Alpelisib for Insulin Resistance

Overseen By Julia J Wattacheril, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Columbia University

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

Disqualifiers: Diabetes, Cardiovascular, Liver, Psychiatric, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 2-8 weeks

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how insulin, the hormone that controls blood sugar, functions differently in individuals at risk of type 2 diabetes compared to healthy individuals. The study will use a drug called alpelisib (also known as Piqray) to determine if the liver still responds to insulin's effects on fat production when it cannot stop sugar production. Participants will receive both alpelisib and a placebo to compare their effects. The trial seeks adults who can speak English or Spanish and have a BMI of either 18-25 (insulin sensitive) or 30-45 (insulin resistant), with specific insulin sensitivity or resistance levels that can be verified with their doctor. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that alpelisib is generally safe, but it can cause some side effects. In studies with breast cancer patients, about 64.5% experienced high blood sugar levels after taking alpelisib. Doctors monitor this closely and have ways to manage it if it occurs.

Another study found that alpelisib can cause skin rashes. Doctors have guidelines to help manage these as well. Although these side effects might seem concerning, they are well-known and manageable with medical support.

Overall, while alpelisib can cause side effects, they are mostly understood and can be controlled with proper care. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about alpelisib for insulin resistance because it targets the PI3K pathway, which is a novel approach compared to standard treatments like metformin and lifestyle changes. Unlike these traditional options that primarily focus on improving insulin sensitivity indirectly, alpelisib directly inhibits the PI3K enzyme, potentially offering a more precise method to reduce insulin resistance. This targeted action could lead to more rapid and effective control of blood sugar levels, marking a significant advancement in treatment options.

What evidence suggests that alpelisib might be an effective treatment for insulin resistance?

Research has shown that taking just one dose of alpelisib can raise blood sugar levels and reduce the body's insulin sensitivity. In studies, individuals who took alpelisib exhibited higher levels of sugar and insulin in their blood. This suggests that alpelisib might affect how the body manages sugar, particularly in those at risk of diabetes. The drug appears to disrupt insulin's usual functions, potentially altering how the liver produces sugar and fats. In this trial, participants will receive either alpelisib or a placebo to study these effects. While alpelisib is useful for studying insulin resistance, its side effects, such as increased blood sugar, require careful management. ^{4 6 7 8 9}

Who Is on the Research Team?

Joshua R Cook, MD, PhD

Principal Investigator

Columbia University

Are You a Good Fit for This Trial?

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.

My blood sugar and insulin levels are within a healthy range.

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Alpelisib

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.

How Is the Trial Designed?

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.

Alpelisib is already approved in United States, European Union for the following indications:

Approved in United States as Piqray for:

• Hormone receptor-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen

Approved in European Union as Piqray for:

• Hormone receptor-positive, HER2-negative, PIK3CA-mutated, locally advanced or metastatic breast cancer in combination with fulvestrant

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+

Published Research Related to This Trial

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]

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]

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]

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]

In a phase 2 study involving 87 patients with ALK-positive non-small-cell lung cancer who had progressed after crizotinib, alectinib demonstrated a 48% objective response rate, indicating significant clinical activity.

Alectinib was generally well tolerated, with most adverse events being mild (grade 1 or 2), although there were some serious events related to laboratory values; this suggests it could be a suitable treatment option for patients who have not responded to crizotinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Shaw, AT., Gandhi, L., Gadgeel, S., et al.[2022]

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 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]

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]

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]

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]

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]

Citations

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ALPELISIB - INDUCED HYPERGLYCEMIA - PMC Alpelisib has been shown to cause a dose dependent rise in plasma glucose, insulin and C-peptide concentrations. Moreover, a decrease in glucose uptake was also ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2376060524001111

Alpelisib-Induced Diabetic Ketoacidosis and Insulin- ... Although more effective for glycemic control, insulin therapy has the potential to decrease the antitumor effects of alpelisib.

3. diabetesjournals.org diabetesjournals.org/diabetes/article/73/12/2003/157196/Single-Dose-of-Phosphatidylinositol-3-Kinase

Single Dose of Phosphatidylinositol 3-Kinase Inhibitor ... A single dose of alpelisib versus placebo clearly induced biochemical evidence of insulin resistance both while fasting and during an oral ...

4. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.34928

Incidence, risk factors, and management of alpelisib ... A total of 100 patients (40.5%) received alpelisib on a clinical trial; rates of hyperglycemia were significantly higher in patients treated as ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10164376/

Treating Alpelisib-Induced Hyperinsulinemia in Patients with ... All patients achieved glycemic control and were able to maintain alpelisib dose intensity. Duration of response to alpelisib was longer than ...

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Management Strategies for Hyperglycemia Associated with ... As alpelisib may lead to life-threatening hyperglycemia within 2–3 days in patients with diabetes, oncologists should prescribe it with extreme ...

7. ema.europa.eu ema.europa.eu/fr/media/48505

Alpelisib EU Safety Risk Management Plan Overview of study BYL719C2301 which contributed to safety data ... ... be the result of insulin resistance. Evidence source(s) and strength.

8. novartis.com novartis.com/sg-en/sites/novartis_sg/files/Piqray-Dec2021.SIN-app080322.pdf

PIQRAY® (alpelisib) Summary of the safety profile. SOLAR-1 safety information: The overall safety evaluation of Piqray is based on data from the phase III clinical study of. 572 ...

9. nature.com nature.com/articles/s41523-024-00613-x

Managing hyperglycemia and rash associated with alpelisib Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib.