Immune Checkpoint Inhibitor (ICI)-Drug-Drug Interaction (DDI) Study

Официальное название

Assessment of Drug-Drug Interactions Between Immune Checkpoint Inhibitors and Cytochrome P450 Substrates: Immune Checkpoint Inhibitor (ICI)-Drug-Drug Interaction (DDI) Study

Обзор

Immune checkpoint inhibitors (ICIs) (also called "immunotherapy") are an effective family of anti-cancer drugs, but they can cause serious side effects. Some evidence suggests these side effects might happen because ICIs interact with other drugs that you may already be taking, making those drugs work differently, or causing more side effects. The purpose of this study is to see whether ICIs impact how the liver processes other drugs. To do this, participants will be given a probe cocktail of 7 different FDA-approved drugs that are processed in different ways in the liver.

Подробное описание

Findings suggest that adverse events during checkpoint inhibitor therapy may, in part, be caused by drug-drug interactions that increase the risk of adverse events with co-administered medications. Identifying these novel drug-drug interactions will likely inform clinical strategies to reduce adverse events during checkpoint inhibitor therapy and enhance their clinical benefits.

This current research aims to systematically explore the impact of ICIs on CYP/transporter function and the associated risks for adverse events, thereby informing clinical strategies to mitigate these risks and optimize the therapeutic benefits of checkpoint inhibitors. By employing a rigorous crossover drug-drug interaction design, this study seeks to enhance understanding of drug interactions during ICI therapy, ultimately improving patient outcomes in oncology.

The long-term goal of this research is to find ways to manage adverse events that occur during treatment with ICIs. The research has two main aims:

1. To understand how ICI therapy affects the metabolism of certain drugs named CYP/transporter probe drugs and to also understand the risk of side effects from commonly prescribed drugs that are affected by these enzymes and transporters in cancer patients. 2. To examine the relationship between levels of pro-inflammatory cytokines (signaling molecules involved in inflammation) and how well these probe drugs are metabolized before and during ICI therapy.

A two-phase clinical study will be conducted to achieve these aims: patients will be given seven different probe drugs that interact with key enzymes and transporters (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A, BCRP, and SLCO1B1) both before they start ICI treatment and after they have begun therapy.

Adverse events will be assessed by looking at how changes in the function of these enzymes and transporters affect the metabolism of drugs that cancer patients commonly use. Special computer models, known as physiologically-based pharmacokinetic (PBPK) models, will be used to simulate how these drugs behave in the body and predict potential serious adverse events.

Вмешательства

• Препарат ICI Therapy
  Low dose of a cocktail of probe substrates for eight major CYP enzymes/drug transporters.

Первичные конечные точки

• Change in plasma concentrations from drug exposure during ICI therapy [Срок оценки: baseline (before start of ICI therapy) up to day 84]
• Toxicity concentrations for CYP/transporter substrate drugs in plasma [Срок оценки: baseline (day before Cycle 1 start) up to day 84]
• Associations between pro-inflammatory cytokine concentrations and CYP/transporter probe drug concentrations in plasma [Срок оценки: baseline (day before Cycle 1 start) up to day 84]

Вторичные конечные точки (5)

• Assess associations between T cells populations and CYP/transporter probe drug concentrations [Срок оценки: baseline (day before Cycle 1 start) up to day 84]
• Concentrations of endogenous biomarkers [Срок оценки: baseline (day before Cycle 1 start) up to day 84]
• CYP/transporter endogenous biomarker concentrations [Срок оценки: baseline (day before Cycle 1 start) up to day 84]
• Correlation of concentration of population of activated T cells and CYP/transporter endogenous biomarkers [Срок оценки: baseline (day before Cycle 1 start) up to day 84]
• CYP/transporter substrate-related adverse events and immune related (ir) adverse events [Срок оценки: Baseline (before starting ICI cycle 1) and study visit 2 (up to day 84)]

Критерии участия

Критерии включения

• ≥ 18 years old at the time of informed consent
• Diagnosed with cancer AND initiating therapy with single agent or combination therapy that includes an immune checkpoint inhibitor (e.g., atezolizumab, cemiplimab, durvalumab, ipilimumab, nivolumab, pembrolizumab, relatlimab, tremelimumab)
• Ability to provide written informed consent and HIPAA authorization

Критерии исключения

• Actively pregnant or breastfeeding
• Body weight less than 50 kg or a BMI >35
• Low baseline hemoglobin, defined as <10 g/dL

• Note: if a prospective patient's hemoglobin returns to the normal range, they can be re-screened for trial inclusion)
• Past medical history of chronic liver disease, signs and symptom of liver disease (e.g., jaundice, ascites), or aspartate aminotransferase >96 U/L, alanine aminotransferase > 80 IU/L, alkaline phosphatase >260 U/L, or total bilirubin > 2.6 mg/dL

• Note: if a prospective patient's liver function tests return to the normal ranges, they can be re-screened for trial inclusion)
• Past medical history of chronic kidney disease, signs and symptom of kidney disease (e.g., decreased urine output, swelling in feet and ankles), or estimated glomerular filtration rate <45 mL/minute/1.73 m2 BSA

• Note: if a prospective patient's kidney function returns to the normal range, they can be re-screened for trial inclusion)
• Poor performance status that makes it unlikely the patient will complete 3 cycles of immune checkpoint inhibitor (at the treating oncologist's discretion)
• 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
• History of intolerance, allergic reaction, or hypersensitivity to any of the study drugs (tizanidine, bupropion, flurbiprofen, omeprazole, dextromethorphan, midazolam, rosuvastatin)
• Current infection requiring medical treatment (note: if a prospective patient's infection resolves, they can be re-screened for trial inclusion)
• Concomitant treatment with systemic immunosuppressant drugs (see Appendix 3 for list)

• Note: patients may be re-screened for trial eligibility if they discontinue any exclusionary drugs for ≥7 days prior to Study Visit 1
• Concomitant treatment with a CYP/transporter probe cocktail drug or strong inhibitors, inducers, or agents that affect the pharmacokinetics of the relevant CYP enzymes or drug transporters (see Appendix 4 for list)

• Note: patients may be re-screened for trial eligibility if they discontinue any exclusionary drugs for ≥7 days prior to Study Visit 1
• Are unwilling/unable to avoid drugs of abuse, tobacco products or marijuana, or consuming more than 2 alcoholic drinks per day during the study
• Inability to take oral medication

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Перекрёстный дизайн

Маскирование

Открытое

Основная цель

Фундаментальное исследование

Центры проведения

США · 1 центр

• Indiana University Melvin and Bren Simon Comprehensive Cancer Center — Indianapolis

Идентификаторы

NCT: NCT07389525 · PHARM-IUSCCC-0938

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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