PD-1 Inhibitor + Diabetes Drugs for Solid Malignant Tumors

Overseen By Jennifer Ruth, RN, BSN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Dan Zandberg

Must not be taking: Metformin, Insulin, Sulfonylureas, Thiazolidinediones

Disqualifiers: Type I DM, Active autoimmune, Uncontrolled cardiac, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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: 5

Duration: Up to 104 weeks

72 Participants Needed

Trial Summary

What is the purpose of this trial?

Patients with histologically or cytologically confirmed advanced melanoma, renal cell carcinoma, NSCLC, HCC (Child Pugh Class A only), MSI-High solid tumors, Urothelial Cancer, GE junction/Gastric Adenocarcinoma, or HNSCC for which current standard of care treatment for their stage of disease would be with Pembrolizumab or Nivolumab monotherapy, who meet eligibility criteria will undergo a biopsy (core or excisional/incisional; FNA not adequate) for baseline tissue. Patients will then be randomized to one of 3 arms: Anti-PD-1 mAb plus Metformin 500mg po BID, Anti-PD-1 mAb alone, Anti-PD-1 mAb plus Rosiglitazone 4mg po qdaily. Five weeks (+/- 7 days) after initiation of therapy a patient will undergo a repeat biopsy (core or excisional/incisional; FNA not adequate) for correlative analysis. The patient will then continue on study therapy for up to 2 years, or until progression of disease or unacceptable toxicity, whichever occurs first. RECIST 1.1 with modifications, to allow for continued therapy until progressive disease is confirmed if the patient is clinically stable, will be used in the trial.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you have taken metformin, insulin, sulfonylureas, or thiazolidinediones within 60 days before starting the study. If you are on these medications, you may need to stop them before joining the trial.

What data supports the effectiveness of the drug combination of PD-1 inhibitors and diabetes drugs for treating solid malignant tumors?

Recent evidence suggests that combining PD-1 inhibitors like nivolumab with metformin, a diabetes drug, may have synergistic (working together to enhance effect) antitumor effects in diabetic cancer patients. Additionally, pembrolizumab, another PD-1 inhibitor, has shown effectiveness in treating advanced melanoma, indicating potential benefits in cancer treatment. ^{1 2 3 4 5}

Is the combination of PD-1 inhibitors and diabetes drugs safe for humans?

PD-1 inhibitors like pembrolizumab and nivolumab have been associated with immune-related side effects, including the rare development of type 1 diabetes (a condition where the body cannot produce insulin). While these drugs are approved for several cancers, they can trigger autoimmune reactions, so monitoring for such effects is important. ^{6 7 8 9 10}

How is the drug combination of PD-1 inhibitors and diabetes drugs unique for treating solid tumors?

This treatment is unique because it combines PD-1 inhibitors, which help the immune system attack cancer cells, with diabetes drugs like metformin, which may enhance the anti-cancer effects. This combination is being explored for its potential to work better together than either drug alone, especially in diabetic cancer patients. ^{1 3 11 12 13}

Research Team

Dan P. Zandberg

Principal Investigator

UPMC Hillman Cancer Center

Eligibility Criteria

Adults with certain advanced cancers (like melanoma, lung, liver, stomach cancer) who can take pills and have a tumor that can be biopsied. They should not have had recent treatment with similar drugs or have serious health issues like uncontrolled heart disease or active autoimmune diseases. Women of childbearing age must test negative for pregnancy and agree to use birth control.

Inclusion Criteria

platelets ≥100,000/mcL

absolute neutrophil count ≥1,500/mcL

My kidneys are functioning well enough for treatment.

Exclusion Criteria

I am not allergic to metformin, rosiglitazone, pembrolizumab, or nivolumab.

I am currently taking Rifampin or Gemfibrozil for another health condition.

I have severe heart failure symptoms.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Anti-PD-1 mAb therapy alone or with Metformin or Rosiglitazone for up to 2 years

Up to 104 weeks

Biopsy at baseline and after 5 weeks, regular treatment visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

48 months

Treatment Details

Interventions

• Metformin
• Nivolumab or Pembrolizumab
• Rosiglitazone

Trial Overview The trial tests Anti-PD-1 antibodies (Nivolumab or Pembrolizumab) alone or combined with Metformin or Rosiglitazone in patients with specific solid tumors. Participants will be randomly assigned to one of three groups and treated for up to two years unless they experience unacceptable side effects.

Participant Groups

Group I: Anti-PD-1 mAb (nivolumab or pembrozilumab) plus Rosiglitazone Experimental Treatment 2 Interventions

nivolumab (480mg IV q 4 weeks) or pembrozilumab (200mg IV q 3 weeks) - dependent upon approved indication. (If both agents are approved for the disease indication, selection is at the discretion of the investigator) Rosiglitazone - 4 mg by mouth once daily

Group II: Anti-PD-1 mAb (nivolumab or pembrozilumab) plus Metformin Experimental Treatment 2 Interventions

nivolumab (480mg IV q 4 weeks) or pembrozilumab (200mg IV q 3 weeks) - dependent upon approved indication. (If both agents are approved for the disease indication, selection is at the discretion of the investigator) Metformin - 500 mg by mouth twice daily

Group III: Anti-PD-1 mAb (nivolumab or pembrozilumab) Active Control 1 Intervention

nivolumab (480mg IV q 4 weeks) or pembrozilumab (200mg IV q 3 weeks) - dependent upon approved indication. (If both agents are approved for the disease indication, selection is at the discretion of the investigator)

Nivolumab or Pembrolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma

Approved in United States as Keytruda for:

• Melanoma
• Non-small cell lung cancer
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Gastric and gastroesophageal carcinoma
• Hepatocellular carcinoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Urothelial carcinoma
• Colorectal cancer

Approved in European Union as Keytruda for:

• Melanoma
• Non-small cell lung cancer
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer

Who Is Running the Clinical Trial?

Dan Zandberg

Lead Sponsor

Trials

7

Recruited

330+

Findings from Research

The combination of nivolumab, an immune checkpoint inhibitor, and metformin, an oral diabetes medication, was found to be safe for use in 40 diabetic cancer patients, with 75% experiencing mild adverse events like fatigue and rash, and only 20% experiencing more severe side effects.

Higher doses of metformin (over 1,000 mg daily) were associated with significantly improved progression-free survival and overall survival rates, suggesting a potential synergistic antitumor effect when combined with nivolumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent Nivolumab and Metformin in Diabetic Cancer Patients: Is It Safe and More Active? Ciccarese, C., Iacovelli, R., Buti, S., et al.[2022]

In a study of 168 patients with advanced melanoma treated with pembrolizumab in community oncology settings, the median overall survival was 19.4 months, indicating its effectiveness in real-world scenarios.

Treatment-related toxicity led to discontinuation in 25% of patients, highlighting the importance of monitoring side effects, although the safety profile of pembrolizumab aligns with clinical trial results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Utilization and Outcomes for Advanced Melanoma in US Community Oncology Practices. Cowey, CL., Liu, FX., Black-Shinn, J., et al.[2021]

In a study of 1,395 patients with solid tumors receiving immune checkpoint inhibitors, those on glucose-lowering medications (GLM) for type 2 diabetes mellitus (T2DM) had a significantly increased risk of death and disease progression, indicating poorer outcomes from immunotherapy.

Specifically, patients exposed to metformin showed the highest risk of death and progression compared to controls, suggesting that metformin may negatively influence the effectiveness of immunotherapy in T2DM patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Type 2 Diabetes Mellitus and Efficacy Outcomes from Immune Checkpoint Blockade in Patients with Cancer. Cortellini, A., D'Alessio, A., Cleary, S., et al.[2023]

Pembrolizumab combined with adjuvant chemotherapy significantly improves one-year survival rates, overall response rates, and progression-free survival in patients with advanced non-small cell lung cancer (NSCLC), based on a meta-analysis of 14 studies.

This treatment not only enhances efficacy but also reduces the incidence of adverse drug reactions, indicating a favorable safety profile, although further validation through larger randomized controlled trials is needed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Efficacy and Safety Analysis of PD-1/PD-L1 Inhibitor vs. Chemotherapy in the Treatment of Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. Guo, WW., Zhang, TW., Wang, BL., et al.[2023]

In a randomized trial comparing FDA-approved immune checkpoint inhibitors for advanced melanoma, pembrolizumab showed significantly better treatment outcomes than ipilimumab.

This study is notable as it is the first to directly compare these two therapies as first-line treatments, highlighting pembrolizumab's potential as a more effective option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab superior to ipilimumab in melanoma. [2017]

Pembrolizumab, an immune checkpoint inhibitor used for treating various cancers, has been associated with the rare development of type 1 diabetes mellitus, as illustrated by a case of a patient with metastatic lung adenocarcinoma.

The report highlights the importance of monitoring for this adverse effect as the use of pembrolizumab and similar drugs becomes more common, suggesting a need for awareness of potential autoimmune responses triggered by these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. Chae, YK., Chiec, L., Mohindra, N., et al.[2022]

In a study of 88 advanced melanoma patients treated with pembrolizumab, 81.8% experienced any-grade toxicities, with skin and gastrointestinal issues being the most common side effects.

Despite the high incidence of side effects, pembrolizumab was found to be well tolerated in real-world settings, and severe toxicities were manageable with systemic steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. So, AC., Board, RE.[2022]

This case study reports the first instance of autoimmune diabetes potentially triggered by the PD-1 inhibitor pembrolizumab in an adult patient, highlighting a new and serious side effect of this cancer treatment.

The patient's high levels of anti-glutamic acid decarboxylase antibodies and genetic predisposition suggest that PD-1 inhibition may activate autoimmune processes leading to insulin-dependent diabetes, indicating the need for monitoring this risk in patients receiving PD-1 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Martin-Liberal, J., Furness, AJ., Joshi, K., et al.[2022]

Anti-PD-1 drugs significantly increase the risk of immune-related adverse events compared to control treatments, with a risk ratio of 2.65, indicating more than double the likelihood of experiencing these events.

Among the specific immune-related adverse events, conditions like hypothyroidism and hepatitis showed particularly high risk increases, with risk ratios of 7.87 and 9.31 respectively, highlighting the need for careful monitoring in patients receiving these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Systematic Review and Meta-Analysis of Immune-Related Adverse Events of Anti-PD-1 Drugs in Randomized Controlled Trials. Wang, Y., Kong, D., Wang, C., et al.[2021]

Nivolumab and pembrolizumab are FDA-approved monoclonal antibodies that target PD-1, helping to enhance T cell activity against cancer by blocking the PD-1/PD-L1 interaction, which allows cancer cells to escape immune detection.

Both drugs have shown efficacy across multiple cancer types, including melanoma and non-small cell lung cancer, and are considered interchangeable options for treating these conditions, which may help manage the rising costs of cancer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. Prasad, V., Kaestner, V.[2022]

Immune checkpoint inhibitors (ICIs), particularly PD-1 and PD-L1 inhibitors, can lead to a rare but serious side effect known as ICI-induced diabetes (ICI-DM), occurring in about 1% of patients, which can result in severe hyperglycemia and diabetic ketoacidosis.

The paper highlights the importance of recognizing ICI-DM as a potential life-threatening adverse event, emphasizing the need for clinicians to be vigilant in monitoring and managing this complication as ICI therapies become more widely used in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[IMMUNE CHECKPOINT INHIBITOR-INDUCED DIABETES MELLITUS]. Fischer, M., Amos, S., Levy, L., et al.[2022]

A 50-year-old man developed new onset diabetes mellitus (DM) with diabetic ketoacidosis after receiving nivolumab for metastatic renal cell carcinoma, highlighting a rare endocrine immune-related adverse event (irAE) associated with immune checkpoint inhibitors.

Treatment with the TNF inhibitor infliximab did not restore β-cell function in this case, emphasizing the need for prompt insulin management and the lack of effective immunosuppressive options for ICI-induced DM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab-induced diabetes mellitus-a case report with literature review of the treatment options. Daetwyler, E., Zippelius, A., Danioth, S., et al.[2023]

A systematic review of 12 clinical trials involving 5577 patients found that PD-1 inhibitors, specifically nivolumab and pembrolizumab, significantly increase the risk of immune-related endocrine disorders compared to chemotherapy, with risk ratios of 13.89 and 9.85 respectively.

Nivolumab therapy was associated with a notably higher risk of hypothyroidism (RR 10.07) and hyperthyroidism (RR 4.29), while pembrolizumab also showed increased risks for both conditions (hypothyroidism RR 7.73, hyperthyroidism RR 5.09), indicating the need for careful monitoring of thyroid function in patients undergoing these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The risk of immune-related endocrine disorders associated with anti-PD-1 inhibitors therapy for solid tumors: A systematic review and meta-analysis. Su, Q., Zhang, XC., Wang, DY., et al.[2018]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Concurrent Nivolumab and Metformin in Diabetic Cancer Patients: Is It Safe and More Active? [2022]

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

Pembrolizumab Utilization and Outcomes for Advanced Melanoma in US Community Oncology Practices. [2021]

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

Type 2 Diabetes Mellitus and Efficacy Outcomes from Immune Checkpoint Blockade in Patients with Cancer. [2023]

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

Clinical Efficacy and Safety Analysis of PD-1/PD-L1 Inhibitor vs. Chemotherapy in the Treatment of Advanced Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis. [2023]

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

Pembrolizumab superior to ipilimumab in melanoma. [2017]

6. Germany pubmed.ncbi.nlm.nih.gov

A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. [2022]

7. England pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. [2022]

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

A Systematic Review and Meta-Analysis of Immune-Related Adverse Events of Anti-PD-1 Drugs in Randomized Controlled Trials. [2021]

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

Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. [2022]

11. Israel pubmed.ncbi.nlm.nih.gov

[IMMUNE CHECKPOINT INHIBITOR-INDUCED DIABETES MELLITUS]. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Nivolumab-induced diabetes mellitus-a case report with literature review of the treatment options. [2023]

13. Netherlands pubmed.ncbi.nlm.nih.gov

The risk of immune-related endocrine disorders associated with anti-PD-1 inhibitors therapy for solid tumors: A systematic review and meta-analysis. [2018]