Alpelisib for Insulin Resistance

Overseen By Joshua R Cook, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Columbia University

Must not be taking: Antidiabetics, Lipid-lowering, Antipsychotics, Corticosteroids

Disqualifiers: Diabetes, Cardiovascular, Liver, Psychiatric, others

No Placebo Group

Breakthrough Therapy

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to understand how the blood sugar-lowering hormone insulin works in healthy adults versus those who are at risk for type 2 diabetes. The study will use a drug called alpelisib, which interferes with insulin's actions in the body, to answer the study's main question: does the liver continue to respond to insulin's stimulation of fat production even when it loses the ability to stop making glucose (sugar) in response to insulin. Researchers will compare the impact of single doses of both alpelisib and placebo (inert non-drug) in random order (like flipping a coin) in study participants. Participants will be asked to stay twice overnight in the hospital, take single doses of alpelisib and placebo (one or the other on each of the two hospital stays), and receive intravenous (into the vein) infusions of non-radioactive "tracer" molecules that allow researchers to measure the production of glucose (sugar) and fats by the liver. Measurements will be done both overnight, while participants are asleep and fasting (not eating or drinking other than water) and while consuming a standardized diet of nutritional beverages during the following day. The objective is to evaluate the effect of lowering insulin levels, while maintaining constant mild hyperglycemia, on plasma glucose and lipid levels.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it does exclude those who have used most antidiabetic medications (except metformin) within 90 days before screening and certain lipid-lowering drugs within 14 days before screening. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug Alpelisib for insulin resistance?

Alpelisib, a drug used for breast cancer, can cause insulin resistance, leading to high blood sugar levels. However, managing these side effects with other medications like pioglitazone has shown to help maintain the drug's effectiveness and improve outcomes in patients. ^{1 2 3 4 5}

What safety data exists for Alpelisib in humans?

Alpelisib, also known as Piqray, has been associated with common side effects like high blood sugar (hyperglycemia), diarrhea, and skin rash. In some cases, high blood sugar can be severe, and managing it may require dietary changes or additional medications. ^{3 4 5 6 7}

What makes the drug Alpelisib unique for treating insulin resistance?

Alpelisib is unique for treating insulin resistance because it targets a specific pathway involved in cell growth and metabolism, which is different from traditional treatments that primarily focus on increasing insulin sensitivity or reducing blood sugar levels. ^{8 9 10 11 12}

Research Team

Joshua R Cook, MD, PhD

Principal Investigator

Columbia University

Eligibility Criteria

This trial is for healthy adults and those at risk for type 2 diabetes, specifically with conditions like liver disease, obesity, non-alcoholic fatty liver disease (NAFLD), prediabetes, and insulin resistance. Participants should be willing to stay overnight in the hospital twice and follow study procedures.

Inclusion Criteria

For Group IS: BMI 18.0-29.9 kg/m2

I can understand both written and spoken English or Spanish.

I am between 18 and 70 years old and use effective birth control.

Exclusion Criteria

Laboratory evidence of diabetes mellitus: (1) Hemoglobin A1c ≥ 6.5%, and/or (2) Fasting plasma glucose ≥ 126 mg/dL

Reproductive concerns: (i) Positive qualitative β-hCG (i.e., pregnancy test) in women of childbearing potential, (ii) Women of childbearing potential not using highly effective contraception, defined as specified methods, (iii) Women currently pregnant, (iv) Women currently breastfeeding

Prior participation in other studies led by Dr. Cook (PI) is excluded from this prohibition according to his medical/scientific judgment

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive single doses of alpelisib and placebo in a randomized crossover design, with measurements of de novo lipogenesis and endogenous glucose production.

2-8 weeks

2 inpatient visits (overnight stays)

Washout

A washout period between the two inpatient admissions to clear the effects of the first treatment.

2-8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Alpelisib (PI3K Inhibitor)

Trial Overview Researchers are testing alpelisib's effects on how the body responds to insulin by comparing it with a placebo. The study involves taking single doses of both substances during separate hospital stays and measuring glucose and fat production using special tracer molecules.

Participant Groups

Group I: Placebo then alpelisib (Insulin Sensitive group) Experimental Treatment 5 Interventions

On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.

Group II: Placebo then alpelisib (Insulin Resistant group) Experimental Treatment 5 Interventions

On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of placebo. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of alpelisib 300 mg.

Group III: Alpelisib then placebo (Insulin Sensitive group) Experimental Treatment 5 Interventions

On Study Visit 1, participants in the Insulin Sensitive (IS) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.

Group IV: Alpelisib then placebo (Insulin Resistant group) Experimental Treatment 5 Interventions

On Study Visit 1, participants in the Insulin Resistant (IR) group will undergo fasting and refed measurement of de novo lipogenesis (DNL) and endogenous glucose production (EGP) following a single dose of alpelisib 300 mg. Then, 2-8 weeks later on Study Visit 2, participants will undergo measurement of DNL and EGP after a single dose of placebo.

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

University of California, Berkeley

Collaborator

Trials

193

Recruited

716,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Stanford University

Collaborator

Trials

2,527

Recruited

17,430,000+

Findings from Research

Alpelisib is effective for treating HR+, HER2-, PIK3CA-mutated breast cancer, but it causes hyperglycemia in about 60% of patients, which can lead to dose adjustments or treatment interruptions.

A proactive glycemic support program involving lifestyle changes and personalized antihyperglycemic treatments is recommended to manage alpelisib-induced hyperglycemia and maintain treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer. Tankova, T., Senkus, E., Beloyartseva, M., et al.[2023]

In a study of 247 patients with metastatic hormone receptor-positive, PIK3CA-mutant breast cancer, 61.5% developed any-grade hyperglycemia after treatment with alpelisib, with a median onset time of just 16 days.

Patients receiving alpelisib as standard care experienced significantly higher rates of hyperglycemia compared to those in clinical trials, highlighting the importance of monitoring and optimizing glycemic status before starting treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer. Shen, S., Chen, Y., Carpio, A., et al.[2023]

In a small study of 4 breast cancer patients with metabolic syndrome treated with alpelisib, the addition of pioglitazone successfully controlled insulin levels and allowed patients to maintain the alpelisib dosage, suggesting a safe and effective strategy to manage hyperinsulinemia.

The treatment resulted in longer-than-expected responses to alpelisib, indicating that addressing metabolic issues like hyperinsulinemia and hyperglycemia may enhance the efficacy of PI3K inhibitors in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating Alpelisib-Induced Hyperinsulinemia in Patients with Advanced Breast Cancer - A Real-Life Experience. Percik, R., Oedegaard Smith, C., Leibovici, A., et al.[2023]

In a study of 92 patients with metastatic breast cancer treated with alpelisib, 64.1% experienced hyperglycemia, a rate similar to that seen in clinical trials, indicating that hyperglycemia is a common side effect in real-world settings.

Risk factors for developing more severe hyperglycemia (grades 2-4) included pre-existing diabetes, pre-diabetes, Asian ancestry, and higher body mass index (BMI), suggesting that these patients should be closely monitored during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predicting Hyperglycemia Among Patients Receiving Alpelisib Plus Fulvestrant for Metastatic Breast Cancer. Ge, X., Behrendt, CE., Yost, SE., et al.[2023]

Alpelisib is an effective treatment for advanced breast cancer in patients with specific genetic mutations, but it often causes hyperglycemia, which can lead to treatment complications.

In a case series of 3 patients, dietary changes and the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i) were successful in managing hyperglycemia, suggesting potential strategies for improving patient outcomes during alpelisib therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treating Alpelisib-Induced Hyperglycemia with Very Low Carbohydrate Diets and Sodium-Glucose Co-Transporter 2 Inhibitors: A Case Series. Blow, T., Hyde, PN., Falcone, JN., et al.[2021]

In a Phase Ib study involving 19 patients with advanced solid tumors, the combination of alpelisib (a PI3K p110α inhibitor) and paclitaxel was assessed for safety and maximum tolerated dose, revealing that the maximum tolerated dose of alpelisib was 150 mg per day.

The treatment showed a challenging safety profile, with significant adverse effects including high rates of hyperglycemia (57.9%) and diarrhea (73.7%), leading to the decision not to proceed with the planned dose-expansion phase.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors. Rodon, J., Curigliano, G., Delord, JP., et al.[2019]

Alpelisib is an effective treatment for advanced breast cancer in patients with PIK3CA mutations, but it can cause significant side effects, including hyperglycemia, diarrhea, and rash, necessitating careful management.

In a study of 8 patients, 5 experienced hyperglycemia, with one case requiring hospitalization, highlighting the importance of patient education and a multidisciplinary approach to manage these side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First Experiences with Alpelisib in Clinical Routine: Case Reports from a German Breast Center. Hester, A., Henze, F., Travi, C., et al.[2023]

Metformin has been shown to enhance the effectiveness of crizotinib in both crizotinib-sensitive and -resistant non-small cell lung cancer (NSCLC) cells by reducing cell proliferation and invasion while increasing apoptosis, indicating its potential as a resistance-reversing agent.

The study demonstrated that metformin works by inhibiting the IGF-1R signaling pathway, which is activated in crizotinib-resistant cells, suggesting that combining metformin with crizotinib could help overcome resistance and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway. Li, L., Wang, Y., Peng, T., et al.[2022]

Alectinib significantly improved progression-free survival (PFS) compared to chemotherapy, with a median PFS of 10.9 months versus 1.4 months in patients with advanced ALK-positive non-small-cell lung cancer.

The objective response rate (ORR) was also much higher with alectinib at 50.6% compared to only 2.5% with chemotherapy, and it showed a remarkable CNS ORR of 66.7% in patients with measurable CNS metastases, indicating its efficacy in treating brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer. Wolf, J., Helland, Å., Oh, IJ., et al.[2022]

Crizotinib is effective for lung cancer patients with ALK gene fusions, but its effectiveness can be limited by resistance; however, combining it with IGF-1R inhibitors shows promise in overcoming this resistance.

Research indicates that the IGF-1R pathway becomes activated in cases of resistance to ALK inhibitors, suggesting that targeting both ALK and IGF-1R could enhance treatment efficacy, as seen in patient biopsy samples.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Lovly, CM., McDonald, NT., Chen, H., et al.[2022]

The newly synthesized ALK inhibitor, KRCA-0080, demonstrates greater potency against various ALK mutants associated with crizotinib resistance, making it a promising option for patients with these mutations.

In both in vitro and in vivo studies, KRCA-0080 effectively inhibits cancer cell proliferation by downregulating key signaling pathways and inducing apoptosis, resulting in a significant reduction in tumor size compared to existing treatments like crizotinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of potent ALK inhibitor and its molecular inhibitory mechanism against NSCLC harboring EML4-ALK proteins. Kang, CH., Yun, JI., Lee, K., et al.[2018]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Management Strategies for Hyperglycemia Associated with the α-Selective PI3K Inhibitor Alpelisib for the Treatment of Breast Cancer. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Incidence, risk factors, and management of alpelisib-associated hyperglycemia in metastatic breast cancer. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Treating Alpelisib-Induced Hyperinsulinemia in Patients with Advanced Breast Cancer - A Real-Life Experience. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Predicting Hyperglycemia Among Patients Receiving Alpelisib Plus Fulvestrant for Metastatic Breast Cancer. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Treating Alpelisib-Induced Hyperglycemia with Very Low Carbohydrate Diets and Sodium-Glucose Co-Transporter 2 Inhibitors: A Case Series. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors. [2019]

7. Switzerland pubmed.ncbi.nlm.nih.gov

First Experiences with Alpelisib in Clinical Routine: Case Reports from a German Breast Center. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Metformin restores crizotinib sensitivity in crizotinib-resistant human lung cancer cells through inhibition of IGF1-R signaling pathway. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Development of potent ALK inhibitor and its molecular inhibitory mechanism against NSCLC harboring EML4-ALK proteins. [2018]

12. England pubmed.ncbi.nlm.nih.gov

Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. [2022]