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Exclusion of Patients with Brain Metastases From Early-Phase Systemic Therapy Trials: A Cross-Sectional Analysis of Eligibility Criteria

This cross-sectional analysis of 873 phase I systemic therapy trials reveals that while the inclusion of patients with brain metastases has improved over time—particularly for immunotherapy and targeted therapy trials—restrictive eligibility criteria frequently exclude those with symptomatic, active, or untreated brain metastases.

Original authors: Cody Zatzman, Italo Fernandes, Isabella Kojundzic, Natasha D’Souza, Evan Cescon, Eva Zhang, Meghna Katyal, Farideh Tavangar, Martin Smoragiewicz, Mary-Jane Lim-Fat, Arjun Sahgal, Katarzyna J. Jerzak

Published 2026-06-28

📖 5 min read🧠 Deep dive

CC BY 4.0

Original authors: Cody Zatzman, Italo Fernandes, Isabella Kojundzic, Natasha D’Souza, Evan Cescon, Eva Zhang, Meghna Katyal, Farideh Tavangar, Martin Smoragiewicz, Mary-Jane Lim-Fat, Arjun Sahgal, Katarzyna J. Jerzak

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

The Big Picture: The "VIP Room" Problem

Imagine a new, exciting drug is being tested in a special "VIP room" (a Phase I clinical trial) to see if it works against cancer. The goal is to find out if the drug is safe and effective before it is released to the general public.

However, there is a specific group of people who are often told, "Sorry, you can't come in." These are patients with brain metastases (cancer that has spread from elsewhere in the body to the brain).

This paper is like a detective report that looked at hundreds of these VIP rooms (clinical trials) to see who is allowed in and who is locked out. The main finding? The door is technically open for many, but there are so many bouncers and rules that most people with brain cancer still can't get through.

The Investigation: What the Researchers Did

The researchers (a team from the University of Ottawa and Sunnybrook Health Science Centre) acted like librarians. They went to the world's biggest library of medical studies (ClinicalTrials.gov) and pulled out 873 different "recipes" (trial protocols) for new cancer drugs.

They wanted to answer one simple question: Do these recipes say "No Brain Cancer Allowed," or do they say "Yes, but..."?

The Findings: The "Yes, But..." Trap

Here is what they discovered, broken down into everyday terms:

1. The "Open Door" Illusion
If you just looked at the headline of the trial, you might think the door is wide open.

The Stat: About 70% of the trials said, "Yes, you can enter if you have brain cancer."
The Catch: But once you look at the fine print, it's like walking through a door that leads to a maze. Most of these "Yes" trials come with a long list of strict conditions.

2. The "Bouncers" (The Strict Rules)
Even if a trial says "Yes," the rules act like very strict bouncers at a club. If you don't meet their specific criteria, you are turned away. The most common reasons for being turned away include:

The "Silent" Rule: If you have any symptoms (like a headache or confusion), you are out. The problem? The trials rarely define what "symptoms" actually mean. It's like a bouncer saying, "No one with a bad vibe allowed," without defining what a bad vibe is.
The "Stable" Rule: Your brain cancer must be "stable" (not growing). Many trials demand that the cancer hasn't grown for at least 4 weeks before you can even apply.
The "Medication" Rule: If you are taking steroids (to reduce brain swelling) or anti-seizure meds, you are often excluded. Some trials demand you stop taking these life-saving meds for 4 weeks just to join the trial. Imagine being told, "You can't take your heart medicine for a month to try this new diet."
The "Treatment" Rule: You usually can't join if you haven't had prior treatment for the brain cancer.

3. Who Gets In vs. Who Gets Kicked Out
The rules aren't the same for everyone.

The "Cool Kids" (Immunotherapy & Targeted Therapy): Trials testing new "smart" drugs (immunotherapy and targeted therapy) are much friendlier. They are more likely to let people with brain cancer in.
The "Old School" (Chemotherapy): Trials testing traditional, harsh chemotherapy are the strictest. They are the most likely to say "No" to anyone with brain cancer.
The "Time Travel" Effect: Trials started in recent years (2015–2024) are more welcoming than those from 10 years ago. Things are getting better, but slowly.
The "Location" Factor: Trials in North America and Europe are stricter than those in Asia or trials that happen across multiple continents.

Why Does This Matter? (The Paper's Conclusion)

The paper argues that we are stuck in a weird middle ground.

The Problem: Because so many patients with brain cancer are excluded, we don't actually know if these new drugs work for them. It's like testing a new parachute only on people who are already falling slowly, and then wondering if it works for people falling from a plane.
The Reality: Even though the "door" is technically open in 70% of trials, the "bouncers" (the strict rules about symptoms, steroids, and stability) are keeping the door effectively shut for the sickest patients.
The Future: The authors say we need to stop using vague terms like "symptomatic" and create clear, standard rules. If we want to know if these new drugs save lives, we need to let the people with brain cancer actually try them.

Summary Analogy

Think of clinical trials as a new restaurant trying a new menu.

The Goal: To see if the food is good for everyone.
The Current Situation: The sign says, "Everyone Welcome!"
The Reality: The manager (the trial rules) only lets in people who aren't hungry, who haven't eaten in 4 hours, who aren't wearing a hat, and who have already tried the soup.
The Result: The restaurant thinks it's serving everyone, but it's actually only serving a tiny, very specific group of people. The people who are actually starving (the patients with brain metastases) are still standing outside, hungry and unsure if the food would help them.

The Bottom Line: We are making progress, but until we simplify the rules and stop excluding people based on vague or overly strict conditions, we won't know if our best new cancer drugs actually work for the people who need them most.

Technical Summary: Exclusion of Patients with Brain Metastases From Early-Phase Systemic Therapy Trials

Problem Statement
Patients with brain metastases (BrM) represent a significant and growing population within metastatic solid tumours, particularly in melanoma, breast, and lung cancers. Despite the high morbidity and mortality associated with BrM, these patients have historically been underrepresented in clinical trials. This exclusion limits the evaluation of the central nervous system (CNS) efficacy and safety of novel systemic therapies. While regulatory bodies like the FDA and ASCO–Friends of Cancer Research have advocated for broader inclusion, concerns regarding life expectancy, CNS complications, and blood-brain barrier penetration have led to restrictive eligibility criteria. Furthermore, existing literature lacks a granular, protocol-level analysis of how these criteria are operationalized in early-phase (Phase I) trials, specifically regarding definitions of "stable" disease, corticosteroid thresholds, and antiseizure medication use.

Methodology
This study conducted a cross-sectional analysis of the ClinicalTrials.gov database, searched in July 2024. The search utilized the term "cancer" filtered for interventional studies in "early phase 1" and "phase 1" with publicly available protocols.

Inclusion Criteria: Trials registered between January 1, 2000, and June 30, 2024, investigating systemic therapies for advanced solid tumours (unresectable, recurrent, locally advanced, refractory stage 3, or stage 4).
Exclusion Criteria: Trials involving haematologic malignancies, primary brain tumours, interventions not evaluating anticancer efficacy, or those without accessible full protocols. Studies focused solely on leptomeningeal carcinomatosis without parenchymal BrM were also excluded.
Data Abstraction: Four reviewers independently abstracted eligibility criteria related to BrM from the full protocols. Discrepancies were resolved by a third reviewer.
Variables: Data included trial characteristics (cancer type, investigational agent, location, start year) and specific BrM eligibility parameters (symptomatic status, prior treatment, radiographic stability, corticosteroid use, antiseizure use).
Definitions: "Complete exclusion" was defined as explicit disallowance of any patient with BrM. "Conditional eligibility" (or inclusion with stipulations) permitted enrolment provided specific criteria (e.g., stability, prior local therapy) were met.
Statistical Analysis: Categorical variables were expressed as frequencies and percentages. Chi-square goodness-of-fit tests were used to examine proportions across categories, with a significance threshold of $p < 0.05$ .

Key Results
From an initial pool of 3,210 studies, 873 trials with accessible protocols were analyzed.

Overall Inclusion Trends: Patients with BrM were completely excluded in 13.2% of trials, eligible with stipulations in 70.3%, and had unspecified eligibility in 16.5%.
Temporal Trends: Trials initiated between 2015 and 2019 permitted BrM enrolment more frequently (72.8%) than those from 2010–2014 (66.2%).
Cancer Type Variance: Genitourinary (GU) trials were significantly more likely to exclude patients with BrM (33.9%) compared to lung (3.5%), breast (4.3%), and melanoma (0.9%) trials.
Therapeutic Class: Immunotherapy trials were most likely to include patients with BrM (47.4% of included trials), followed by combination chemo-immunotherapy (15.8%) and targeted therapy (14.2%). Cytotoxic chemotherapy trials were least likely to include BrM patients (2.9%).
Restrictive Stipulations: Among the 614 trials that nominally permitted BrM enrolment, significant restrictive criteria persisted:
- Symptomatic Disease: 58.5% excluded patients with symptomatic BrM, yet none provided objective, symptom-based definitions.
- Active/Unstable Disease: 84.0% excluded patients with active, unstable, or progressing BrM. Of these, 38.3% required more than four weeks of radiographic stability.
- Prior Treatment: 75.9% excluded patients with previously untreated BrM.
- Corticosteroids: 19.2% completely excluded patients on corticosteroids. Among those with conditional criteria, 98.2% mandated a washout period of at least four weeks prior to enrolment.
- Antiseizure Medication: 9.3% strictly forbade antiseizure medication use.

Key Contributions
This paper provides the first systematic, granular cataloging of Phase I trial eligibility criteria regarding brain metastases. Unlike prior analyses of registrational or mixed-phase trials, this study details specific protocol-level architecture, including:

Operational Gaps: It highlights the discrepancy between nominal inclusion and functional access, demonstrating that "conditional" eligibility often functions as de facto exclusion due to vague definitions (e.g., "symptomatic") and strict washout periods for supportive care medications.
Therapeutic Disparities: It quantifies the shift toward inclusion in immunotherapy and targeted therapy trials versus the continued exclusion in cytotoxic chemotherapy trials.
Standardization Needs: The study identifies the lack of standardized definitions for "symptomatic" disease and radiographic stability as a major barrier to consistent patient selection.

Significance and Claims
The authors claim that while formal inclusion of patients with BrM in Phase I trials has improved over time—particularly for immunotherapy and targeted therapies—restrictive and inconsistently defined eligibility criteria continue to limit meaningful participation. The paper argues that the current landscape of "conditional" eligibility often masks functional exclusion, preventing the generation of prospective intracranial efficacy and safety data necessary for designing future Phase II/III trials.

The significance of this work lies in its demonstration that early-phase trials represent a critical opportunity to characterize CNS activity. By excluding patients with symptomatic, untreated, or active BrM, the field risks missing early signals of intracranial efficacy that could inform broader therapeutic strategies. The authors conclude that standardizing BrM-related eligibility criteria is essential to expand patient access to investigational therapies and to generate the data required for a growing population of patients with brain metastases.