Tadalafil + Pembrolizumab for Head and Neck Cancer

Overseen By Khushbu Singh

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, San Diego

Must not be taking: PDE5 inhibitors, Nitrates, CYP3A4 inhibitors, GC stimulators

Disqualifiers: Autoimmune disease, Stroke, Heart disease, 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 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

7 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial will test a combination of two drugs, pembrolizumab and tadalafil, to treat advanced head and neck cancer. The goal is to see if this combination is safe and more effective than using pembrolizumab alone. Pembrolizumab helps the immune system attack cancer by blocking a specific protein, while tadalafil helps by blocking another pathway. This approach aims to strengthen the immune system's ability to fight cancer. Pembrolizumab has been approved by the FDA for various cancers and has shown significant activity in treating advanced head and neck cancer.

Will I have to stop taking my current medications?

The trial requires stopping certain medications, such as long-acting PDE5 inhibitors, nitrates, potent CYP3A4 inhibitors, and guanylate cyclase stimulators. 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 Tadalafil and Pembrolizumab for head and neck cancer?

Research suggests that Tadalafil can enhance the immune response in head and neck cancer by reducing certain immune-suppressing cells, while Pembrolizumab has shown effectiveness in treating recurrent or metastatic head and neck cancer. Combining these drugs may improve the body's ability to fight the cancer by boosting the immune system. ^{1 2 3 4 5}

Is the combination of Tadalafil and Pembrolizumab safe for humans?

Pembrolizumab has been used in patients with head and neck cancer, and while it can cause serious side effects like pneumonia and thyroid issues, its safety profile is considered acceptable. Tadalafil, when combined with another drug, was hypothesized to be safe in a study, but specific safety data for the combination with Pembrolizumab is not detailed. ^{1 2 6 7 8}

How is the drug combination of Tadalafil and Pembrolizumab unique for treating head and neck cancer?

The combination of Tadalafil and Pembrolizumab is unique because Tadalafil, a drug typically used for erectile dysfunction, may enhance the immune response when used with Pembrolizumab, an immune therapy that blocks a protein called PD-1 to help the immune system attack cancer cells. This combination aims to improve the body's natural ability to fight head and neck cancer, which is different from traditional chemotherapy or radiation treatments. ^{1 3 6 8 9}

Research Team

Joseph Califano

Principal Investigator

UCSD

Eligibility Criteria

Adults with recurrent or metastatic head and neck squamous cell carcinoma who have not used PD-1 or PD-L1 inhibitors in this setting, nor had certain heart conditions, autoimmune diseases, severe drug allergies, organ transplants, or are pregnant. They must have a life expectancy over 12 weeks and normal organ/marrow function.

Inclusion Criteria

You are expected to live for at least 12 more weeks.

My organs and bone marrow are functioning normally.

I am 18 or older with recurrent or metastatic squamous cell carcinoma of the head and neck.

Exclusion Criteria

My brain metastases are stable.

I am not on strong immune system suppressing drugs.

I haven't had a heart attack, heart surgery, or severe heart disease in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive tadalafil for up to 12 months and pembrolizumab for up to 24 months

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Pembrolizumab
• Tadalafil

Trial Overview The trial is testing the safety and effectiveness of combining two drugs: pembrolizumab (an immunotherapy) and tadalafil (a medication originally for erectile dysfunction), to treat advanced head and neck cancer.

Participant Groups

Group I: Tadalafil and Pembrolizumab Experimental Treatment 2 Interventions

Tadalafil for up to 12 months and pembrolizumab for up to 24 months.

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

University of California, San Diego

Lead Sponsor

Trials

1,215

Recruited

1,593,000+

Findings from Research

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 with 882 patients over a median follow-up of 45 months, pembrolizumab and pembrolizumab-chemotherapy showed significant improvements in overall survival compared to cetuximab-chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma, particularly in patients with high PD-L1 expression (CPS ≥ 20).

The analysis also indicated that patients who received pembrolizumab-based therapies had favorable outcomes in subsequent treatments, with improved progression-free survival on next-line therapies, highlighting the long-term efficacy of pembrolizumab in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. Harrington, KJ., Burtness, B., Greil, R., 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 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]

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]

References

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

Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma. [2023]

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

Discordant Responses Between Primary Head and Neck Tumors and Nodal Metastases Treated With Neoadjuvant Nivolumab: Correlation of Radiographic and Pathologic Treatment Effect. [2022]

3. United States 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. [2022]

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

Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

The Reversal of Immune Exclusion Mediated by Tadalafil and an Anti-tumor Vaccine Also Induces PDL1 Upregulation in Recurrent Head and Neck Squamous Cell Carcinoma: Interim Analysis of a Phase I Clinical Trial. [2020]

6. 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]

7. Greece pubmed.ncbi.nlm.nih.gov

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

8. United States 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. [2023]

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

Severe immune mucositis and esophagitis in metastatic squamous carcinoma of the larynx associated with pembrolizumab. [2019]