Bile Acids in Acute Insulin Resistance

Cancer Clinical Trial

Official title:

Bile Acid and Lipid Metabolism in Patients With Drug-induced Acute Insulin Resistance

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05571670
• Other study ID #: AAAU0504
• Status: Recruiting
• Start date: June 10, 2022
• Est. completion date: June 10, 2026

Study information

• Verified date: December 2023
• Source: Columbia University
• Contact: Research Nurse Navigator
• Phone: 212-342-5162
• Email: cancerclinicaltrials[@]cumc.columbia.edu
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This is a prospective observational study with a primary goal of monitoring changes in circulating bile acid profiles and parameters of glucose and lipid metabolism prior, during, and after cancer treatment with agents that directly impair insulin action: PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. Patients will not receive any cancer treatment specifically for the purposes of this study. Rather, this study will be based on treatment decisions made independently by participants' oncologists according to standard of care or other clinical trial protocol. This study seeks to enroll at least 25 participants each for PI3K inhibitors, mTOR inhibitors and, once available for open-label treatment, AKT inhibitors.

Description:

The primary objective of this study is to determine the effect of drug-induced acute insulin resistance (diaIR) on the ratio of 12α-hydroxylated bile acids (12-HBA) to 12α-hydroxylated bile acids (non-12-HBA) in cancer patients treated with phosphatidylinositol-4,5-bisphosphate kinase (PI3K) inhibitors (PI3Ki), mammalian target of rapamycin (mTOR) inhibitors (mTORi), and AKT inhibitors (AKTi) once possible. Specifically, this study will: (1) verify the induction of diaIR by monitoring changes in fasting ± postprandial blood glucose, insulin/c-peptide, and fructosamine; and (2) assess qualitative and quantitative changes in the circulating bile acid (BA) pool (including bile acid intermediary metabolites) by mass spectrometry in the fasting ± postprandial states prior to and then at 2 and 4 weeks after starting treatment. This study focuses in particular on determining changes in the 12α-hydroxylated bile acids to 12α-hydroxylated bile acids, as well as each of these subclasses and their individual substituents as a proportion of the overall BA pool.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 75
• Est. completion date: June 10, 2026
• Est. primary completion date: June 10, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 99 Years

Eligibility

Inclusion Criteria:

• Age = 18 years

• Speaks English and/ or Spanish

• Any cancer diagnosis

• Planned for treatment with:

• PI3K inhibitors

• Alpelisib

• Inavolisib

• Any experimental PI3K inhibitor

• AKT inhibitors (if these become available for open-label use during the study course)

• Afuresertib

• Capivasertib

• Ipatasertib

• Miransertib

• Uposertib

• mTOR inhibitors

• Everolimus

• Sirolimus

• Temsirolimus

• Signed informed consent

Exclusion Criteria:

• Known dysglycemia

• Known diagnosis of diabetes mellitus

• Treatment with glucose-lowering medications at baseline

• Insulin

• Sulfonylureas or meglitinides

• Metformin >1000mg total daily dose

• Thiazolidinediones

• SGLT2 inhibitors

• GLP-1 receptor agonists

• DPP4 inhibitors

• Amylin mimetics

• Acarbose

• Significant biochemical evidence of liver dysfunction on lab tests within 30 days before starting drug that have not fallen to below the following thresholds prior to starting drug

• Significant functional or anatomical abnormalities of the small intestine

• Use of certain medications at baseline, within 7 days of starting cancer drug

• Allergy to cow dairy or soy (only excludes from MMTT, does not exclude from fasting blood draws)

• Inability to provide informed consent

Related Conditions & MeSH terms

• Cancer
• Insulin Resistance
• MTOR Gene Mutation
• PI3K Gene Mutation

Intervention

Drug:
• Drug-induced acute insulin resistance due to PI3K inhibitor, AKT inhibitor, or mTOR inhibitor
Participants will be treated with PI3K/AKT/mTOR inhibitors by their treating oncologist based on standard of care. This study will prospectively monitor bile acids and parameters of insulin resistance before and during treatment with these drugs.

Locations

Country	Name	City	State
United States	Columbia University Medical Center	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Columbia University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ratio of 12-HBA to non-12-HBA	Insulin resistance is expected to cause a rise in total bile acids, but with 12-alpha-hydroxylated bile acid (12-HBA) species outpacing non-12-alpha-hydroxylated bile acid (non-12-HBA) species, leading to a rise in the 12-HBA:non-12-HBA ratio. This would indicate that insulin resistance per se is sufficient to alter 12-HBA balance, and thus 12-HBA may be a useful therapeutic target for management of the macrovascular complications of insulin resistance. BA profile and levels of BA intermediates 7-HCO and 7,12-diHCO will be measured by LC-MS/MS when fasting +/- after 2-hour mixed meal tolerance test.	1-2 Months
Primary	Insulin resistance	Determine the timing and extent of PI3K/AKT/mTOR inhibitor treatment on parameters of insulin resistance: glucose, insulin, c-peptide, and adiponectin when fasting +/- following 2-hour mixed meal tolerance test	1-2 months
Secondary	Lipid profile	The primary endpoint is the outcome of the secondary objective: namely, evaluation of the effect of PI3Ki/AKTi/mTORi-induced insulin resistance on the lipid profile (total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, free fatty acids) when fasting +/- after 2-hour mixed meal tolerance test	1-2 months
Secondary	Surrogate markers of BA signaling	Determine the timing and extent of PI3K/AKT/mTOR inhibitor treatment on parameters of bile acid signaling: fibroblast growth factor 19 (FGF-19) and glucagon-like peptide-1 (GLP-1). We expect that a shift in BA pool composition (especially as regards 12-HBA vs non-12-HBA) will impact differentially on FGF-19 and GLP-1 levels.	1-2 months