Understanding Clinical Trials

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Understanding Clinical Trials

• Chris Twelves
• Professor of Clinical Cancer Pharmacology
• University of Leeds and
• Tom Connors Cancer Research Centre Bradford
• UK

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European age-standardised breast cancer death
rate in UK (women aged 50-69 over 1950-1999)
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Why are clinical trials needed?

• Despite recent advances the need remains for
  better
• ways of preventing, diagnosing and treating
  cancer
• Cancer is a matter of life and death
• Treatments are often
• Unpleasant for the patient
• Costly to society
• Need to establish new treatments which
• Benefit patients
• Represent value for money

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What are the different types of trial?

• Prevention
• Screening
• Treatment
• Early disease (no visible spread)
• Advanced disease (disease has spread)

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Prevention trials

• Intervention to prevent cancer developing
• Need to understand cause of that type of cancer
• Can be done by
• Lifestyle e.g. smoking and lung cancer asbestos
  and mesothelioma
• Drugs e.g. COX-2 inhibitors in familial bowel
  cancer tamoxifen in breast cancer
• Need to show fewer deaths in intervention group
• Randomised individually e.g. tamoxifen trials
• Comparing populations e.g. smoking

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Screening trials

• Screening aims to detect cancer
• At a pre-cancerous stage e.g. DCIS
• Before it has started to spread so local
  treatment can be effective
• Can be done by
• Scans e.g. breast cancer
• Blood test e.g. prostate cancer
• Others e.g. colonoscopy for bowel cancer
• Need to show fewer deaths in comparing screened
  and un-screened patients
• Randomised individually
• Comparing geographical areas with and without
  screening

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Treatment trials

• Directed at patients diagnosed with cancer
• Adjuvant treatment given after surgery to reduce
  risk of recurrence of cancer or death
• Advanced/metastasis treatment given once the
  cancer has spread to reduce symptoms, prolong
  life or cure patient
• Can use
• Surgery
• Radiotherapy
• Drugs
• Cytotoxic i..e. chemotherapy
• Non-cytotoxic e.g. tamoxifen, novel agents

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Oncology Drugs in Development Preclinical to
Phase III (n 374)
Others

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Signal
transduction
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Cytotoxics
22
Gene therapy
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Monoclonal
antibodies
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Vaccines
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Supportive care
Novel agents
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Hormones

Antiangiogenic
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Includes antisense, peptides,
oligonucleotides Includes immunomodulators,
radiosensitizers, chemoprevention PhRMA, New
Medicines in Development for Cancer
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How is a new anti-cancer drug testedin patients?

• Phase I
• Is it safe?
• Phase II
• Does it work?
• Phase III
• Is it more effective than current treatments?

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Rationale for the development of capecitabine
(Xeloda)

• 1. Oral administration
• mimics infusional 5-FU
• provide convenient, home-based therapy
• eliminate problems associated with i.v. access
• 2. Tumour-selective activation, targeted
  therapy

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How Does Xeloda Work?
Liver
Xeloda
Tumour gtgt healthy tissue
Enzyme
5'-DFCR
Enzyme
5'-DFUR
Thymidine Phosphorylase (TP)

• Xeloda is converted to 5-FU in the tumor

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How is a new anti-cancer drug testedin patients?

• Phase I
• Is it safe?
• Phase II
• Does it work?
• Phase III
• Is it more effective than current treatments?

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Phase I trials Key points

• First testing in man
• Want to know how much drug to give, how often
• Start at low dose and increase dose in successive
  groups of patients (36 patients), monitoring
  carefully
• Stop once significant toxicity seen (maximum
  tolerated dose)
• Treatment experimental so major ethical issues
• Patients unlikely to benefit, may have toxicity
• Offer only to patients with advanced disease and
  no standard therapy options

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Ethics of Phase I trial

• Unlikely to respond to new drug
• Limited knowledge of potential side-effects and
  may experience serious toxicity
• Free to decline or withdraw
• But many agree - still hope for benefit
• - prefer doing something
• - want to help others
• - quality of care

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Phase I trial capecitabine (Xeloda) day 1 14,
every 3 weeks
Eligibility criteria Quite fit, good
liver/renal function, no standard treatment
options Starting dose 500 mg/m2 p.o. in
divided dose x 14 days Dose levels (pts) 500
3,500 mg/m2/ day p.o (34 pts) Toxicities diarr
hoea, hand-foot syndrome Safe dose 2,510
mg/m2/day (recommended dose) Response 1
complete response, 3 partial response
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Other Phase I trials

• Patients with liver or renal impairment
• Effect of food (with oral drugs)
• Drug interactions
• In combination with other anti-cancer drugs

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How is a new anti-cancer drug testedin patients?

• Phase I
• Is it safe?
• Phase II
• Does it work?
• Phase III
• Is it more effective than current treatments?

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Phase II trials Key points

• Testing whether new treatment is active and safe
• Looking for tumour shrinkage, responses
• Usually several trials, each in a specific tumour
  type
• Typically 14 100 patients treated
• If no responses, stop
• If responses seen, treat more patients

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Pivotal US trial of Xeloda in paclitaxel-pretreat
ed MBC

• Large, multicenter trial (163 patients)
• High rate of disease control (63)
• 20 confirmed tumor response rate
• 43 stable disease
• Palliative benefit with durable pain reduction in
  47 of patients with considerable baseline pain
• Median time to progression 3.0 months
• Median survival 11.6 months

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How is a new anti-cancer drug testedin patients?

• Phase I
• Is it safe?
• Phase II
• Does it work?
• Phase III
• Is it more effective than current treatments?

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Phase III trials Key points

• Comparison of new versus standard treatment
• Advanced disease or adjuvant setting
• Patients allocated treatment arm randomly
• Usually looking for improved survival (or time to
  progression of disease)
• Typically several hundred or thousands of
  patients
• Independent monitoring of trial
• If one arm clearly better stop the trial early

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Randomisation in Phase III trials

• To reduce risk that results are biased
• Outside control of patient / doctor / nurse
• Informed consent vital
• Patient can opt out to choose standard but not
  new treatment
• Blinding
• Placebo
• Single blind
• Double blind

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Analysis of Phase III trials

• Comparison
• Survival, Time to progression, Response rates
• Need large numbers of patients
• To detect small but important benefits
• To be confident of getting the right answer
• Dont want to miss showing one treatment is
  better
• Want to be sure any apparent benefit is real and
  not chance
• Statistical analysis
• P lt 0.05 less than 1 in 20 chance results
  occurred by chance
• Hazard ratio e.g. HR for death lt 1 reduced risk
  of death

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Xeloda plus Taxotere (XT) versus Taxotere phase
III study design
Xeloda 1,250mg/m2 twice daily, days 114
plusTaxotere 75mg/m2, day 1
Randomization(3-weekly cycles)
Taxotere 100mg/m2, day 1

• Patients continued until disease progression or
  unacceptable toxicity
• Primary endpoint time to disease progression

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Xeloda plus Taxotere (XT) significantly superior
tumor response rates
Independent review committee confirmed, p0.025
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Xeloda plus Taxotere (XT) significantly superior
time to disease progression
1.0 0.8 0.6 0.4 0.2 0.0
Hazard ratio 0.652
Log-rankp0.0001
Estimated probability
4.2
6.1
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Time (months)
Median Survival Time (plt0.01) XT 14.5 months T
11.5 months
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XT most common (gt5) grade 3/4 treatment-related
toxicities
50 40 30 20 10 0
XT (n251)
Grade 3 Grade 4 Grade 3 Grade 4
Taxotere (n255)
Patients ()
Stomatitis
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Other aspects of Phase III trials

• Quality of life
• Health economics
• Real world

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Randomised, phase III trials in breast cancer
utility of QoL

• If the survival difference between two treatments
  is small
• QoL assessment may enable identification of the
  treatment with the most favourable therapeutic
  index
• When a new treatment is clearly more effective
• it is important that it does not impair patients
  QoL

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QoL assessment in the Xeloda plus Taxotere (XT)
versus Taxotere trial
Questionnaires EORTC QLQ-C30 (version
2.0) Breast Cancer Module QLQ-BR23
Treatment period
Week
0
6
12
18
24
30
36
42
48
Predefined primary QoL endpoint global health
status at week 18
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QoL parameters assessed by QLQ-C30 and QLQ-BR23
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QoL (global health status) improves over time
with XT versus Taxotere
80 70 60 50 40
Global health status
0
0 6 12 18 24 30 36 42 48
Time (weeks)
XT 219 187 127 97 57 41 31 21 13 Taxotere
224 190 133 85 42 20 14 12 5
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Cost analysis Xeloda plus Taxotere (XT) versus
Taxotere

• Data collected during the XT trial including the
  costs of
• chemotherapy and its administration
• side effects and their treatment
• Measures of clinical effectiveness and economic
  data combined in a model based on the US
  healthcare system

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Key medical resource costs are similar with XT
and Taxotere alone
24,000 20,000 16,000 12,000 8,000 4,000 0
XT
T
Mean total costs per patient (US)
Total Chemotherapy Hospitalisations Treatments Co
nsultations Infusions costs drugs (AEs) (AEs)
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Clinical trials do not represent typical cancer
patients

• Most patients in clinical trials are younger
  healthier
• Patients with other illnesses (e.g. liver or
  kidney disease) are usually excluded from
  clinical trials concomitant medications
• Drug interaction risk increases with of
  medications

Number of drugs

Drug interaction risk ()

2
5.6


34.3
4


6
72.0


100.0
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Karas S. Ann Emerg Med 19811062730





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Thank you for listening

• Do you understand clinical trials any better now
  than you did an hour ago?
• Do you have any questions?