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

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Advanced Solid Tumors	Drug: Elimusertib (BAY1895344); Drug: Pembrolizumab	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 56 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: September 30, 2019
• Actual Primary Completion Date: November 24, 2022
• Actual Study Completion Date: April 11, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dose escalation of Elimusertib; 2 dose levels of Elimusertib are planned	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled
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	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled
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.	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled
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.	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled
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.	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled
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.	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled
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.	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled
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.	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled
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.	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled
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.	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled
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.	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled
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.	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled
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.	Drug: Elimusertib (BAY1895344); Study drugs will be administered as scheduled; Drug: Pembrolizumab; Study drugs will be administered as scheduled

Outcome Measures

Primary Outcome Measures :

1. 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 ]
2. 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 ]
3. Frequency of Dose limiting toxicities (DLTs) at each dose level during dose escalation of BAY1895344 [ Time Frame: Cycle 1 (21 days) ]
4. 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).

Secondary Outcome Measures :

1. Cmax of Elimusertib [ Time Frame: Cycle 1 (21 days), Day 8 (dosing schedule 1) or Cycle 1 (21 days), Day 1 (dosing schedule 2) ]
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.
3. 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) ]
4. 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.
5. 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)
6. 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)
7. 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)
8. 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)
9. Objective Response Rate (ORR) [ Time Frame: Up to 24 months ]
10. Disease control rate (DCR) [ Time Frame: Up to 24 months ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

Stanford University

Palo Alto, California, United States, 94304

United States, Connecticut

Yale Cancer Center

New Haven, Connecticut, United States, 06519

United States, Maryland

Johns Hopkins Hospital/Health System

Baltimore, Maryland, United States, 21287

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02115-6084

United States, New York

Weill Cornell Medical College

New York, New York, United States, 10065

United States, North Carolina

Levine Cancer Institute

Charlotte, North Carolina, United States, 28204-2990

United States, Ohio

Ohio State University

Columbus, Ohio, United States, 43210

United States, Texas

University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030-4000

Germany

Universitätsklinikum Heidelberg

Heidelberg, Baden-Württemberg, Germany, 69120

Eberhard-Karls-Universität Tübingen

Tübingen, Baden-Württemberg, Germany, 72076

Spain

Fundacion Jimenez Diaz (Clinica de la Concepcion)

Madrid, Spain, 28040

Hospital Madrid Norte Sanchinarro

Madrid, Spain, 28050

Switzerland

Kantonsspital St. Gallen

St. Gallen, Sankt Gallen, Switzerland, 9007

Ospedale Regionale di Bellinzona e Valli

Bellinzona, Ticino, Switzerland, 6500

United Kingdom

Royal Marsden NHS Trust (Surrey)

Sutton, Surrey, United Kingdom, SM2 5PT

Freeman Hospital

Newcastle Upon Tyne, Tyne And Wear, United Kingdom, NE7 7DN

Sponsors and Collaborators

Bayer

More Information

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT04095273
• Other Study ID Numbers: 19741; Keynote 919 ( Other Identifier: Merck ); 2018-003420-36 ( EudraCT Number )
• First Posted: September 19, 2019
• Last Update Posted: May 3, 2023
• Last Verified: May 2023

Individual Participant Data (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.

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

Keywords provided by Bayer:

DDR (Deoxyribonucleic acid damage repair),; ATR (ataxia-telangiectasia and Rad3 related protein)inhibitor,

Additional relevant MeSH terms:

Neoplasms; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action