Neoplasms

All Conditions

Symptoms and General Pathology

Mouth and Tooth Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Ear, Nose, and Throat Diseases

Rare Diseases

Carcinoma

Carcinoma, Squamous Cell

Recurrence

Head and Neck Neoplasms

Squamous Cell Carcinoma of Head and Neck

Mouth Neoplasms

Salivary Gland Neoplasms

Laryngeal Neoplasms

Oropharyngeal Neoplasms

Lip Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Neoplasms, Squamous Cell

Mouth Diseases

Stomatognathic Diseases

Salivary Gland Diseases

Otorhinolaryngologic Neoplasms

Laryngeal Diseases

Respiratory Tract Diseases

Respiratory Tract Neoplasms

Otorhinolaryngologic Diseases

Pharyngeal Neoplasms

Pharyngeal Diseases

Oral Squamous Cell Carcinoma

Oral Cancer

Laryngeal Cancer

Hypopharyngeal Cancer

Lip and Oral Cavity Cancer

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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.

Biospecimen Collection

Computed Tomography

Elimusertib

Positron Emission Tomography

Quality-of-Life Assessment

Stereotactic Body Radiation Therapy

Yvonne M Mowery

This phase I trial evaluates the best dose, possible benefits and/or side effects of combination therapy with elimusertib (BAY 1895344), stereotactic body radiation, and pembrolizumab in treating patients with head and neck squamous cell cancer that has come back (recurrent) and cannot be removed by surgery (unresectable). BAY 1895344 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. 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 BAY 1895344, stereotactic body radiation therapy in combination with pembrolizumab may shrink or stabilize head and neck squamous cell cancer for longer than treatment with radiation and immunotherapy without BAY 1895344.

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of BAY 1895344 with concurrent head and neck stereotactic body radiation therapy (SBRT) reirradiation and pembrolizumab.

II. To determine the recommended phase 2 dose (RP2D) of BAY 1895344 in combination with concurrent head and neck SBRT and pembrolizumab.

SECONDARY OBJECTIVE:

I. To observe and record anti-tumor activity (overall response rate, progression-free survival, and overall survival) of BAY 1895344, SBRT, and pembrolizumab for recurrent head and neck squamous cell carcinoma (HNSCC).

EXPLORATORY OBJECTIVE:

I. To identify predictive biomarkers of response to BAY 1895344, SBRT, and pembrolizumab, including, but not limited to the following: genetic alterations of ATM and other deoxyribonucleic acid (DNA) damage response genes, tumor mutational load, circulating tumor DNA, baseline tumor ATM expression, tumor PD-L1 expression, and change in circulating Ki67+ CD8+ T-cells relative to baseline.

OUTLINE: This is a dose-escalation study of BAY 1895344 and stereotactic body radiation therapy (SBRT) given with fixed-dose pembrolizumab.

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle. Starting on day 7, patients also receive BAY 1895344 orally (PO) twice daily (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 computed tomography (CT) scan and/or positron emission tomography (PET)-CT scan and collection of blood samples throughout the trial.

After completion of study treatment, patients are followed up every 13 weeks for at least 24 months.

Testing the Addition of an Anti-cancer Drug, BAY 1895344, With Radiation Therapy to the Usual Pembrolizumab Treatment for Recurrent Head and Neck Cancer

Phase I Trial of BAY 1895344 ATR Inhibitor Combined With Stereotactic Body Radiation Therapy and Pembrolizumab for Recurrent Head and Neck Squamous Cell Carcinoma

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Will investigate the association between potential predictive biomarkers of response to treatment. Tumor mutation burden will be categorized as high (above median) or low (equal to or below median). Other biomarker expression levels will be categorized as high versus absent/reduced. The chi-square or Fisher exact test will be used to study associations between expression levels and tumor response (complete response/partial response; stable/progressive disease). Associations with time-to-event endpoints will be investigated using the log rank test. Differences in change in circulating Ki67+ CD8+ T-cells relative to baseline between levels of tumor response will be explored using the t-test or non-parametric equivalent (e.g., Mann-Whitney) if appropriate. Cox regression will be used to explore associations between change in in circulating Ki67+ CD8+ T-cells and time-to-event endpoints. Other biomarkers will be analyzed similarly.

Will be assessed per Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Will be assessed per CTCAE version 5. The frequency and percentage of adverse events will be provided overall and by dose level for any grade and attribution as well as for grade 3 or greater adverse events, at least possibly related to treatment.

A competing risk analysis will be conducted with local failure, distal failure, and death as competing events. The cumulative incidence and 95% confidence interval for local failure will be estimated. Time to each event will be measured from the start of treatment regimen (day 1 pembrolizumab).

Will be estimated using the method of Kaplan-Meier.

Defined as a complete response or partial response based on the Response Evaluation Criteria in Solid Tumors 1.1 criteria. The proportion of patients responding to the treatment regimen and corresponding 95% confidence interval estimates will be calculated.

Will be assessed by the Functional Assessment of Cancer Therapy for Patients With Head and Neck Cancer, version 4. The frequency and percentage of responses to the quality of life questionnaire will be summarized at 3, 6, and 12 months post-treatment and interpreted descriptively.

National Cancer Institute (NCI)

Spots Global Cancer Trial Database for unresectable hypopharyngeal squamous cell carcinoma