
Systems
Physician
Families
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Key Barriers: Physician
Lack of knowledge
of available
options
Time needed to
enroll on trial
Lack of motivation
Clinical equipoise
Lack of resources /
research personnel
/Cost of trials
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Key Barriers: Patient wishes
Side effects of the
experimental drug
Lack of effect,
Is this actually the
best option for me
Financial / Logistics
/costs /Travel /
Health Insurance
wont pay
Sugar Pill / Placebo
Randomization/
Loss of autonomy
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Background: effects of low accrual to CT
• The success of a clinical trial is dependent upon accrual within a
specified time frame
• Low accrual leads to
– Inadequate statistical analysis of outcomes
– Premature trial closure
– Increased costs
– Ethically unfair to the patients who enrolled in the trials
Myth 1: I will be a guinea pig
Depends on the definition of Guinea pig
– Several committees and agencies watch over patient safety before, during, and after a
clinical trial.
– Most regulated : Institutional Review Board
• Includes doctors, statisticians, community advocates, clergy, lawyers, patient advocates
• Mandated by federal law:
– Risk – benefit ratio
– Informed consent, option to withdraw
– Data Safety Monitoring Board
Myth 2: I will get a sugar pill (placebo): Not necessary
S1406: Randomized Phase II Study of Irinotecan and Cetuximab with or without
Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer
Patients with
BRAF positive
CRC
Irinotecan and
cetuximab
Irinotecan and
cetuximab and
vemurafenib
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Myth 3: I will get a sugar pill (placebo): yes
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Some key things to remember…..
• Statistical significance and clinical significance
• A similar setting, a similar population, similar disease stage….
But still it does not account for individual differences
– Inclusion criteria help make sure that people in a clinical trial are medically
similar
– Exclusion criteria help keep people safe.
Targeting Efforts to Ensure Access and Optimize
Decisions About Clinical Trials
• Use the internet
• Seek Patient
advocates
• Seek support groups
• ASK your oncologist
Patients
Healthcare
teams
• Train all staff
• Invest in trial
infrastructure
Physicians
• Informed consent
• Cultural sensitivity
• Understand patients
point of view
• Invest in trial
resources: easy
matching
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• http://www.cancer.net/navigating-cancer-care/how-cancertreated/clinical-trials/pre-act/play-oneall/what_is_randomization
• http://www.cancer.net/navigating-cancer-care/how-cancertreated/clinical-trials/pre-act/play-oneall/who_pays_cost_clinical_trial
• http://www.cancer.net/navigating-cancer-care/how-cancertreated/clinical-trials/pre-act/play-oneall/what_pharmaceutical_drug_companies_gain
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Starting points for Information on cancer clinical trials
• Cancer.net including the PREACT videos
• Cancer.gov (NCI Clinical trials.gov) with database
• American Cancer Society: Free phone searches
• Website of your local Academic Oncology Centers
• Calls to your community oncology centers
• Colon Cancer Alliance
• Webchats, blogs, Youtube, Twitter (with a grain of salt..not your first stop !)
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Advances in Colorectal
cancer
Latest results, the buzz….whats in the pipeline
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Updates from recent key clinical trials in colon cancer
• 18 months
• Major national / international meetings
– ASCO, ESMO, AACR, GI ASCO
• By intervention group
– Prevention, Diagnosis, Treatment advances, Supportive care
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Practice changing / Key observations
• Screening guidelines
• Prevention strategy
• Detection of recurrence
• Right vs Left
• Immunotherapy
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1. Prevention (Why are we talking about this?)
• Adults aged 50 to 59 years with a ≥10% 10-year CVD risk,
USPSTF recommends initiating low-dose aspirin use for the
primary prevention of cardiovascular disease (CVD) and
colorectal cancer (CRC).
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2. Screening: which test?
• Colon cancer screening in patients 50-75yrs of age – but can
use ANY test
– Stool based tests like guaic testing, stool DNA testig
– Direct visualization like colonoscopies, sigmoidoscopies
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3. Surveillance: How much is needed?
POST
SURGICAL
FOLLOWUP
INTENSIVE
SYMPTOMATIC
SCREENING
F/UP
CEA
CEA + CT scans
CT scans
Visits +/- single
baseline CT
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Testing is important in
colon cancer
POST
SURGICAL
FOLLOWUP
INTENSIVE
SYMPTOMATIC
SCREENING
F/UP
CEA
CEA + CT scans
CT scans
Maybe not in rectal
cancer
Visits +/- single
baseline CT
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4. Side matters!
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4. Right vs Left
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Retrospective analysis
• Right colon (Median overall survival) • Left colon
• 19.4 months
• 33.3 months
• With cetuximab: 16.7 mo
• With cetuximab: 36mo
• With Bevacizumab: 24.2 mo
• With Bevacizumab: 31.4mo
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5. Is ‘more the merrier’ or is ‘four a crowd’ ?
• Slowed down progression
• Had better responses
• Had more side-effects
• Improved survival
CHARTA Phase 2 trial
6 mo induction  maintenance
•
•
•
•
Positive study
Slowed progression
Improved response rate
More side-effects / Dose decr
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6. Immunotherapy in Colon cancer please!
Checkpoint inhibitors, how they work?
Immune system contacts
the cancer cells
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Immunotherapy: Checkpoint inhibitors, how they work.
Immune system contacts
the cancer cells
The immune system brakes
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Immunotherapy: Checkpoint inhibitors, how they work.
Immune system contacts
the cancer cells
The immune system brakes
The brakes are released,
Immune system attacks cancer
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Immunotherapy in colon cancers
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Newer approaches to immunotherapy
• Cobimetinib + Atezolizumab in KRAS-Mutant mCRC
– 17% ORR, 72% 6-mo OS higher than rates observed for individual agents
or standard of care
– Current phase Ib study accumulating more mCRC pts
– Phase III trial also recruiting mCRC pts to evaluate this combination therapy
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7. A look at the future.
• Stem cells are important in self renewal of cancer cells
– Recurrence
– Metastases
– Resistance
8. Genomics
Mismatch repair
Kras
Extended Kras and Nras
BRAF
POLE
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SUMMARY
Aspirin for primary prevention -50-59yrs, at least 10 yrs
Screening for colon cancer is key….which test may not be !
Surveillance may be tailored for colon / rectal cancer
Different antibodies for different sides.. Ready for prime-time?
4 drug regimen for response in selected patients
Immunotherapy in the works – compelling evidence for MSI-H tumors
Stem cell inhibitors, POLE mutations, BRAF inhibitors in the pipeline
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Thank You