The most common spread of metastatic solid tumours in central nerve system (CNS) is as parenchymal brain metastases or as leptomeningeal disease (metastases in brain membrane or spinal cord). Because the brain is protected by blood-brain barrier many drugs in standard dose will not achieve the required concentrations to be effective in CNS. Some anti-cancer drugs, however, do not cross blood-brain barrier at all but activate lymphocytes that can penetrate to CNS; while other drugs do not have effect on CNS.

For many experimental anti-cancer therapeutics there may be not sufficient information regarding their activity on CNS. As a result if the studied drugs do not have effect on CNS patients with brain metastases will progress quickly and this may affect the overall outcome of the clinical trials. On the other hand if the anti-cancer drugs have CNS activity and patients with brain metastases are excluded from the clinical trials there will be no information on drug activity on CNS and patients will miss new treatment option. 

What types of clinical trial designs are possible for patients with CNS disease?

Design 1 – if the drug is considered unlikely to have CNS activity or efficacy

There are 2 possible designs to overcome the challenges above:

  • Exclude patients with CNS disease 
  • Exclude patients with untreated or unstable CNS disease  – CNS disease has to be either asymptomatic on stable dose of corticosteroids or off corticosteroids.

Design 2 – if the drug is considered likely to have CNS activity or efficacy

• Permit untreated CNS metastases

• If untreated CNS disease is measurable, mandate that these lesions be captured as target lesions

• Define whether a growing CNS lesion previously treated with radiotherapy is permissible as a target lesion

• Standardise CNS imaging frequency

• Define if symptomatic, or if steroids or anticonvulsants permitted initially, or later

• Specify bicompartmental endpoints and action if progression is observed in one but not both compartments

• For randomised studies, stratify according to:

  • Whether CNS disease is present or absent
  • Whether CNS disease is treated or untreated
  • If treated, whether CNS progression has occurred

Design 3 – if there is minimum information on drug activity on CNS

Appropriate for phase 1 studies

This model includes dose escalation until the optimum dose is achieved. Then it is followed by molecularly or histologically defined efficacy expansion cohorts; food effect and drug-drug  interaction sub-studies and CNS metastases sub-study. 

Appropriate for phase 2 and 3 studies

• Initially permit only absent or treated and non-progressing CNS metastases in general trial population

• Permit separate single-arm early CNS cohort with defined number of patients with measurable untreated or progressing CNS disease with separate early efficacy analysis such as CNS objective response

• Minimise risk in this early CNS cohort by only allowing in asymptomatic cases

• Modify protocol (as either amendments or following pre-written decision pathways) as data emerge to be like either scenario A or scenario B

CNS progression is a big challenge in treating patients with metastatic solid tumours. New approaches are required to assess when patients with CNS disease could be appropriately included or excluded from clinical trials. 


Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group

Author: Olga Peycheva

Olga is a clinical research professional who has been working in clinical research since 2005. She has extensive experience in clinical research in Eastern and Western Europe. 

Originally published on 1 Oct 2018