PD-1 Inhibitor + Diabetes Drugs for Solid Malignant Tumors
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Dan Zandberg
Must not be taking: Metformin, Insulin, Sulfonylureas, Thiazolidinediones
Disqualifiers: Type I DM, Active autoimmune, Uncontrolled cardiac, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Approved in 4 Jurisdictions
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.
12345Is 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.
678910How 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.
13111213Eligibility 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.
+14 more
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.
+14 more
Trial 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
Participant Groups
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.
3Treatment groups
Experimental Treatment
Active Control
Group I: Anti-PD-1 mAb (nivolumab or pembrozilumab) plus RosiglitazoneExperimental Treatment2 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 MetforminExperimental Treatment2 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 Control1 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, United States, European Union, 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
UPMC Hillman Cancer CenterPittsburgh, PA
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Who Is Running the Clinical Trial?
Dan ZandbergLead Sponsor
References
Concurrent Nivolumab and Metformin in Diabetic Cancer Patients: Is It Safe and More Active? [2022]Recent evidence suggests potential synergistic antitumor effects of the combination of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors with the oral hypoglycemic agent metformin. The aim of this study was to investigate the safety and activity of metformin combined with nivolumab in diabetic cancer patients.
Pembrolizumab Utilization and Outcomes for Advanced Melanoma in US Community Oncology Practices. [2021]The programmed death-1 inhibitor pembrolizumab has demonstrated efficacy and safety in clinical trials for treating advanced (unresectable/metastatic) melanoma. We investigated the real-world utilization of pembrolizumab and associated patient outcomes for advanced melanoma in US community oncology practices. This retrospective, observational study used deidentified data from electronic health records for adult patients with advanced melanoma who received pembrolizumab at The US Oncology Network sites from September 2014 through December 2015, with follow-up through September 2016. Patients enrolled in clinical trials were excluded. Overall survival (OS) and physician-stated progression-free survival (PFS) were analyzed from pembrolizumab initiation using Kaplan-Meier, and associations between pembrolizumab therapy and OS/PFS, using multivariable Cox regression. Of 168 patients studied, 110 (65%) were male; the median age was 66 years (range, 26-over 90). Pembrolizumab was prescribed as first-line, second-line, and third-line/later for 39 (23%), 87 (52%), and 42 (25%) patients, respectively. In total, 41 patients (24%) had brain metastases. At pembrolizumab initiation, 21/129 (16%) had Eastern Cooperative Oncology Group performance status (ECOG PS) >1; 51/116 (44%) had elevated lactate dehydrogenase. Median follow-up was 10.5 months (range, 0-25.1); median OS was 19.4 months (95% confidence interval, 14.0-not reached); median PFS was 4.2 months (95% confidence interval, 2.9-5.3). Brain metastases, ECOG PS>1, elevated lactate dehydrogenase, and third-line/later (vs. first-line) pembrolizumab were significant predictors (P
Type 2 Diabetes Mellitus and Efficacy Outcomes from Immune Checkpoint Blockade in Patients with Cancer. [2023]No evidence exists as to whether type 2 diabetes mellitus (T2DM) impairs clinical outcome from immune checkpoint inhibitors (ICI) in patients with solid tumors.
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]To systematically evaluate the efficacy and safety of pembrolizumab (PD-1/PD-L inhibitor) and adjuvant chemotherapy to treat NSCLC and provide evidence-based reference for clinical use.
Pembrolizumab superior to ipilimumab in melanoma. [2017]In the first randomized trial to compare FDA-approved immune checkpoint inhibitors as first-line therapy for patients with advanced melanoma, pembrolizumab yielded significantly better treatment outcomes than ipilimumab.
A case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes. [2022]Immune checkpoint inhibitors such as pembrolizumab, ipilimumab, and nivolumab, now FDA-approved for use in treating several types of cancer, have been associated with immune-related adverse effects. Specifically, the antibodies targeting the programmed-cell death-1 immune checkpoint, pembrolizumab and nivolumab, have been rarely reported to induce the development of type 1 diabetes mellitus. Here we describe a case of a patient who developed antibody-positive type 1 diabetes mellitus following treatment with pembrolizumab in combination with systemic chemotherapy for metastatic adenocarcinoma of the lung. We will also provide a brief literature review of other rarely reported cases of type 1 diabetes presenting after treatment with pembrolizumab and nivolumab, as well as discussion regarding potential mechanisms of this adverse effect and its importance as these drugs continue to become even more widespread.
Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. [2022]We aimed to characterize the safety profile of pembrolizumab in advanced melanoma patients at our center to better reflect 'real-world' data on anti-PD-1 inhibitors.
Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. [2022]The anti programmed cell death-1 (PD-1) antibodies pembrolizumab and nivolumab have been recently licensed by the Food and Drug Administration for the treatment of advanced melanoma. Immune checkpoint inhibitors such as these can induce endocrine adverse events but autoimmune diabetes has not been described to date. However, there is a strong preclinical rationale that supports this autoimmune toxicity. We describe for the first time the case of an adult patient who developed autoimmune diabetes likely as a consequence of PD-1 inhibition with pembrolizumab. The presence of high serum titres of anti-glutamic acid decarboxylase antibodies together with a suggestive clinical presentation, age of the patient and preclinical data strongly support an autoimmune aetiology of the diabetes. Moreover, the patient was found to have a well-known high-risk human leucocyte antigen type for the development of type 1 diabetes in children, so the PD-1 inhibition is very likely to have triggered the autoimmune phenomenon. Our case suggests that insulin-dependent diabetes might be a rare but important anti-PD-1 immune-related adverse event.
A Systematic Review and Meta-Analysis of Immune-Related Adverse Events of Anti-PD-1 Drugs in Randomized Controlled Trials. [2021]We aimed to evaluate immune-related adverse events occurring in clinical trials of anti-programmed cell death 1 (PD-1) drugs, compared with control treatments, including chemotherapy, targeted drugs, or placebo. Further we compared the occurrence of immune -related events in patients treated with different anti-PD-1 drugs.
Nivolumab and pembrolizumab: Monoclonal antibodies against programmed cell death-1 (PD-1) that are interchangeable. [2022]Nivolumab (Opdivo, Bristol Meyer Squibb, New York, NY) and pembrolizumab (Keytruda, Merck, Kenilworth, NJ) are the first two US Food and Drug Administration (FDA)-approved monoclonal antibodies targeting programmed death-1 (PD-1). Nivolumab and pembrolizumab work by interfering with the interaction between PD-1 and programmed death ligand-1 (PD-L1), whose unimpeded interaction downregulates T cells allowing cancer cells to evade immune surveillance. These drugs have earned a series of FDA approvals for melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC), urothelial cancer, classical Hodgkin lymphoma, and renal cell cancer. In this review we will summarize the data for efficacy and toxicity for these two agents. We conclude that they represent two valuable but interchangeable alternatives to target their approved indications. We will discuss how this can help global payers seeking to contain the cost of cancer therapeutics that continues to spiral out of control.
[IMMUNE CHECKPOINT INHIBITOR-INDUCED DIABETES MELLITUS]. [2022]Immune checkpoint inhibitors (ICIs) have transformed the care of cancer patients, providing therapeutic options for advanced malignancies considered otherwise untreatable. However, these agents have been associated with immune-related adverse events (irAEs). ICI-induced diabetes (ICI-DM) is a rare complication of programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor therapy (~1%) and can be life-threatening, as patients often present with severe hyperglycemia and in diabetic ketoacidosis. We describe two patients with rapid-onset diabetes mellitus associated with anti PD-1 therapy followed by an in-depth review of the literature. We discuss the clinical presentation, potential mechanisms and optimal management of patients with ICI-DM. As ICI use continues to expand across a wide variety of malignancies, clinicians must be aware of this potentially life-threatening irAE to prevent significant morbidity and mortality.
Nivolumab-induced diabetes mellitus-a case report with literature review of the treatment options. [2023]Immune checkpoint inhibitor (ICI) treatment has become important for treating various cancer types, including metastatic renal cell carcinoma. However, ICI treatment can lead to endocrine immune-related adverse events (irAEs) by overstimulating the patient's immune system. Here, we report a rare case of a new onset of diabetes mellitus (DM), caused by nivolumab, and we discuss the feasible treatment options with a focus on TNF antagonism.
The risk of immune-related endocrine disorders associated with anti-PD-1 inhibitors therapy for solid tumors: A systematic review and meta-analysis. [2018]We performed a systematic review and meta-analysis to evaluate the risk of immune-related endocrine disorders associated with PD-1 inhibitors therapy for solid tumors.