Trial Outcomes & Findings for Testing the Addition of an Anti-cancer Drug, BAY 1895344, With Radiation Therapy to the Usual Pembrolizumab Treatment for Recurrent Head and Neck Cancer (NCT NCT04576091)

Note: One (1) patient started pembro but not the study drug and was lost to follow-up completely after the first dose of pembro.

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

Dose of elimusertib (BAY 1895344) and concurrent stereotactic (8 Gy x 3 RT) body radiation therapy. Two 3-week cycles of therapy.

Number of patients who experienced Dose Limiting Toxicities. DLTs are defined as occurrence of any of the following events, if judged by the Investigator to be possibly, probably or definitely related to study drug administration 1. Any Grade 4 or greater adverse event per the Common Terminology Criteria for Adverse Events version 5 (CTCAE v5.0) observed within 90 days of the last dose of radiation therapy. 2. Grade 3 nonhematologic toxicity (not laboratory) lasting \>5 days despite optimal supportive care. 3. Any Grade 3 nonhematologic laboratory value if: • Medical intervention is required to treat the patient, or • The abnormality leads to hospitalization, or • The abnormality persists for \>1 week. 4. Febrile neutropenia. 5. Thrombocytopenia \<25000/mm3 if associated with bleeding requiring intervention. 6. Prolonged delay (\>2 weeks) in initiating Cycle 2 due to treatment-related toxicity.

Dose of elimusertib (BAY 1895344) and concurrent stereotactic (8 Gy x 3 RT) body radiation therapy. Two 3-week cycles of therapy.

Number of patients that experienced Adverse Events and/or Serious Adverse Events assessed per Common Terminology Criteria for Adverse Events (CTCAE) version 5, at least possibly related to treatment.

Number of patients that experienced AEs and/or SAEs per CTCAE version 5 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).

Number of patients experiencing Complete response or partial response per Response Evaluation Criteria in Solid Tumors 1.1 criteria. Per RECIST v1.1: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to \<10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD):≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

Median time from start of treatment regimen (day 1 pembrolizumab) until documented local or distal failure or death from any cause. Will be estimated using the method of Kaplan-Meier. Per RECIST 1.1, Disease Progression is defined as ≥20%increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

Percentage of patients alive without disease progression at 1 year. Per RECIST 1.1, Disease Progression is defined as ≥20%increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

Percentage of patients alive without disease progression at 2 years. Per RECIST 1.1, Disease Progression is defined as ≥20%increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

Median time from start of treatment regimen (day 1 pembrolizumab) until death from any cause. Will be estimated using the method of Kaplan-Meier.

Percentage of patients alive at one-year post treatment.

Percentage of patients alive at two years post treatment.

The FACT-H\&N (v4) consists of a cancer-specific questionnaire, FACT-G, in addition to 12 H\&N cancer specific items (the HN subscale, scores 0 to 40). FACT-G is a 27-item measure that assesses general cancer quality of life. The FACT-G contains 4 subscales: physical, social/family, emotional, and functional well-being. Patients indicate how true 27 statements are for them during the past 7 days. Responses range from not at all (0), to very much (4) on a 5-point scale, with total scores of 0 to 108. Total scores for the 39 items range from 0 to 148 with higher scores indicating better quality of life.

The FACT-H\&N (v4) consists of a cancer-specific questionnaire, FACT-G, in addition to 12 H\&N cancer specific items (the HN subscale, scores 0 to 40). FACT-G is a 27-item measure that assesses general cancer quality of life. The FACT-G contains 4 subscales: physical, social/family, emotional, and functional well-being. Patients indicate how true 27 statements are for them during the past 7 days. Responses range from not at all (0), to very much (4) on a 5-point scale, with total scores of 0 to 108. Total scores for the 39 items range from 0 to 148 with higher scores indicating better quality of life.

The FACT-H\&N (v4) consists of a cancer-specific questionnaire, FACT-G, in addition to 12 H\&N cancer specific items (the HN subscale, scores 0 to 40). FACT-G is a 27-item measure that assesses general cancer quality of life. The FACT-G contains 4 subscales: physical, social/family, emotional, and functional well-being. Patients indicate how true 27 statements are for them during the past 7 days. Responses range from not at all (0), to very much (4) on a 5-point scale, with total scores of 0 to 108. Total scores for the 39 items range from 0 to 148 with higher scores indicating better quality of life.

The FACT-H\&N (v4) consists of a cancer-specific questionnaire, FACT-G, in addition to 12 H\&N cancer specific items (the HN subscale, scores 0 to 40). FACT-G is a 27-item measure that assesses general cancer quality of life. The FACT-G contains 4 subscales: physical, social/family, emotional, and functional well-being. Patients indicate how true 27 statements are for them during the past 7 days. Responses range from not at all (0), to very much (4) on a 5-point scale, with total scores of 0 to 108. Total scores for the 39 items range from 0 to 148 with higher scores indicating better quality of life.

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.