BAY 1895344 + Radiation + Pembrolizumab for Head and Neck Cancer

Not currently recruiting at 13 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 substrates

Disqualifiers: Nasopharyngeal carcinoma, Widely metastatic, others

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

Compensation: Varies

Number of Visits: 13

Duration: 6 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination to manage head and neck cancer that has recurred and cannot be surgically removed. The treatment includes elimusertib, an experimental drug that might block enzymes aiding cancer growth; precise radiation targeting tumors; and pembrolizumab, which boosts the immune system to fight cancer. It targets individuals with recurrent, inoperable squamous cell head and neck cancer who have previously undergone treatments like chemotherapy or radiation. The trial aims to determine the best dose and assess any benefits or side effects. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment combination.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop your current medications. However, if you are taking medications that interact with CYP3A4, you may need to switch to alternatives. It's best to discuss your current medications with the study team.

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

Research has shown that pembrolizumab, one of the treatments in this trial, has been used successfully in patients with head and neck cancer. One study found it improved the time patients lived without the cancer worsening, without causing new safety problems. This suggests that pembrolizumab is generally safe, with no unexpected side effects reported.

For elimusertib, detailed information about its safety in humans is limited. However, as the trial is in an early stage, researchers are closely monitoring its safety and determining the best dose.

Stereotactic body radiation therapy is another part of this trial. This precise type of radiation treatment aims to protect healthy tissues and is generally well-tolerated by patients.

Overall, this combination of treatments is being tested for safety and effectiveness in the trial, with researchers carefully monitoring patient responses to ensure safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment combination for head and neck cancer because it integrates Elimusertib, a new active ingredient, with Pembrolizumab and Stereotactic Body Radiation Therapy (SBRT). Elimusertib targets cancer cells by inhibiting a specific enzyme involved in DNA repair, potentially enhancing the effectiveness of radiation therapy. This approach is different from standard treatments like surgery or chemotherapy, which don't target the DNA repair mechanism. By combining Pembrolizumab, an immune checkpoint inhibitor, with targeted DNA repair disruption and precise radiation, this treatment could improve outcomes by more effectively attacking cancer cells while sparing healthy tissue.

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

Research shows that pembrolizumab, one of the treatments in this trial, effectively treats head and neck squamous cell cancer (HNSCC). Studies have found that pembrolizumab can extend patients' lives, particularly when used as the initial treatment, making it a common first choice for this condition. Pembrolizumab has also proven effective in real-life situations for patients with recurrent or difficult-to-remove HNSCC. In this trial, participants will receive pembrolizumab alongside elimusertib and stereotactic body radiation therapy (SBRT). Although less information exists about elimusertib, it likely works by blocking certain enzymes that cancer cells need to grow. Overall, combining these treatments with precise radiation aims to effectively target and manage cancer in these patients. ^{1 5 6 7 8}

Who Is on the Research Team?

Yvonne M. Mowery

Principal Investigator

University of Pittsburgh Cancer Institute LAO

Are You a Good Fit for This Trial?

Adults with recurrent, unresectable head and neck squamous cell carcinoma are eligible for this trial. They must have had disease progression on or after anti-PD-1/L1/L2 therapy or be new to such treatment. Prior radiotherapy should be completed at least 6 months before joining, and they should not have contraindications to pembrolizumab. Participants need a negative HIV test under certain conditions, no severe cardiac issues, agree to contraception if applicable, and meet specific health criteria.

Inclusion Criteria

I can care for myself and doctors expect me to live for at least 3 more months.

Patients must have a way to measure their disease according to specific guidelines.

I have had brain metastases treated and they are now stable.

Exclusion Criteria

My cancer has spread extensively.

I have specific allergies or an active autoimmune disease.

I have received a blood transfusion within a specific timeframe.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab IV on day 1 of each cycle, BAY 1895344 orally on specified days, and undergo SBRT during cycle 2

6 weeks

Multiple visits for IV administration and SBRT

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Follow-up every 13 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Elimusertib
• Pembrolizumab
• Stereotactic Body Radiation Therapy

Trial Overview

The trial is testing the combination of BAY 1895344 (elimusertib), stereotactic body radiation therapy, and pembrolizumab in patients with advanced head and neck cancer. It aims to find the optimal dose while assessing the potential benefits and side effects of this regimen compared to standard treatments involving radiation and immunotherapy without elimusertib.

How Is the Trial Designed?

Group I: Treatment (pembrolizumab, BAY 1895344, SBRT) Experimental Treatment 7 Interventions

Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Starting on day 7, patients also receive BAY 1895344 PO BID on days 7-9 and 14-16 during cycle 1, and before and after each SBRT treatment during cycle 2 for a total of 9 doses. Beginning cycle 2, patients undergo SBRT starting between days 2 and 8 for 3 fractions with 2-3 days between fractions. Treatment repeats every 21 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan and/or PET-CT scan and collection of blood samples throughout the trial.

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 Phase III trial KEYNOTE-412 is designed to evaluate the efficacy and safety of pembrolizumab, an immune checkpoint inhibitor, when used alongside chemoradiation therapy (CRT) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).

Previous Phase Ib studies have indicated that combining pembrolizumab with CRT is safe and feasible, supporting its potential use in this larger trial to improve treatment outcomes for patients with locally advanced HNSCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412. Machiels, JP., Tao, Y., Burtness, B., et al.[2021]

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 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]

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 II study involving 29 patients with locally advanced head and neck squamous cell carcinoma who were ineligible for cisplatin, the combination of pembrolizumab and radiotherapy showed promising efficacy, with a 24-month progression-free survival rate of 71%.

The treatment was generally well-tolerated, although a significant number of patients experienced grade 3/4 lymphopenia (58.6%), indicating the need for monitoring immune cell changes during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent Definitive Immunoradiotherapy for Patients with Stage III-IV Head and Neck Cancer and Cisplatin Contraindication. Weiss, J., Sheth, S., Deal, AM., 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]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Citations

1.

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.

2.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2415434

Neoadjuvant and Adjuvant Pembrolizumab in Locally ...

The addition of neoadjuvant and adjuvant pembrolizumab to standard care significantly improved event-free survival among participants with locally advanced ...

3.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.21.02508

Updated Results of the Phase III KEYNOTE-048 Study

Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02252042

Study Details | NCT02252042 | Pembrolizumab (MK-3475) ...

The primary study hypothesis is that pembrolizumab treatment prolongs Overall Survival (OS) when compared to standard treatment.

5.

merck.com

merck.com/news/mercks-keytruda-pembrolizumab-significantly-improved-overall-survival-compared-to-standard-of-care-as-monotherapy-and-in-combination-with-chemotherapy-as-first-line-treatment-for-patients/

Merck's KEYTRUDA (pembrolizumab) Significantly ...

“In this study, KEYTRUDA showed the potential to significantly prolong survival when used as first-line therapy for patients whose head and neck cancer had ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT02252042?tab=results

Study Results | Pembrolizumab (MK-3475) Versus ...

Serious AEs and Other AEs were reported according to treatment course for all randomized participants who received ≥1 dose of study treatment. Per protocol, ...

7.

merck.com

merck.com/news/keytruda-pembrolizumab-as-perioperative-treatment-with-standard-of-care-soc-adjuvant-therapy-significantly-improved-event-free-survival-compared-to-soc-alone-in-patients-with-resectable-loca/

KEYTRUDA® (pembrolizumab) as Perioperative Treatment ...

Results at the first interim analysis of the trial showed KEYTRUDA significantly improved event-free survival (EFS) as part of a perioperative treatment regimen ...

8.

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 ...