. 2021 Jun 22;153(3):375–381. doi: 10.1007/s11060-021-03789-5

Table 2.

Recommendations for clinical trial inclusion among patients with CNS metastases

CNS disease type	Recommendations
Treated/stable brain metastases	(1) Patients with treated/stable brain metastases should be included in trials unless there is a strong rationale to exclude such patients (2) Inclusion of patients with treated/stable brain metastases should not be dependent on whether the drug’s pharmacological properties predict penetration of the blood–brain barrier (3) Patients should be neurologically stable prior to study entry to mitigate the uncertainty of attributing CNS toxicity to the investigational drug or underlying disease. To achieve this, consider limiting enrollment to patients receiving a stable or decreasing corticosteroid dose at the time of study entry
Active brain metastases	(1) Patients with active brain metastases should not be automatically excluded from trials and should be included if the treating physician determines that immediate CNS specific treatment is unlikely to be required and: (a) there is a strong rationale for likelihood of CNS activity, or (b) CNS metastases are common in the target population (2) For drugs with known CNS toxicities, exclusion of patients with active brain metastases may be justified, especially early in drug development
Leptomeningeal metastases	(1) Patients with LMD should not be automatically excluded from trials and should be included if:—the treating physician determines that immediate CNS specific treatment is unlikely to be required, (a) the drug is anticipated to have CNS activity and is relevant for the primary tumor, and (b) there is strong scientific rationale to support the likelihood of benefit, based on pre-existing data

CNS disease type

Recommendations

Treated/stable brain metastases

(1) Patients with treated/stable brain metastases should be included in trials unless there is a strong rationale to exclude such patients

(2) Inclusion of patients with treated/stable brain metastases should not be dependent on whether the drug’s pharmacological properties predict penetration of the blood–brain barrier

(3) Patients should be neurologically stable prior to study entry to mitigate the uncertainty of attributing CNS toxicity to the investigational drug or underlying disease. To achieve this, consider limiting enrollment to patients receiving a stable or decreasing corticosteroid dose at the time of study entry

Active brain metastases

(1) Patients with active brain metastases should not be automatically excluded from trials and should be included if the treating physician determines that immediate CNS specific treatment is unlikely to be required and:

(a) there is a strong rationale for likelihood of CNS activity, or

(b) CNS metastases are common in the target population

(2) For drugs with known CNS toxicities, exclusion of patients with active brain metastases may be justified, especially early in drug development

Leptomeningeal metastases

(1) Patients with LMD should not be automatically excluded from trials and should be included if:—the treating physician determines that immediate CNS specific treatment is unlikely to be required,

(a) the drug is anticipated to have CNS activity and is relevant for the primary tumor, and

(b) there is strong scientific rationale to support the likelihood of benefit, based on pre-existing data

CNS central nervous system, LMD leptomeningeal disease

Adapted from: US Food and Drug Administration (2019) Cancer Clinical Trial Eligibility Criteria: Brain Metastases Guidance for Industry [28]