Pembrolizumab + Valemetostat for Head and Neck Cancer

Overseen By Vassiliki Saloura, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A inhibitors, P-gp inhibitors

Disqualifiers: Autoimmune disease, Cardiovascular diseases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 9

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of two drugs, valemetostat (a potential new drug) and pembrolizumab (also known as KEYTRUDA), for treating head and neck squamous cell carcinoma (HNSCC). Researchers focus on cases not linked to the human papillomavirus (HPV), as these are more likely to return after treatment. The trial will first determine the safest dose and then evaluate the combination's effectiveness, particularly for patients with HPV-negative HNSCC. Individuals with HPV-negative HNSCC, sinonasal carcinoma, or squamous non-small cell lung cancer that has returned or spread might be suitable for this trial. As a Phase 1 trial, the research aims to understand how the treatment works in people, offering participants the chance to be among the first to receive this potential new drug.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but you cannot take certain medications that affect liver enzymes (CYP3A) or are P-gp inhibitors. It's best to discuss your current medications with the trial team to see if they are allowed.

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

Research is examining the safety of combining two drugs, pembrolizumab and valemetostat, to treat head and neck cancer. Pembrolizumab, an immunotherapy drug, has been used in other cancer treatments and is FDA-approved for certain conditions. Studies have shown it is generally well-tolerated, with common side effects such as tiredness, rash, and mild diarrhea.

Valemetostat is a newer drug still under investigation. Early research suggests it might be well-tolerated when combined with pembrolizumab. Some patients have experienced mild side effects like nausea and tiredness, but more information is needed to fully understand its safety.

This trial is in the early stages and aims to determine the right dose and assess safety. This phase is crucial for identifying potential risks before progressing to larger studies. Participants will be closely monitored for any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Pembrolizumab and Valemetostat for head and neck cancer because this duo targets the cancer cells in a novel way. Pembrolizumab is an immunotherapy drug that enhances the body's immune response against cancer cells, while Valemetostat is a newer agent that inhibits specific enzymes (EZH1/2) linked to cancer cell growth. This combination could offer a more targeted and effective approach compared to traditional therapies like chemotherapy and radiation, potentially leading to better outcomes for patients.

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

Research has shown that pembrolizumab, a medicine that helps the immune system fight cancer, effectively treats various cancers, including head and neck cancer. Studies have found it particularly helpful when the cancer is difficult to remove or has returned. In this trial, researchers are evaluating the effectiveness of combining valemetostat with pembrolizumab. Early results in other cancers, such as lung cancer, suggest that this combination might be more effective than using pembrolizumab alone. The goal of this combination is to enhance the immune system's ability to find and destroy cancer cells. ^{1 3 6 7 8}

Who Is on the Research Team?

Vassiliki Saloura, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

Adults with HPV-negative head and neck squamous cell carcinoma, sinonasal cancer, or squamous non-small cell lung cancer. They must have good organ function, be able to undergo biopsies, not be pregnant or breastfeeding, agree to use contraception, and sign a consent form. Excluded are those with autoimmune diseases, prior malignancies within a certain period, uncontrolled infections or illnesses.

Inclusion Criteria

I agree to use birth control during the study.

My organs and bone marrow are working well.

I am willing and able to have biopsies for my condition.

Exclusion Criteria

You have had allergic reactions to similar drugs in the past.

I have a history of autoimmune disease, cancer, or ongoing infections.

I am not pregnant and do not have any uncontrolled illnesses.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment Phase Ib

Participants receive pembrolizumab and de-escalating doses of valemetostat to determine the recommended phase II dose (RP2D) and evaluate safety.

6 weeks

3 visits (in-person)

Treatment Phase II

Participants receive pembrolizumab and valemetostat at the RP2D to evaluate efficacy and continue safety assessment.

Up to 2 years

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment.

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Valemetostat

Trial Overview The PANTHERAS trial is testing the safety and effectiveness of combining pembrolizumab (an IV drug) with valemetostat (a daily oral tablet). Participants will receive treatments in cycles of 21 days for up to two years while their health is closely monitored through exams and tests.

How Is the Trial Designed?

Group I: Arm 2 Experimental Treatment 2 Interventions

RP2D of valemetostat in combination with pembrolizumab

Group II: Arm 1 Experimental Treatment 2 Interventions

Pembrolizumab + de-escalating doses of valemetostat

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The study evaluated the effectiveness of pembrolizumab and cetuximab, both alone and in combination, on head and neck squamous cell carcinoma (HNSCC) using the FLAVINO assay, revealing significant variability in patient responses, particularly in those with cisplatin-resistant cases.

An 'IP-10 score' was developed to predict patient outcomes based on their response to treatment, indicating that higher levels of IP-10 release in response to interferon gamma (IFN-γ) stimulation may correlate with better outcomes for certain HNSCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytokine Profiles of Head and Neck Squamous Cell Carcinoma Undergoing Dual Immunotherapy With Cetuximab and Pembrolizumab Identify Interferon Gamma-Induced Protein 10 as Novel Biomarker. Berszin, M., Michaelides, I., Siemert, J., et al.[2022]

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 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]

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 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 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]

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 phase III trial, pembrolizumab, a single-agent treatment, showed significant effectiveness in patients with head and neck tumors that had high PD-L1 expression, leading to deep and lasting responses.

This study highlights the potential of pembrolizumab as a first-line therapy for this specific group of cancer patients, suggesting a targeted approach based on PD-L1 levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembro Ups Survival in PD-L1-positive HNSCC. [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 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]

Citations

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NCT06644768 | A Study of Valemetostat Tosylate Plus ... This trial will evaluate the safety and efficacy of valemetostat tosylate (DS-3201b) in combination with fixed-dose pembrolizumab versus pembrolizumab alone ...

2. everyone.org everyone.org/explore/compare?id1=35&id2=577

Keytruda (pembrolizumab) vs Ezharmia (valemetostat ... Keytruda, known generically as pembrolizumab, is an immune checkpoint inhibitor that has shown efficacy in the treatment of various types of cancer, including ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11694497/

Real-World Evidence on the Effectiveness of Pembrolizumab ... The study showed some beneficial effects of pembrolizumab monotherapy in recurrent/metastatic/unresectable HNSCC patients in real-world scenarios.

4. clinicaltrials.ucsd.edu clinicaltrials.ucsd.edu/trial/NCT06644768

A Study of Valemetostat Tosylate Plus Pembrolizumab Versus ... This study will compare Valemetostat Tosylate Plus Pembrolizumab vs Pembrolizumab Alone in First-line NSCLC Without Actionable Genomic Alterations.

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Valemetostat + Pembrolizumab for Lung Cancer The effectiveness of pembrolizumab was consistent across both archival and newly collected tumor samples, with better outcomes observed in patients with higher ...

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Valemetostat in combination with pembrolizumab in head and ... Based on the above, we propose a phase Ib dose finding and safety study of valemetostat in combination with pembrolizumab. ... While this study opened, it was ...

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Valemetostat Plus Pembrolizumab in 1L NSCLC Without ... • DS3201-330 (jRCT2031240572; NCT06644768) is a multicenter, randomized, open-label, phase 1b/2 study evaluating the safety and efficacy of valemetostat ...

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Study Details | NCT02252042 | Pembrolizumab (MK-3475) ... The primary study hypothesis is that pembrolizumab treatment prolongs Overall Survival (OS) when compared to standard treatment. Official Title. A Phase III ...