L16: clinical trials for new cancer drugs

Question 1

What are the types of cancer clinical trials?

Answer 1

• Prevention (epidemiological, interventional) – reducing risk factors
• Screening (imaging, biomarkers) – screening cancer patients early
• Diagnosis (imaging, biomarkers) – understanding where cancer is, its biology
• Treatment (drug, device, technique, combo)
• Palliation / supportive care

Question 2

What is the current drug development path?

Answer 2

• Identify what drives cancer to grow (target)
• Design a treatment to block that drive (assay)
• Demonstrate preclinical activity (model), safety (toxicology) and pharmacological properties (pharmacokinetics)
• Develop the therapy in advanced disease:
  o Safety, biological effects (small numbers)
  o Clinical effects: palliation, extend survival (large numbers)
• Test the therapy in early, curable cancers
  o Clinical effects: improve cures

Question 3

What are the outcome measures of clinical trials, what are the endpoints?

Answer 3

• Tolerability
  o Adverse events, dose reduction / interruptions / discontinuations
• Pharmacokinetic measures (PK)
• Pharmacodynamic (PD) measures
• Response rate
• Progression free survival
• Overall survival
• Quality of life / patient preference

Question 4

Describe phase I trials, what questions does it raise?

Answer 4

Phase I – what it tests, mostly about safety
15-30 pts
- What dose is safe? (dose finding)
- How should it be given? (scheduling)
- How does it affect the body? (toxicity)
- How does the body handle the drug? (PK)
- What biological effect does it have? (PD)

Question 5

Describe phase II trials

Answer 5

• Less than 100 people
  o Often single tumour type
  o Increasingly molecularly-selected
  o Usually 2nd/3rd line or addition to standard therapy
• Does treatment show sign of activity?
  o Pathway activity: expected molecular target
  o Biological effect: expected downstream effects
  o Clinical activity: radiological response (tumour size)
• What is the tolerability profile – acute, chronic?
• How to give?
• Is this likely to succeed in phase 3? Many treatments never get past phase II

Question 6

Describe phase III trials

Answer 6

Phase III
- 100s – 1000s of people
- Usually multi-centre, randomized, controlled trials
- Compare new treatment with current standard
- Increasingly mandatory ‘translational’ component
- Primary endpoint is what would determine use
- Can be 1st, 2nd, 4rd line or adjuvant / neo-adjuvant
- Usually need metastatic data before inclusion of adjuvant patients
- Can result in licensing of drug for use and new ‘standard of care’

Question 7

Describe phase IV trials

Answer 7

Phase IV
- 1000s+ patients
- Usually after drug licence
- Enables widespread use of a drug in controlled manner
- Used to evaluate long-term safety, real-world effectiveness and cost:benefit

Question 8

What are biomarker trials?

Answer 8

• Biomarker trials – esp neo-adjuvant / window (i.e. short course of treatment before planned surgery to assess effects)

Question 9

What are platform trials?

Answer 9

• Platform trials
  o Basket trials (single selection biomarker, any cancer type)
   Same mutation for different types of cancer
  o Umbrella trials (single tumour type, multi-arms according to biomarkers)
   1 type of cancer, different genetic mutations
  o Octopus trials (often mix of above, multi arm)
  o Multi-arm multi-stage trials (MAMS – late-phase trials platform)
  o Adaptive trials (ability to adapt arms / design)