Pilot Study to Determine Pro-Inflammatory Cytokine Kinetics During Immune Checkpoint Inhibitor Therapy

Active, not recruiting

• Conditions: Melanoma; Gastrointestinal Neoplasms; Genitourinary Cancer; Thoracic Cancer; Sarcoma

• Registration Number: NCT05707286
• Lead Sponsor: Indiana University

Brief Summary

This research aims to identify clinical strategies to manage adverse events during immune checkpoint inhibitor therapy by (1) determining the impact of checkpoint inhibitors on metabolism through major CYP enzymes and (2) identifying associations between pro-inflammatory cytokine concentrations and negative clinical outcomes during checkpoint inhibitor therapy.

Detailed Description

The long-term goal of this research is to identify clinical strategies to manage adverse events during checkpoint inhibitor therapy. The research aims of the current project are (1) to determine the impact of checkpoint inhibitor therapy on the metabolism of CYP probe drugs and the risk for adverse events with CYP substrate drugs commonly prescribed to cancer patients and (2) to identify associations between pro-inflammatory cytokine concentrations and CYP probe drug metabolism before and during checkpoint inhibitor therapy. To investigate these aims, we plan to conduct a two-phase crossover clinical drug interaction study in which a cocktail containing probe drugs for six CYP enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A) is administered to subjects before and after they initiate checkpoint inhibitor therapy. However, the kinetics of changes in pro-inflammatory cytokines during checkpoint inhibitor therapy are not well established, and this knowledge is critical to inform timing of the on-treatment phase of the clinical drug interaction study. Accordingly, this pilot study will investigate when blood concentrations of pro-inflammatory cytokines peak after initiation of checkpoint inhibitor therapy. Blood cytokine concentrations will be assayed at baseline, \~7 and \~14 days following the first checkpoint inhibitor cycle (± 2 days surrounding each timepoint), and at cycles 2, 3, and 4 based on the strongest current in vitro (7-14 days) and clinical evidence (21-42 days). In addition to plasma concentrations of pro-inflammatory cytokines, the study will also assay plasma concentrations of immune checkpoint inhibitors, co-administered CYP substrates, and perform genetic sequencing to assess associations between these variables and clinical outcomes, including the development of immune-related adverse events, the potential for drug-drug interactions with CYP substrates, and checkpoint inhibitor treatment response.

Study Timeline

• Study First Submitted: 2023-01-20
• Study First Submitted QC: 2023-01-30
• Study First Posted: 2023-01-31
• Study Start: 2023-09-07
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-21
• Last Update Posted: 2025-03-25
• Primary Completion: 2026-03
• Study Completion: 2026-03

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 98

Inclusion Criteria

1. ≥ 18 years old at the time of informed consent
2. Diagnosed with non-small cell lung cancer (NSCLC) OR melanoma AND initiating therapy with single agent or combination therapy that includes an immune checkpoint inhibitor, (e.g., atezolizumab, cemiplimab, durvalumab, ipilimumab, nivolumab, pembrolizumab)
3. Ability to provide written informed consent and HIPAA authorization

Exclusion Criteria

1. Diagnosis or past medical history of autoimmune disorder, including systemic lupus erythematosus, Crohn's disease, Sjogren's syndrome, multiple sclerosis, type 1 diabetes mellitus, Behcet's disease, and ankylosing spondylitis
2. Current infection requiring medical treatment (note: if a prospective subject's infection resolves, they can be re-screened for trial inclusion)
3. Concomitant treatment with systemic immunosuppressant drugs (see Table A1 in appendix for complete list)

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Increases in pro-inflammatory cytokines	From baseline (day -30) up to cycle 4 (day 126)	Determine the time course of increases in pro-inflammatory cytokines during treatment with immune checkpoint inhibitor regimens, via plasma cytokine concentrations present in blood samples.
Populations of activated T cells	From baseline (day -30) up to cycle 4 (day 126)

Secondary Outcome Measures

Name	Time	Method
Plasma concentrations of co-administered CYP substrate medications	From baseline (day -30) up to cycle 4 (day 126)	Assess baseline and on-treatment concentrations of co-administered CYP substrate medications
Checkpoint inhibitor treatment response	From treatment initiation (day 0) until the time of the treatment response event or the end of the study evaluation period (maximum of 2 years from the date of treatment initiation).	Checkpoint inhibitor treatment response will be collected retrospectively from the electronic health record
The development of adverse drug events attributable to co-administered CYP substrate medications	From baseline (day -30) up to cycle 4 (day 126)	Adverse drug events attributable to co-administered CYP substrate medications will be assessed via patient survey at all study visits
Plasma concentrations of immune checkpoint inhibitors	From baseline (day -30) up to cycle 4 (day 126)	Assess on-treatment concentrations of immune checkpoint inhibitors
Increases in other cytokines	From baseline (day -30) up to cycle 4 (day 126)	Determine the time course of increases in other cytokines during treatment with immune checkpoint inhibitor regimens, including anti-inflammatory cytokines (e.g., IL-10, TGF-β) present in blood samples.
The development of immune-related adverse events	From baseline (day -30) up to cycle 4 (day 126)	Immune-related adverse events will be assessed via patient survey at all study visits

Trial Locations

Locations (1)

Indiana University Melvin and Bren Simon Comprehensive Cancer Center; 🇺🇸 Indianapolis, Indiana, United States