EBUS-TBNA vs Transbronchial Mediastinal Cryobiopsy for Adequacy of Next Generation Sequencing (FROSTBITE-3)

A Multicenter Randomized Trial of EBUS-TBNA Versus Transbronchial Mediastinal Cryobiopsy for Adequacy of Next Generation Sequencing

This is a multi-center clinical trial evaluating the effect of transbronchial mediastinal cryobiopsy for its ability to improve the likelihood of obtaining tissue sufficient for molecular analysis. Patients in outpatient clinics or pre-operative holding areas planning to undergo a bronchoscopic biopsy of a suspected malignant lesion (peripheral or mediastinal) for initial diagnosis, staging, or tissue acquisition for molecular analysis will be considered for enrollment and consented. Patients will only be enrolled if intraoperative ROSE suggests malignancy. Patients will be randomized to continue with the operator's initial EBUS-TBNA needle or switch to a cryoprobe to perform a sampling.

Study Overview

• Status: Recruiting
• Conditions: Lung Cancer
• Intervention / Treatment: Procedure: Endobronchial ultrasound with transbronchial needle aspiration; Procedure: Bronchoscopy; Procedure: Cryobiopsy

Detailed Description

Primary Objective:

- To evaluate the utility of transbronchial mediastinal cryobiopsy on its ability to improve the likelihood of acquiring tissue sufficient for next-generation sequencing (NGS).

Safety Endpoints:

• Pneumothorax within 7 days of procedure
• Moderate bleeding defined as controlled with bronchoscope, saline, or epinephrine
• Serious bleeding is defined as uncontrolled, leading to respiratory failure, need for transfusion, or cardiovascular instability
• Respiratory failure is defined as a new oxygen requirement or escalation in oxygen delivery within 7 days of procedure
• Unplanned hospitalization related to the procedure within 7 days of procedure
• Death

Exploratory Endpoints:

• The proportion of samples adequate for NGS testing
• The proportion of samples with adequate PD-1 / PD-L1 immunohistochemical staining
• Proportion of samples that are adequate for complete NGS library sequencing
• Estimated total number of tumor cells per H&E-stained slide
• Histological disease subtyping

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Vanderbilt-Ingram Services for Timely Access; Phone Number: 800-811-8480; Email: cip@vumc.org

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Recruiting
      • Vanderbilt University/Ingram Cancer Center
      • Principal Investigator: Fabien Maldonado, MD
      • Contact: Vanderbilt-Ingram Service Services for Timely Access; Phone Number: 800-811-8480; Email: cip@vumc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Lesions on PET or CT concerning for primary or metastatic malignancy that are amenable to biopsy by linear EBUS
• Malignant cells present on rapid on-site cytological evaluation (ROSE)

Exclusion Criteria:

• Patient is known to be less than 18 years old
• Patient is known to be pregnant
• Patient is known to be a prisoner
• Operator deems lesion is not safe to biopsy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: EBUS-TBNA Group; The same needle gauge will be used for these participant to acquire the initial diagnosis on ROSE (either 21 or 22G). Using standard sampling techniques, the mass or LN will be penetrated with the needle as confirmed by ultrasound, and the needle will be passed back from the proximal to the distal ends of the node to obtain the samples for an adequate cell block.	Procedure: Endobronchial ultrasound with transbronchial needle aspiration; Participants will undergo Endobronchial ultrasound with transbronchial needle aspiration; Procedure: Bronchoscopy; Participants will undergo Bronchoscopy
Experimental: Transbronchial Mediastinal Cryobiopsy Group; The operator will switch to a flexible, single-use, 1.1 mm cryoprobe (Erbe 20402-401, Erbe, Tübingen, Germany) for these participants to obtain cryobiopsies. The operator will introduce the probe into the working channel of the EBUS bronchoscope. The cryoprobe will then be advanced toward the puncture site and inserted gently through the previous puncture site created by the initial EBUS-TBNA needle. The operator will confirm the placement of the probe via the EBUS image, and photo capture will be done. The cryo-probe will be activated and cooled for 3 seconds before retracting with the bronchoscope with the frozen biopsy tissue attached to the tip.	Procedure: Endobronchial ultrasound with transbronchial needle aspiration; Participants will undergo Endobronchial ultrasound with transbronchial needle aspiration; Procedure: Bronchoscopy; Participants will undergo Bronchoscopy; Procedure: Cryobiopsy; Participants will undergo Cryobiopsy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of samples sufficient for next-generation sequencing testing	Comparison of samples between arms that meet sufficiency criteria for NGS	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of samples with adequate PD-1 / PD-L1 immunohistochemical staining	Comparison of samples between arms that meet PD-1/PD-L1 adequacy	Up to 12 months
Proportion of samples that are adequate for complete NGS library sequencing	Comparison of samples between arms that meet sufficiency criteria and then are adequate for complete NGS library sequencing	Up to 12 months
Estimated total number of tumor cells per H&E-stained slide	Comparison of samples between arms of estimated tumor cells per H&E-stained field	Up to 12 Months
Histological disease subtyping	Comparison of samples between arms for subtypes of lung malignancies (primary or metastatic)	Up to 12 Months

Collaborators and Investigators

• Sponsor: Vanderbilt-Ingram Cancer Center
• Collaborators: Medical University of South Carolina; Johns Hopkins University; Duke University; Virginia Commonwealth University; Northwestern Medicine
• Investigators: Principal Investigator: Fabien Maldonado, MD, Vanderbilt University/Ingram Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): September 13, 2024
• Primary Completion (Estimated): October 31, 2027
• Study Completion (Estimated): October 31, 2028

Study Registration Dates

• First Submitted: October 23, 2023
• First Submitted That Met QC Criteria: October 23, 2023
• First Posted (Actual): October 30, 2023

Study Record Updates

• Last Update Posted (Actual): February 2, 2026
• Last Update Submitted That Met QC Criteria: January 29, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Minimally Invasive Surgical Procedures; Diagnostic Techniques, Surgical; Endoscopy; Diagnostic Techniques, Respiratory System; Thoracic Surgical Procedures; Pulmonary Surgical Procedures; Bronchoscopy
• Other Study ID Numbers: VICC-VDTHO23177; NCI-2023-08954 (Registry Identifier: NCI, Clinical Trials Reporting Program)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No