Lovastatin + Pembrolizumab for Head and Neck Cancer

Overseen By Nabil F Saba, MD, FACP

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must not be taking: Statins, Cimetidine, Spironolactone, others

Disqualifiers: Liver dysfunction, Recent radiation, 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: 1

Duration: 12 months

28 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking any statin drugs and any drugs that interact with lovastatin, such as cimetidine, spironolactone, and ketoconazole, before participating.

What data supports the effectiveness of the drug pembrolizumab for head and neck cancer?

Pembrolizumab has been shown to be effective in treating recurrent or metastatic head and neck cancer, especially after other treatments like platinum-based chemotherapy have failed. It was approved by the FDA based on studies showing that some patients experienced a reduction in tumor size and that these responses could last for several months. ^{1 2 3 4 5}

Is the combination of Lovastatin and Pembrolizumab safe for humans?

Pembrolizumab has been studied for safety in patients with head and neck cancer, showing some serious side effects like pneumonia and thyroid disorders, but it was considered to have an acceptable safety profile. However, there is no specific safety data available for the combination of Lovastatin and Pembrolizumab. ^{1 3 4 6 7}

How does the drug combination of Lovastatin and Pembrolizumab differ from other treatments for head and neck cancer?

This drug combination is unique because it combines Lovastatin, which may enhance antitumor immunity by affecting cholesterol levels, with Pembrolizumab, an immune checkpoint inhibitor that helps the immune system attack cancer cells. This approach aims to improve the effectiveness of immune therapy in head and neck cancer, which typically has limited treatment options. ^{1 3 6 8 9}

What is the purpose of this trial?

This phase II trial tests how well lovastatin and pembrolizumab work in treating patients with head and neck cancer that has come back after a period of improvement (recurrent) or that has spread from where it first started (primary site) to other places in the body (metastatic). Lovastatin is a drug used to lower the amount of cholesterol in the blood and may also cause tumor cell death. In addition, studies have shown that lovastatin may make the tumor cells more sensitive to immunotherapy. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving lovastatin and pembrolizumab may kill more tumor cells in patients with recurrent or metastatic head and neck cancer.

Research Team

Nicole C. Schmitt, MD, FACS

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Eligibility Criteria

This trial is for patients with head and neck cancer that has either returned after getting better or spread to other body parts. Participants should have a type of cancer listed in the trial conditions, such as nasopharyngeal carcinoma or laryngeal squamous cell carcinoma.

Inclusion Criteria

* Adult patients, male or female, aged ≥ 18, able to provide informed consent

* Subjects with pathologically proven, recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) involving the oral cavity, oropharynx, larynx, hypopharynx, nasopharynx, or paranasal sinuses; patients with unknown primary HNSCC involving the cervical lymph nodes can be included if human papillomavirus (HPV)-positive

* PD-L1 combined positive score (CPS) ≥ 1 (i.e., must be a candidate for treatment with pembrolizumab alone)

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive lovastatin orally once daily and pembrolizumab intravenously on day 1 of each cycle. Cycles repeat every 21 days for up to 12 months.

12 months

1 visit every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, including blood sample collection and imaging studies.

Up to 2 years

Treatment Details

Interventions

• Lovastatin
• Pembrolizumab

Trial Overview The LAPP Trial is testing lovastatin combined with pembrolizumab on recurrent or metastatic head and neck cancers. Lovastatin lowers cholesterol but may also make tumor cells more sensitive to immunotherapy, while pembrolizumab boosts the immune system's ability to fight cancer.

Participant Groups

Group I: Treatment (lovastatin, pembrolizumab) Experimental Treatment 6 Interventions

Patients receive lovastatin PO QD and pembrolizumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days for up to 12 months in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, and CT, MRI or PET/CT throughout the study.

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

Approved in United States as Mevacor for:

• High cholesterol
• Hyperlipidemia
• Cardiovascular disease prevention

Approved in Canada as Lovastatin for:

• High cholesterol
• Hyperlipidemia
• Cardiovascular disease prevention

Approved in European Union as Lovastatin for:

• Primary hypercholesterolaemia
• Mixed dyslipidaemia
• Prevention of cardiovascular events

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

The ADRISK trial is investigating whether adding pembrolizumab to standard adjuvant radio(chemo)therapy (aRCT) improves event-free survival in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are at intermediate to high risk after surgery.

This phase II multicenter trial will involve 240 patients and aims to compare the effectiveness of aRCT alone versus aRCT combined with pembrolizumab, with endpoints focused on event-free and overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postoperative adjuvant radiochemotherapy with cisplatin versus adjuvant radiochemotherapy with cisplatin and pembrolizumab in locally advanced head and neck squamous cell carcinoma- the study protocol of the Adrisk trial. Wiegand, S., Wichmann, G., Vogt, J., et al.[2023]

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 167 patients with recurrent/metastatic squamous cell carcinoma of the head and neck treated with pembrolizumab, the median overall survival was 22.7 months and progression-free survival was 5.1 months for those receiving pembrolizumab alone, indicating significant efficacy.

The presence of immune-related adverse events (irAEs) was associated with better progression-free survival, suggesting that these side effects may serve as important prognostic factors in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Pembrolizumab in Recurrent/Metastatic Squamous Cell Head and Neck Carcinoma: A Multicenter Retrospective Study. Okada, T., Fushimi, C., Matsuki, T., et al.[2023]

In a study involving 133 patients with locally advanced squamous cell carcinoma of the head and neck, pembrolizumab combined with radiotherapy did not show a significant improvement in locoregional control or survival compared to the standard treatment of cetuximab with radiotherapy.

However, patients receiving pembrolizumab experienced significantly lower toxicity, with only 74% reporting severe adverse events compared to 92% in the cetuximab group, suggesting it may be a safer option for patients unfit for high-dose cisplatin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial. Tao, Y., Biau, J., Sun, XS., et al.[2023]

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]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a Phase I study involving 26 patients with advanced head and neck squamous cell carcinoma (HNSCC) or cervical cancer (CC), lovastatin was found to be well tolerated at a maximum tolerated dose (MTD) of 7.5 mg/kg/day for 21 days, with reversible muscle toxicity as the main dose-limiting side effect.

Although no objective responses were observed, 23% of patients experienced stable disease for more than 3 months, with one patient achieving clinical benefit for 14 months, suggesting that lovastatin may have potential for further evaluation in these cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix. Knox, JJ., Siu, LL., Chen, E., et al.[2013]

In murine models of head and neck squamous cell carcinoma, statin drugs like simvastatin and lovastatin not only inhibited tumor cell growth but also enhanced T-cell activity against tumors, suggesting a potential mechanism for improved antitumor immunity.

When combined with PD-1 blockade, lovastatin led to tumor rejection in 30% of treated mice, indicating that statins could be a promising, low-cost addition to immunotherapy strategies for enhancing treatment responses in HNSCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models. Kansal, V., Burnham, AJ., Kinney, BLC., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab and its use in the treatment of recurrent or metastatic head and neck cancer. [2019]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Postoperative adjuvant radiochemotherapy with cisplatin versus adjuvant radiochemotherapy with cisplatin and pembrolizumab in locally advanced head and neck squamous cell carcinoma- the study protocol of the Adrisk trial. [2023]

3. England 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. [2019]

4. Greece pubmed.ncbi.nlm.nih.gov

Effects of Pembrolizumab in Recurrent/Metastatic Squamous Cell Head and Neck Carcinoma: A Multicenter Retrospective Study. [2023]

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

Pembrolizumab versus cetuximab concurrent with radiotherapy in patients with locally advanced squamous cell carcinoma of head and neck unfit for cisplatin (GORTEC 2015-01 PembroRad): a multicenter, randomized, phase II trial. [2023]

6. England 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. [2019]

7. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

8. England pubmed.ncbi.nlm.nih.gov

A Phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix. [2013]

9. England pubmed.ncbi.nlm.nih.gov

Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models. [2023]