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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of pembrolizumab and tadalafil to evaluate its safety and effectiveness in treating advanced head and neck cancer. Pembrolizumab boosts the immune system, while tadalafil is commonly used for blood flow issues. The trial targets individuals with recurring or spreading squamous cell carcinoma in the head and neck who have not previously received similar treatments. Participants should have a visible tumor and be in generally good health. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

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.

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

Research is examining the safety of combining two drugs, tadalafil and pembrolizumab, to treat advanced head and neck cancer. Although specific safety data for this combination is not yet available, the FDA has approved pembrolizumab for other uses, indicating its general safety. Tadalafil is also considered safe for other conditions. This trial is in its early stages, focusing on the safety of the combination for patients. Previous studies suggest that adding tadalafil to pembrolizumab might be safe, but the exact effects are still under investigation. Participants in the trial will receive close monitoring for any side effects. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for head and neck cancer?

Researchers are excited about the combination of Tadalafil and Pembrolizumab for head and neck cancer because it introduces a unique approach by pairing a well-known immune checkpoint inhibitor with a drug traditionally used for erectile dysfunction. Most treatments for this type of cancer rely on surgery, radiation, and chemotherapy, which often come with significant side effects. Pembrolizumab works by unleashing the immune system to attack cancer cells, and when combined with Tadalafil, which may improve immune cell infiltration into tumors, it has the potential to enhance the overall anti-tumor response. This combination could offer a more focused attack on cancer cells with potentially fewer side effects than conventional therapies.

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

Research suggests that combining tadalafil with pembrolizumab, as studied in this trial, may enhance the immune system's ability to fight head and neck cancer by reducing cells that weaken the immune response. Pembrolizumab already helps the immune system attack cancer cells in various cancers. Studies have shown that using these two treatments together might be more effective than using pembrolizumab alone for head and neck cancer. This combination aims to strengthen the body's ability to combat the cancer, potentially leading to better outcomes for patients. ^{1 2 3 4 6}

Who Is on the Research Team?

Joseph Califano

Principal Investigator

UCSD

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03993353?cond=%22Squamous%20Cell%20Carcinoma,%20Head%20and%20Neck%22&intr=%22Phosphodiesterase%20Inhibitors%22&viewType=Table&rank=5

Tadalafil and Pembrolizumab in Recurrent or Metastatic ... This study will examine the combination of pembrolizumab and tadalafil for safety and efficacy in advanced head and neck cancer. Detailed Description. Immune ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2020-03674

Tadalafil and Pembrolizumab for the Treatment of ... Giving tadalafil and pembrolizumab together may work better in treating patients with head and neck squamous cell cancer compared to pembrolizumab alone.

3. withpower.com withpower.com/trial/phase-3-mouth-neoplasms-3-2020-d18b1

Tadalafil + 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 ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9599671/

Checkpoint Inhibitors in Cancer Therapy: Clinical Benefits ... A phase II trial examines the combination of pembrolizumab and tadalafil for safety and efficacy in advanced head and neck cancer (NCT03993353). 8.6. SMO.

5. clinconnect.io clinconnect.io/trials/NCT03993353

Tadalafil and Pembrolizumab in Recurrent or Metastatic This study will examine the combination of pembrolizumab and tadalafil for safety and efficacy in advanced head and neck cancer.

6. clinicaltrialsarena.com clinicaltrialsarena.com/news/msd-keytruda-combo/

MSD reports outcomes from trial of Keytruda combination ... After a median follow-up at 38.3 months, the therapy had decreased the EFS event risk by 34% in subjects whose combined positive score (CPS) was ...