Study to Test How Well Patients With Advanced Solid Tumors Respond to Treatment With the Elimusertib in Combination With Pembrolizumab, to Find the Optimal Dose for Patients, How the Drug is Tolerated and the Way the Body Absorbs, Distributes and Discharges the Drug

• Elimusertib (BAY1895344) (Drug): Study drugs will be administered as scheduled
• Pembrolizumab (Keytruda®) (Drug): Study drugs will be administered as scheduled

Primary outcomes

• Incidence of Treatment Emergent Adverse Events (TEAEs) including Treatment Emergent Serious Adverse Events (TESAEs) [Up to 30 days after last study intervention administration]
• Severity of Treatment Emergent Adverse Events (TEAEs) including Treatment Emergent Serious Adverse Events (TESAEs) [Up to 30 days after last study intervention administration]
• Frequency of Dose limiting toxicities (DLTs) at each dose level during dose escalation of BAY1895344 [Cycle 1 (21 days)]
• Recommended phase II dose (RP2D) of BAY1895344 [Up to 24 months]: The RP2D will be determined in dose expansion part based on multiple parameters (i.e., safety, tolerability, PK, pharmacodynamics, efficacy) and will be a dose equal to or lower than the MTD (Maximum Tolerated Dose).

Secondary outcomes

• Cmax of Elimusertib [Cycle 1 (21 days), Day 8 (dosing schedule 1) or Cycle 1 (21 days), Day 1 (dosing schedule 2)]
• AUC(0-12) of Elimusertib [Cycle 1 (21 days), Day 8 (dosing schedule 1) or Cycle 1 (21 days), Day 1 (dosing schedule 2)]: If the main parameters AUC(0-12) cannot be calculated reliably, it might become necessary to appoint the additional parameters AUC(0-tlast) as secondary variables.
• Cmax,md of Elimusertib [Cycle 1 (21 days), Day 17 (dosing schedule 1) or Cycle 1 (21 days), Day 10 (dosing schedule 2)]
• AUC(0-12)md of Elimusertib [Cycle 1 (21 days), Day 17 (dosing schedule 1) or Cycle 1 (21 days), Day 10 (dosing schedule 2)]: If the main parameters AUC(0-12)md cannot be calculated reliably, it might become necessary to appoint the additional parameters AUC(0-tlast)md as secondary variables.
• Incidence of Complete response (CR) [Up to 24 months]: Per RECIST 1.1 and for participants with mCRPC consistent with recommendations of the Prostate Cancer Working Group (PCWG3)
• Incidence of partial response (PR) [Up to 24 months]: Per RECIST 1.1 and for participants with mCRPC consistent with recommendations of the Prostate Cancer Working Group (PCWG3)
• Incidence of stable disease (SD) [Up to 24 months]: Per RECIST 1.1 and for participants with mCRPC consistent with recommendations of the Prostate Cancer Working Group (PCWG3)
• Incidence of progressive disease (PD) [Up to 24 months]: Per RECIST 1.1 and for participants with mCRPC consistent with recommendations of the Prostate Cancer Working Group (PCWG3)
• Objective Response Rate (ORR) [Up to 24 months]
• Disease control rate (DCR) [Up to 24 months]

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Participant must be ≥18 years of age inclusive, at the time of signing the informed consent.
* Presence of the putative biomarkers of DDR deficiency in tumor and/or other tissues (dose escalation only).
* Participants must have histologically confirmed solid tumors .
* Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 to 1.
* Adequate bone marrow function as assessed by laboratory tests to be conducted within 7 days before the first dose of study intervention.
* Participants must have adequate kidney function, as assessed by the estimated glomerular filtration rate (eGFR) > 40 mL/min per 1.73 m*2 within 7 days before the first dose of study intervention.
* Participants must have adequate liver function as assessed by laboratory tests to be conducted within 7 days before the first dose of study intervention.
* Participants must have adequate coagulation, as assessed by laboratory tests as applicable, (to be conducted within 7 days before the first dose of study intervention) or be on stable anti-coagulation treatment.
* Adequate cardiac function per institutional normal measured by echocardiography (recommended) or multigated acquisition (MUGA) scan/cardiac MRI per institutional guidelines.
* Participants must have measurable disease (at least one measurable lesion) as per RECIST 1.1, or evaluable disease according to the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) classification as applicable. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions

Exclusion Criteria:

* Ongoing infections of Common terminology criteria for adverse events (CTCAE) grade ≥2 not responding to therapy or active clinically serious infections.
* Participants with

  * Known human immunodeficiency virus (HIV)
  * Active Hepatitis B infection (positive for Hepatitis B surface antigen (HBsAg)/ Hepatitis B virus (HBV) DNA).
  * Active Hepatitis C infection (positive anti-HCV Antibody and quantitative HCV RNA results greater than the lower limits of detection of the assay).
* Active autoimmune disease (active defined as having autoimmune disease related symptoms and detectable autoantibodies) that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
* Diagnosis of immunodeficiency or participant is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention. The use of physiologic doses of corticosteroids may be approved after consultation with the sponsor.
* Pleural effusion or ascites that causes respiratory compromise (CTCAE Grade ≥ 2 dyspnea).
* History of cardiac disease: congestive heart failure New York Heart Association (NYHA) class >II, unstable angina (angina symptoms at rest), new-onset angina (within the past 6 months before study entry), myocardial infarction within the past 6 months before study entry, or cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers, calcium channel blockers, and digoxin are permitted)
* Uncontrolled arterial hypertension despite optimal medical management (per investigator's opinion)
* Moderate or severe hepatic impairment, i.e., Child-Pugh class B or C.
* History of organ allograft transplantation
* Evidence or history of bleeding disorder, i.e., any hemorrhage / bleeding event of CTCAE Grade > 2 within 4 weeks before the first dose of study intervention

NIH grants: 2018