Pembrolizumab + Metformin for Head and Neck Cancer

Overseen By UCCC Clinical Trials Office

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Trisha Wise-Draper

Must not be taking: Metformin

Disqualifiers: Nasopharyngeal HNSCC, 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

Compensation: Varies

Number of Visits: 3

Duration: 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, metformin (a diabetes medication) and pembrolizumab (a cancer drug), to evaluate their effectiveness against recurrent or metastatic head and neck cancer. Researchers aim to determine if these treatments can shrink tumors and improve patients' conditions. They are testing two different schedules to identify the most effective one. The study seeks participants with head and neck cancer that cannot be treated with surgery or radiation and who have tried up to three other treatments without success. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

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

The trial does not specify if you need to stop taking your current medications, but you cannot join if you are currently taking metformin or have taken it in the last 6 months.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Earlier studies have shown that metformin has positive effects for cancer patients. Those who took metformin had a lower risk of dying from cancer compared to those who did not. It also appears to enhance the effectiveness of cancer treatments, suggesting metformin might be safe and beneficial for people with cancer.

Research shows that pembrolizumab, another drug in the trial, is generally safe for patients with head and neck cancer. Real-world data indicate that people treated with pembrolizumab did not experience any unexpected safety issues. While some side effects were reported, they aligned with what is already known about this drug.

Both metformin and pembrolizumab have been used in medical settings before, providing some confidence in their safety. However, consulting a healthcare professional for advice based on personal health needs is always recommended. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine pembrolizumab, an immunotherapy drug, with metformin, commonly used for diabetes, to tackle head and neck cancer. Unlike standard treatments like radiation or chemotherapy, pembrolizumab boosts the immune system to target cancer cells more effectively. Metformin is thought to enhance pembrolizumab's effects by altering the tumor environment, potentially improving outcomes. This novel combination offers a different approach, aiming to make cancer cells more vulnerable to immune attack, which could lead to better patient responses.

What evidence suggests that this trial's treatments could be effective for head and neck cancer?

This trial will compare two treatment approaches for head and neck cancer: administering Metformin before Pembrolizumab and administering Metformin after Pembrolizumab. Studies have shown that Pembrolizumab can significantly increase survival rates for patients with head and neck cancer when used as the first treatment. Research has also indicated that patients with head and neck cancer who take Metformin tend to live longer than those who do not, as Metformin helps control tumors and extends the time patients remain disease-free. Together, these treatments might offer a promising option for patients whose head and neck cancer has returned or spread. ^{1 3 4 6 7}

Who Is on the Research Team?

Trisha Wise-Draper, MD,PhD

Principal Investigator

University of Cincinnati

Are You a Good Fit for This Trial?

This trial is for adults with recurrent or metastatic non-cutaneous head and neck cancers (HNSCC) who have tried up to three treatments without a cure. They should be fairly active and able to care for themselves (ECOG ≤2). People can't join if they've had certain cancer drugs recently, are already on metformin, or have nasopharyngeal HNSCC.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

My head or neck cancer has returned or spread, and surgery or radiation can't cure it.

I have had up to 3 treatments for my cancer since it spread or came back.

Exclusion Criteria

I have cancer in the upper part of my throat behind the nose.

I haven't had chemotherapy or radiotherapy in the last 2 weeks.

I still have side effects from previous cancer treatments.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of Metformin and Pembrolizumab. Arm 1: Metformin before Pembrolizumab. Arm 2: Metformin after Pembrolizumab.

2 years

Pembrolizumab every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including overall response, survival, and adverse events.

2 years

What Are the Treatments Tested in This Trial?

Interventions

• Metformin Extended Release Oral Tablet
• Pembrolizumab

Trial Overview The study tests combining Pembrolizumab, an immune therapy drug, with Metformin Extended Release tablets in patients with advanced head and neck cancer. The goal is to see how well tumors respond to this combination treatment.

How Is the Trial Designed?

Group I: Arm 2: Metformin after Pembrolizumab Experimental Treatment 2 Interventions

D-21 Begin Pembrolizumab 200mg. D-7 begin Metformin ER 1000mg daily. D1 begin Metformin ER 2000mg daily. Continue Pembrolizumab 200mg every 3 weeks.

Group II: Arm 1: Metformin before Pembrolizumab Experimental Treatment 2 Interventions

Metformin ER 1000mg daily D-14 to D-7. Metformin ER 2000mg daily D-7 to D1. D1 Begin Pembrolizumab 200mg every 3 weeks, while continuing Metformin ER 2000mg daily.

Who Is Running the Clinical Trial?

Trisha Wise-Draper

Lead Sponsor

Trials

6

Recruited

230+

American Cancer Society, Inc.

Collaborator

Trials

237

Recruited

110,000+

Published Research Related to This Trial

A 69-year-old patient with relapsed squamous cell carcinoma showed significant improvement after 14 cycles of pembrolizumab, indicating its efficacy as a second-line treatment for metastatic head and neck cancer.

The patient developed severe immune-related adverse effects, specifically grade 4 mucositis and esophagitis, highlighting the importance of monitoring for such complications in patients receiving PD-1 inhibitors like pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe immune mucositis and esophagitis in metastatic squamous carcinoma of the larynx associated with pembrolizumab. Acero Brand, FZ., Suter, N., Adam, JP., et al.[2019]

Pembrolizumab, an immune checkpoint inhibitor, has been approved by the FDA for treating platinum-refractory recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), offering a new option with potentially improved efficacy compared to traditional chemotherapy and EGFR inhibitors.

This review discusses the pharmacology and tolerability of pembrolizumab, emphasizing its mechanism of action by blocking the PD-1 receptor, which may enhance the immune response against HNSCC tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab and its use in the treatment of recurrent or metastatic head and neck cancer. Sheth, S., Weiss, J.[2019]

In a phase 3 study involving 495 patients with recurrent or metastatic head-and-neck squamous cell carcinoma, pembrolizumab demonstrated a median overall survival of 8.4 months, compared to 6.9 months for standard-of-care treatments, indicating a significant improvement in survival rates.

Pembrolizumab was associated with fewer severe treatment-related adverse events (13%) compared to standard-of-care therapies (36%), suggesting a better safety profile for patients receiving pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Cohen, EEW., Soulières, D., Le Tourneau, C., et al.[2019]

Pembrolizumab (KEYTRUDA) received accelerated FDA approval for treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) based on a study of 174 patients, showing an objective response rate of 16% and a duration of response ranging from 2.4 to 27.7 months.

The safety profile included serious adverse reactions such as pneumonia and respiratory failure, but the overall benefit-risk assessment was deemed acceptable, marking pembrolizumab as the first new treatment option for HNSCC since 2006.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma with Disease Progression on or After Platinum-Containing Chemotherapy. Larkins, E., Blumenthal, GM., Yuan, W., et al.[2019]

In a study of 139 patients with recurrent and metastatic head and neck squamous cell carcinoma, pembrolizumab monotherapy showed similar long-term survival rates compared to combination therapy with chemotherapy, with 2-year progression-free survival at 28.6% and overall survival at 41.8%.

Patients receiving pembrolizumab monotherapy who experienced adverse events had a better prognosis than those without adverse events, suggesting that monotherapy may be a safer and more effective long-term treatment option compared to combination therapy, which did not improve prognosis and could lead to more side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Monotherapy Versus Pembrolizumab Plus Chemotherapy in Patients With Head and Neck Squamous Cell Carcinoma. Matsuo, M., Masuda, M., Yamauchi, M., et al.[2023]

In a phase IB study involving 59 patients with locally advanced head and neck squamous cell carcinoma, the combination of pembrolizumab with cisplatin-based chemoradiotherapy was found to be safe, with a high completion rate of treatment and only 8.8% of patients experiencing immune-related adverse events.

The treatment showed promising efficacy, with complete response rates of 85.3% for HPV-positive and 78.3% for HPV-negative patients, suggesting that this combination warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy of Pembrolizumab With Chemoradiotherapy in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Phase IB Study. Powell, SF., Gold, KA., Gitau, MM., et al.[2022]

In a study involving 882 participants with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), pembrolizumab alone significantly improved overall survival compared to cetuximab with chemotherapy, especially in patients with high PD-L1 expression (CPS of 20 or more).

Pembrolizumab combined with chemotherapy also showed improved overall survival compared to cetuximab with chemotherapy across all populations, indicating that pembrolizumab is an effective first-line treatment option for HNSCC, particularly for those with PD-L1 positivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Burtness, B., Harrington, KJ., Greil, R., et al.[2021]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

In a study of 38 patients with p16+ oropharyngeal squamous cell carcinoma, there was a 76% agreement in PD-L1 combined positive scores (CPS) between primary tumors and lymph node metastases, indicating variability in scoring between these specimens.

The interobserver agreement for CPS scoring was fair to substantial, suggesting that additional evaluations may be necessary to ensure accurate scoring, especially for patients who might benefit from immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Death Ligand-1 Combined Positive Score Concordance and Interrater Reliability in Primary Tumors and Synchronous Lymph Node Metastases in Resected Cases of p16+ Oropharyngeal Squamous Cell Carcinoma. Kaur, A., Kuchta, K., Watkin, W., et al.[2023]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4425387/

Effect of Metformin on Progression of Head and Neck ... Metformin users had better survival outcomes than those in the nonmetformin group with regard to cancer-specific death (HR: 0.45; 95% CI: 0.20–0.99; p = .047), ...

2. translational-medicine.biomedcentral.com translational-medicine.biomedcentral.com/articles/10.1186/s12967-023-04263-8

Metformin and cancer hallmarks: shedding new lights on ... Epidemiological studies have revealed that metformin exerts protective effects on people with diabetes suffering from cancer [10,11,12].

3. sciencedirect.com sciencedirect.com/science/article/pii/S0753332225007012

From basics to clinics: New opportunities for metformin in ... Beneficial effect of metformin on the five-year survival in about 40,000 patients with head and neck cancer. Cancers, 16 (5) (2024). Google Scholar. [127]. A ...

4. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1358854/full

The mechanisms of action of metformin on head and neck ... Metformin results in diametrically opposed effects by targeting non-stem cancer cells but protecting cancer stem cells in head and neck squamous cell carcinoma.

5. mdpi.com mdpi.com/2077-0383/14/20/7258

Biological Anti-Tumoral Mechanisms of Metformin in Head ... Clinical data suggest it may improve loco-regional tumor control, disease-free survival, and overall outcomes in head and neck tumors. While the clinical impact ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6497052/

The beneficial effects of metformin on cancer prevention ... Metformin can: 1) reduce the incidence of cancers, 2) reduce the mortality from cancers, 3) increase the response to treatment in cancer cells when using ...

7. mdpi.com mdpi.com/1648-9144/61/6/1021

Metformin: A Dual-Role Player in Cancer Treatment and ... Results: In total, 65 studies were included in the final analyses: Metformin intake was linked to a lower risk of cancer (RR 0.72; 95% CI: 0.64–0.81, ...