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

• ClinicalTrials.gov Identifier: NCT04095273
• Recruitment Status: Completed
• First Posted: September 19, 2019
• Last Update Posted: May 3, 2023
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: September 18, 2019
• First Posted Date: September 19, 2019
• Last Update Posted Date: May 3, 2023
• Actual Study Start Date: September 30, 2019
• Actual Primary Completion Date: November 24, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 18, 2020)

• Incidence of Treatment Emergent Adverse Events (TEAEs) including Treatment Emergent Serious Adverse Events (TESAEs) [ Time Frame: Up to 30 days after last study intervention administration ]
• Severity of Treatment Emergent Adverse Events (TEAEs) including Treatment Emergent Serious Adverse Events (TESAEs) [ Time Frame: Up to 30 days after last study intervention administration ]
• Frequency of Dose limiting toxicities (DLTs) at each dose level during dose escalation of BAY1895344 [ Time Frame: Cycle 1 (21 days) ]
• Recommended phase II dose (RP2D) of BAY1895344 [ Time Frame: 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).

Original Primary Outcome Measures (submitted: September 18, 2019)

• Incidence of Treatment Emergent Adverse Events (TEAEs) including Treatment Emergent Serious Adverse Events (TESAEs) [ Time Frame: Up to 30 days after last study intervention administration ]
• Severity of Treatment Emergent Adverse Events (TEAEs) including Treatment Emergent Serious Adverse Events (TESAEs) [ Time Frame: Up to 30 days after last study intervention administration ]
• Frequency of Dose limiting toxicities (DLTs) at each dose level during dose escalation of BAY1895344 [ Time Frame: Cycle 1 (21 days) ]

Current Secondary Outcome Measures (submitted: October 22, 2021)

• Cmax of Elimusertib [ Time Frame: Cycle 1 (21 days), Day 8 (dosing schedule 1) or Cycle 1 (21 days), Day 1 (dosing schedule 2) ]
• AUC(0-12) of Elimusertib [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Up to 24 months ]
• Disease control rate (DCR) [ Time Frame: Up to 24 months ]

Original Secondary Outcome Measures (submitted: September 18, 2019)

• Cmax of BAY1895344 [ Time Frame: Cycle 1 (21 days), Day 8 (dosing schedule 1) or Cycle 1 (21 days), Day 1 (dosing schedule 2) ]
• AUC(0-12) of BAY1895344 [ Time Frame: 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 BAY1895344 [ Time Frame: Cycle 1 (21 days), Day 17 (dosing schedule 1) or Cycle 1 (21 days), Day 10 (dosing schedule 2) ]
• AUC(0-12)md of BAY1895344 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: Up to 24 months ]
• Disease control rate (DCR) [ Time Frame: Up to 24 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: A Multicenter, Non-randomized, Open-label Phase 1b Study to Determine the Maximum Tolerated and Recommended Phase 2 Dose of the ATR Inhibitor Elimusertib in Combination With Pembrolizumab and to Characterize Its Safety, Tolerability, Pharmacokinetics and Preliminary Anti-tumor Activity in Participants With Advanced Solid Tumors
• Brief Summary: The purpose of the study is to test how well patients with advanced solid tumors respond to treatment with elimusertib (BAY1895344) in combination with pembrolizumab. In addition researchers want to find for patients the optimal dose of elimusertib in combination with pembrolizumab, how the drug is tolerated and the way the body absorbs, distributes and discharges the drug. The study medication, elimusertib, works by blocking a substance (ATR Kinase) which is produced by the body and is important for the growth of tumor cells. Pembrolizumab is an immunologic checkpoint blocker that promotes an immune response against the tumor.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Solid Tumors

Intervention

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

Study Arms

• Experimental: Dose escalation of Elimusertib
  2 dose levels of Elimusertib are planned
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab
• Experimental: Dose expansion cohort 1a of Elimusertib
  Participants with advanced hormone-receptor-positive, Human epidermal growth factor receptor 2 negative breast cancer (HER2-negative BC), known to be positive for Ataxia-telangiectasia mutated (ATM) loss and/or ATM deleterious alterations who have not received prior treatment with immunotherapy. Participants with known microsatellite instability-high (MSI-H) cannot be included
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab
• Experimental: Dose expansion cohort 1b of Elimusertib
  Participants with advanced hormone-receptor-positive, HER2-negative BC, known to be DDR deficiency biomarker-positive (except ATM loss/mutation) who have not received prior treatment with immunotherapy. Participants with known MSI-H cannot be included.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab
• Experimental: Dose expansion cohort 2a of Elimusertib
  Participants with advanced Colorectal cancer (CRC) known to be positive for ATM loss and/or ATM deleterious alterations who have not received prior treatment with immunotherapy. Participants with known MSI-H cannot be included.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab
• Experimental: Dose expansion cohort 2b of Elimusertib
  Participants with advanced CRC, known to be DDR deficiency biomarker -positive (except ATM loss/mutation) who have not received prior treatment with immunotherapy. Participants with known MSI-H cannot be included.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab
• Experimental: Dose expansion cohort 3 of Elimusertib
  Participants with advanced Gastric/gastroesophageal junction cancer (GC/GEJ) known to be DDR deficiency biomarker-positive (incl. ATM mutation) and/or positive for ATM loss. Participants must have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab
• Experimental: Dose expansion cohort 3a of Elimusertib
  Participants with advanced GC/GEJ cancer and without DDR deficiency alterations as described above. Variants of unknown significance (VUS) of the DDR gene alterations are eligible. Participants must have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab
• Experimental: Dose expansion cohort 4 of Elimusertib
  Participants with advanced Non-small cell lung cancer (NSCLC) known to be DDR deficiency biomarker-positive (incl. ATM mutation) and/or positive for ATM loss. Participants must have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab
• Experimental: Dose expansion cohort 4a of Elimusertib
  Participants with advanced NSCLC and without DDR deficiency alterations as described above. VUS of the DDR gene alterations are eligible. Participants must have progressed on treatment with an anti-PD-1/L1 mAb administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab
• Experimental: Dose expansion cohort 5 of Elimusertib
  Participants with advanced pancreatic cancer, known to be DDR deficiency biomarker-positive (incl. ATM mutation) and/or positive for ATM loss who have not received prior treatment with immunotherapy. Participants with known MSI-H cannot be included.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab
• Experimental: Dose expansion cohort 5a of Elimusertib
  Participants with advanced pancreatic cancer and without DDR deficiency alterations as described above, who have not received prior treatment with immunotherapy. VUS of the DDR gene alterations are eligible. Participants with known MSI-H cannot be included.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab
• Experimental: Dose expansion cohort 6 of Elimusertib
  Participants with advanced Metastatic castration-resistant prostate cancer (mCRPC), known to be DDR deficiency biomarker positive (incl. ATM mutation) and/or positive for ATM loss who have not received prior treatment with immunotherapy. Participants with known MSI-H cannot be included.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab
• Experimental: Dose expansion cohort 6a of Elimusertib
  Participants with advanced mCRPC and without DDR deficiency alterations as described above, who have not received prior treatment with immunotherapy. VUS of the DDR gene alterations are eligible. Participants with known MSI-H cannot be included.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Pembrolizumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 5, 2022): 56
• Original Estimated Enrollment (submitted: September 18, 2019): 76
• Actual Study Completion Date: April 11, 2023
• Actual Primary Completion Date: November 24, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany, Spain, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT04095273
• Other Study ID Numbers: 19741; Keynote 919 ( Other Identifier: Merck ); 2018-003420-36 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

Plan Description

Availability of this study's data will be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access.

As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.clinicalstudydatarequest.com to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the Study sponsors section of the portal.

• Current Responsible Party: Bayer
• Original Responsible Party: Same as current
• Current Study Sponsor: Bayer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Bayer
• Verification Date: May 2023