The Effect of Combined Cryotherapy and Immunotherapy on Systemic T Cell Changes and Clinical Outcomes in Metastatic Non-small Cell Lung Cancer (LUCACRIMUNO)

• ClinicalTrials.gov Identifier: NCT06000358
• Recruitment Status: Recruiting
• First Posted: August 21, 2023
• Last Update Posted: August 21, 2023
• Sponsor: Lithuanian University of Health Sciences
• Collaborator: Research Council of Lithuania
• Information provided by (Responsible Party): Marius Zemaitis, Lithuanian University of Health Sciences

Study Description

Brief Summary:

Lung cancer remains one of the most commonly diagnosed oncological diseases worldwide and the first in terms of mortality. Although immune checkpoint inhibitors form the backbone of current metastatic non-small cell lung cancer treatments, there is still no ideal predictive marker for its efficacy and patients still achieve suboptimal results in overall response and survival. While immune checkpoint inhibitors are known to shift systemic anti-tumor immune response from suppression to stimulation in some patients, the investigators hypothesize that this effect can be further enhanced by cryotherapy, especially in "cold" tumors. If proven successful, cryotherapy in combination with immunotherapy, could potentiate a more powerful immune response compared to systemic therapy alone, improve overall response rate, patients' survival without disease progression, and overall survival. The investigators, therefore, aim to use combined local tumor cryotherapy, combined with immune checkpoint inhibitor therapy to induce and evaluate systemic anti-tumor T lymphocyte response and achieve improved non-small cell lung cancer patient outcomes than with immunotherapy alone.

Condition or disease	Intervention/treatment	Phase
Lung Cancer Stage IV	Procedure: Bronchoscopic cryotherapy; Drug: Pembrolizumab; Drug: Platinum based chemotherapy	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Effect of Combined Cryotherapy and Immunotherapy on Systemic T Cell Changes and Clinical Outcomes in Metastatic Non-small Cell Lung Cancer
• Actual Study Start Date: April 1, 2023
• Estimated Primary Completion Date: March 31, 2026
• Estimated Study Completion Date: March 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Cryotherapy and Pembrolizumab monotherapy; Patients with metastatic non-small cell lung cancer, who are eligible for first-line pembrolizumab monotherapy (PD-L1 expression equal to or greater than 50%, no EGFR mutations or ALK translocations). Bronchoscopic cryotherapy procedure is performed before the start of systemic treatment.	Procedure: Bronchoscopic cryotherapy; The cryotherapy procedure is performed before the start of systemic treatment, under visual (for endobronchial cryotherapy) or radial EBUS and fluoroscopy control (for transbronchial cryotherapy), ensuring the correct position of the cryoprobe in the tumor. After being placed in the correct position. After being placed in the correct position, the cryoprobe is cooled using CO2 and allowed to cool passively. The cooling-thawing stages are repeated for a total of 3 cycles.; Drug: Pembrolizumab; As a standard of care, patients will receive pembrolizumab.
Active Comparator: Cryotherapy and Pembrolizumab with platinum-based chemotherapy; Patients with metastatic non-small cell lung cancer, who are eligible for first-line pembrolizumab and platinum-based chemotherapy (PD-L1 expression less than 50%, no EGFR mutations or ALK translocations). Bronchoscopic cryotherapy procedure is performed before the start of systemic treatment.	Procedure: Bronchoscopic cryotherapy; The cryotherapy procedure is performed before the start of systemic treatment, under visual (for endobronchial cryotherapy) or radial EBUS and fluoroscopy control (for transbronchial cryotherapy), ensuring the correct position of the cryoprobe in the tumor. After being placed in the correct position. After being placed in the correct position, the cryoprobe is cooled using CO2 and allowed to cool passively. The cooling-thawing stages are repeated for a total of 3 cycles.; Drug: Pembrolizumab; As a standard of care, patients will receive pembrolizumab.; Drug: Platinum based chemotherapy; As a standard of care, patients will receive platinum-based chemotherapy in addition to pembrolizumab if PD-L1 expression is less than 50%.
Active Comparator: Pembrolizumab monotherapy; Patients with metastatic non-small cell lung cancer, who are eligible for first-line pembrolizumab monotherapy (PD-L1 expression equal to or greater than 50%, no EGFR mutations or ALK translocations).	Drug: Pembrolizumab; As a standard of care, patients will receive pembrolizumab.
Active Comparator: Pembrolizumab with platinum-based chemotherapy; Patients with metastatic non-small cell lung cancer, who are eligible for first-line pembrolizumab and platinum-based chemotherapy (PD-L1 expression less than 50%, no EGFR mutations or ALK translocations).	Drug: Pembrolizumab; As a standard of care, patients will receive pembrolizumab.; Drug: Platinum based chemotherapy; As a standard of care, patients will receive platinum-based chemotherapy in addition to pembrolizumab if PD-L1 expression is less than 50%.

Outcome Measures

Primary Outcome Measures :

1. Changes in T Lymphocyte Count and Function in Response to Cryotherapy and Immunotherapy [ Time Frame: 6 weeks ]
   Changes in T lymphocyte counts and function in peripheral venous blood assessed via flow cytometry

Secondary Outcome Measures :

1. Necrotic cancer cell death [ Time Frame: 6 weeks ]
   A change in the concentration of High mobility group box 1 protein (HMGB-1) in venous blood
2. The influence of immune cell infiltration in tumor tissue on subsequent cryotherapy and immunotherapy treatment [ Time Frame: 1 day ]
   Number of tumor-infiltrating CD4 and CD8 lymphocytes in non-small cell lung cancer biopsy material by immunohistochemistry.
3. Objective response rate [ Time Frame: 1 year ]
   Assessed according to RECIST and iRECIST criteria
4. Progression-free survival [ Time Frame: 1 year ]
   The time from the first cycle of systemic treatment to radiologically confirmed disease progression
5. Overall survival [ Time Frame: 1 year ]
   The time from the first cycle of systemic treatment to death from any cause
6. Safety of bronchoscopic cryotherapy and immunotherapy [ Time Frame: 1 year ]
   Documentation and assessment of adverse treatment events according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.
7. Changes in T Lymphocyte Function in Response to Cryotherapy and Immunotherapy [ Time Frame: 6 weeks ]
   Changes in T lymphocyte function in peripheral venous blood assessed via RNA expression
8. Changes in T Lymphocyte Effector Function in Response to Cryotherapy and Immunotherapy [ Time Frame: 6 weeks ]
   Changes in T lymphocyte effector function in peripheral venous blood evaluated via cytokine panels

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patients with Eastern Cooperative Oncology Group (ECOG) performance score 0 - 1;
• Patients with histologically confirmed metastatic non-small cell lung cancer and PD-L1 expression on tumor cells was evaluated;
• CT examination shows measurable tumor formations according to the RECIST 1.1 criteria;
• Primary lung tumor or metastasis accessible to flexible bronchoscopy;
• Patients may have received surgery, adjuvant or neoadjuvant chemotherapy prior to the study if it was completed at least 12 months before relapse;
• Patients informed about the purpose and course of the study and provided a written consent to participate.

Exclusion Criteria:

• Patients who refused to participate in the clinical trial and did not sign the informed consent form;
• Men and women under the age of 18, pregnant women;
• Patients belonging to a vulnerable social group;
• High risk of general anesthesia, defined as American Society of Anesthesiologists (ASA) class 4 - 6;
• Documented allergy to medications used during general and local anesthesia, systemic cancer treatment;
• Patients previously treated with immune checkpoint inhibitors;
• EGFR mutations or ALK translocations have been identified in patients;
• Patients with previously diagnosed autoimmune diseases, active viral hepatitis, uncontrolled human immunodeficiency virus (HIV) infection or untreated tuberculosis;
• Patients treated with immunosuppressive drugs, systemic corticosteroids, with equivalent doses of prednisolone exceeding 10 mg/day;
• Patients with an increased risk of bleeding during an interventional procedure;
• Acute untreated conditions that would make it impossible to perform an interventional lung procedure.

Contacts and Locations

Contacts

Contact: Marius Zemaitis, PhD, professor; +37061256473; marius.zemaitis@kaunoklinikos.lt

Contact: Gediminas Vasiliauskas, PhD student; +37060403787; gediminas.vasiliauskas@kaunoklinikos.lt

Locations

Lithuania

Lithuanian University of Health Sciences; Recruiting

Kaunas, Lithuania, LT 44307

Contact: Rimantas Benetis, PhD, professor +37037327200 rektoratas@lsmuni.lt

Sponsors and Collaborators

Lithuanian University of Health Sciences

Research Council of Lithuania

More Information

• Responsible Party: Marius Zemaitis, Professor, Lithuanian University of Health Sciences
• ClinicalTrials.gov Identifier: NCT06000358
• Other Study ID Numbers: LUCACRIMUNO-001
• First Posted: August 21, 2023
• Last Update Posted: August 21, 2023
• Last Verified: August 2023

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Marius Zemaitis, Lithuanian University of Health Sciences:

Pulmonology; Oncology; Immunotherapy; Cryotherapy

Additional relevant MeSH terms:

Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action