Glucose Monitoring for Pancreatic Cancer

(PEGASUS Trial)

Overseen By Daniel Renouf, MD, MPH

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: British Columbia Cancer Agency

Disqualifiers: Brain metastases, Type I diabetes, others

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

Compensation: Varies

Number of Visits: 4

Duration: 8 weeks

50 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will investigate whether or not it is feasible to closely monitor and manage glucose levels in people with pancreatic cancer. It will also investigate what impact glucose management may have on pancreatic cancer. This is a pilot study that will use continuous glucose monitors (CGM) to monitor glucose levels in approximately 50 participants with pancreatic cancer. Participants will receive standard chemotherapy with a combination of up to four drugs to treat their pancreatic cancer: oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin (FOLFIRINOX). To treat high glucose levels, participants will be randomly assigned to one of two groups: Group 1 will receive anti-hyperglycemic treatment as guided by an endocrinologist with the aim of maintaining glucose levels between 4 and 10 mmol/L; Group 2 will receive anti-hyperglycemic treatment if their glucose levels are above 15 mmol/L, which is standard care. Participants in both Groups 1 and 2 will receive standard anti-hyperglycemic treatments: metformin, insulin, glucagon-like peptide-1 (GLP-1) receptor agonists, sodium glucose co-transporter (SGLT2) inhibitors, and dipeptidyl peptidase 4 (DPP-4) inhibitors. After 4 cycles of FOLFIRINOX, the CGM will be removed but any anti-hyperglycemic treatments will continue as needed. If participants discontinue treatment with FOLFIRINOX, they will continue to be followed for survival and subsequent anti-cancer therapy and will continue follow-up for glucose-related concerns at the discretion of their endocrinologist and/or medical oncologist.

Do I need to stop my current medications to join the trial?

The trial information does not specify if you need to stop your current medications. However, you will receive standard chemotherapy and may receive additional treatments to manage glucose levels. It's best to discuss your current medications with the study doctor.

What evidence supports the effectiveness of the drugs used in glucose monitoring for pancreatic cancer?

Some studies suggest that GLP-1 receptor agonists, like liraglutide, may enhance the effectiveness of chemotherapy in pancreatic cancer cells, making them more sensitive to treatment. Additionally, sitagliptin, a DPP-4 inhibitor, has been shown to help control blood sugar levels in diabetes patients, which could be beneficial for managing glucose levels in pancreatic cancer patients. ^{1 2 3 4 5}

Is glucose monitoring and related treatments generally safe for humans?

The treatments mentioned, such as DPP-4 inhibitors like saxagliptin and liraglutide, have been studied for type 2 diabetes and are generally considered safe with a low risk of severe side effects. Common side effects include nausea for liraglutide, which is usually temporary, and a low risk of hypoglycemia (low blood sugar) for saxagliptin when used alone. ^{2 3 6 7 8}

How does the drug used in glucose monitoring for pancreatic cancer differ from other treatments?

The drug used in glucose monitoring for pancreatic cancer may involve sitagliptin, a DPP-4 inhibitor, which is unique because it helps manage blood sugar levels by reducing glucose fluctuations, a feature not typically associated with standard cancer treatments. ^{2 6 9 10 11}

Research Team

Daniel J Renouf, MD

Principal Investigator

BC Cancer

Eligibility Criteria

This trial is for adults over 18 with pancreatic cancer who are about to start their first chemotherapy treatment using FOLFIRINOX. They should be relatively healthy and active (ECOG status 0-1) with certain blood counts and kidney function levels within a specific range.

Inclusion Criteria

My blood tests show my organs and bone marrow are working well.

Able to comply with the study visit schedule and other protocol requirements

I can take pills and have no issues with insulin shots.

Exclusion Criteria

Unable to comply with study assessments and follow-up

I am currently undergoing treatment for cancer.

I am pregnant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive standard chemotherapy with FOLFIRINOX and are monitored using continuous glucose monitors (CGM). Anti-hyperglycemic treatments are administered based on glucose levels.

8 weeks

4 cycles of chemotherapy, each cycle typically 14 days

Follow-up

Participants are monitored for survival, subsequent anti-cancer therapy, and glucose-related concerns after discontinuation of FOLFIRINOX.

6 months

Long-term follow-up

Participants continue to be followed for survival and glucose management at the discretion of their endocrinologist and/or medical oncologist.

Up to 43 months

Treatment Details

Interventions

• Anti-hyperglycemic Treatments (Metformin, Insulin, GLP-1 Receptor Agonists, SGLT2 Inhibitors, DPP-4 Inhibitors)
• Continuous Glucose Monitor (CGM)

Trial Overview The study tests if managing glucose levels between 4-10 mmol/L using continuous monitoring improves outcomes in pancreatic cancer patients, compared to standard care where treatment starts if glucose exceeds 15 mmol/L.

Participant Groups

Group I: Standard Care Experimental Treatment 1 Intervention

Participants will receive standard anti-hyperglycemic treatment only if blood glucose level is above 15 mmol/L as measured from standard blood work drawn prior to each cycle of chemotherapy. Participants will wear a CGM but will not be able to view their glucose data. Participants may be referred to an endocrinologist at the discretion of their medical oncologist.

Group II: Intensive Glucose Intervention Experimental Treatment 1 Intervention

Participants will receive standard anti-hyperglycemic treatment as guided by an endocrinologist using a combination of data from a continuous glucose monitor (CGM) and standard blood work drawn prior to each cycle of chemotherapy. Treatment will aim to maintain glucose levels between 4 and 10 mmol/L. Participants will have real-time access to their glucose data via the CGM.

Who Is Running the Clinical Trial?

British Columbia Cancer Agency

Lead Sponsor

Trials

181

Recruited

95,900+

University of British Columbia

Collaborator

Trials

1,506

Recruited

2,528,000+

Findings from Research

Incretin-based therapies, such as GLP-1 receptor agonists and DPP-4 inhibitors, effectively manage blood sugar levels in type 2 diabetes patients with minimal risk of causing low blood sugar episodes.

While there are inconsistent reports of low-grade chronic pancreatitis in animal studies and some cases of acute pancreatitis in humans, current clinical data suggest that these therapies are safe regarding the risk of pancreatic cancer, although the potential link between chronic pancreatitis and cancer remains a concern.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incretin based therapy and pancreatic cancer: Realising the reality. Suryadevara, V., Roy, A., Sahoo, J., et al.[2023]

In a study involving 13 type 2 diabetes patients on insulin therapy, adding sitagliptin significantly reduced 24-hour mean glucose levels and glucose variability, indicating its effectiveness in improving glycemic control.

The addition of sitagliptin did not increase the risk of hypoglycemia, suggesting it is a safe option for enhancing postprandial glucose management in patients already using insulin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of add-on treatment with sitagliptin on narrowing the range of glucose fluctuations in Japanese type 2 diabetes patients receiving insulin therapy. Mori, Y., Taniguchi, Y., Miyazaki, S., et al.[2022]

Saxagliptin significantly reduces glycosylated hemoglobin (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM), with reductions ranging from -0.72% to -0.90% compared to -0.27% with placebo, based on data from 11 Phase III clinical trials.

Saxagliptin is well tolerated, with common side effects including upper respiratory infections and urinary tract infections, and it does not increase cardiovascular risk compared to other treatments, making it a safe option for managing T2DM, especially in combination with other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Saxagliptin: a clinical review in the treatment of type 2 diabetes mellitus. Kania, DS., Gonzalvo, JD., Weber, ZA.[2022]

A systematic review of 11 studies involving 730,664 patients with diabetes found that the use of sulfonylureas (SUs) is associated with a 70% increased risk of pancreatic cancer, while metformin, insulin, and thiazolidinediones (TZDs) showed no significant association with pancreatic cancer risk.

The analysis highlighted considerable variability among studies, suggesting that confounding factors may influence results, and emphasized the need for future well-designed prospective studies to clarify the relationship between anti-diabetic medications and pancreatic cancer risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis. Singh, S., Singh, PP., Singh, AG., et al.[2018]

Liraglutide, a GLP-1 receptor agonist, enhances the sensitivity of gemcitabine-resistant pancreatic cancer cells to chemotherapy by promoting apoptosis and inhibiting cell growth, as shown in both in vitro and in vivo studies.

The study found that liraglutide increases the expression of GLP-1R and PKA in resistant cancer cells, and its effects can be reversed by blocking these pathways, indicating a specific mechanism of action that could benefit patients with pancreatic cancer and diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activation of GLP-1 receptor enhances the chemosensitivity of pancreatic cancer cells. Zhao, HJ., Jiang, X., Hu, LJ., et al.[2022]

DPP-4 inhibitors, including saxagliptin, linagliptin, and alogliptin, are widely used in managing type 2 diabetes, with significant financial investment indicating their importance in therapy.

Recent cardiovascular outcomes studies suggest that these medications not only help lower blood glucose levels but may also have implications for cardiovascular health, although specific results from these studies are not detailed in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on the 'gliptins'. [2017]

Liraglutide is an effective treatment for type 2 diabetes, reducing hemoglobin A1c levels by 0.8% to 1.5%, and is safe for patients at risk of hypoglycemia due to its low incidence of this side effect.

It is particularly beneficial for overweight or obese patients, as it not only helps control blood sugar but also promotes weight loss of about 2%-4% of initial body weight, although nausea can occur but is typically manageable with careful dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical pearls for initiating and utilizing liraglutide in patients with type 2 diabetes. Gross, B.[2015]

Saxagliptin, a DPP-4 inhibitor, significantly reduces HbA1c levels in type 2 diabetes patients when used alone or in combination with common medications like metformin and glyburide, based on a 24-week phase 3 clinical trial involving multiple studies.

The treatment was well tolerated, showed a low risk of hypoglycemia, and did not cause weight gain, making it a safe and effective option for managing blood sugar levels in type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of saxagliptin as monotherapy or adjunct therapy in the treatment of type 2 diabetes. Sharma, MD.[2021]

In a pilot study involving Japanese patients with type 2 diabetes, sitagliptin significantly reduced average 24-hour blood glucose levels and improved glycemic fluctuations, indicating its efficacy in managing diabetes.

The study showed that sitagliptin not only lowered blood glucose levels but also decreased the time spent in hyperglycemic states, suggesting it can help stabilize blood sugar throughout the day.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of sitagliptin on 24-h glycemic changes in Japanese patients with type 2 diabetes assessed using continuous glucose monitoring. Mori, Y., Taniguchi, Y., Matsuura, K., et al.[2015]

In a study involving 36 patients with type 2 diabetes, switching from DPP-4 inhibitors to dapagliflozin did not show significant improvements in glucose fluctuation compared to continuing DPP-4 inhibitors while on insulin therapy.

However, dapagliflozin treatment was associated with reductions in body mass index and albuminuria, suggesting potential metabolic benefits for patients with type 2 diabetes on insulin, despite no significant difference in glucose control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized controlled trial comparing the effects of dapagliflozin and DPP-4 inhibitors on glucose variability and metabolic parameters in patients with type 2 diabetes mellitus on insulin. Nomoto, H., Miyoshi, H., Sugawara, H., et al.[2020]

Dipeptidyl peptidase-4 (DPP-4) inhibitors, including linagliptin, are effective treatments for type-2 diabetes and can be used alone or with other diabetes medications.

Beyond diabetes management, DPP-4 inhibitors may have potential benefits for conditions like obesity, cardiovascular disease, and inflammation, suggesting their versatility in treating various health issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Linagliptin and newer DPP-4 inhibitors: newer uses and newer indications. Kalra, S., Unnikrishnan, AG., Agrawal, N., et al.[2019]

References

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

Incretin based therapy and pancreatic cancer: Realising the reality. [2023]

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

Effects of add-on treatment with sitagliptin on narrowing the range of glucose fluctuations in Japanese type 2 diabetes patients receiving insulin therapy. [2022]

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

Saxagliptin: a clinical review in the treatment of type 2 diabetes mellitus. [2022]

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

Anti-diabetic medications and risk of pancreatic cancer in patients with diabetes mellitus: a systematic review and meta-analysis. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Activation of GLP-1 receptor enhances the chemosensitivity of pancreatic cancer cells. [2022]

6. England pubmed.ncbi.nlm.nih.gov

An update on the 'gliptins'. [2017]

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

Clinical pearls for initiating and utilizing liraglutide in patients with type 2 diabetes. [2015]

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

Role of saxagliptin as monotherapy or adjunct therapy in the treatment of type 2 diabetes. [2021]

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

Effects of sitagliptin on 24-h glycemic changes in Japanese patients with type 2 diabetes assessed using continuous glucose monitoring. [2015]

10. England pubmed.ncbi.nlm.nih.gov

A randomized controlled trial comparing the effects of dapagliflozin and DPP-4 inhibitors on glucose variability and metabolic parameters in patients with type 2 diabetes mellitus on insulin. [2020]

11. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Linagliptin and newer DPP-4 inhibitors: newer uses and newer indications. [2019]