Clinical trial NCT04095273: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Keywords: DDR (Deoxyribonucleic acid damage repair),
ATR (ataxia-telangiectasia and Rad3 related protein)inhibitor,
Lead sponsor: Bayer
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2019-09-19
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Incidence of Treatment Emergent Adverse Events (TEAEs) including Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: Up to 30 days after last study intervention administration
measure: Severity of Treatment Emergent Adverse Events (TEAEs) including Treatment Emergent Serious Adverse Events (TESAEs)
timeFrame: Up to 30 days after last study intervention administration
measure: Frequency of Dose limiting toxicities (DLTs) at each dose level during dose escalation of BAY1895344
timeFrame: Cycle 1 (21 days)
measure: Recommended phase II dose (RP2D) of BAY1895344
timeFrame: Up to 24 months
Secondary outcomes:
measure: Cmax of Elimusertib
timeFrame: Cycle 1 (21 days), Day 8 (dosing schedule 1) or Cycle 1 (21 days), Day 1 (dosing schedule 2)
measure: AUC(0-12) of Elimusertib
timeFrame: Cycle 1 (21 days), Day 8 (dosing schedule 1) or Cycle 1 (21 days), Day 1 (dosing schedule 2)
measure: Cmax,md of Elimusertib
timeFrame: Cycle 1 (21 days), Day 17 (dosing schedule 1) or Cycle 1 (21 days), Day 10 (dosing schedule 2)
measure: AUC(0-12)md of Elimusertib
timeFrame: Cycle 1 (21 days), Day 17 (dosing schedule 1) or Cycle 1 (21 days), Day 10 (dosing schedule 2)
measure: Incidence of Complete response (CR)
timeFrame: Up to 24 months
measure: Incidence of partial response (PR)
timeFrame: Up to 24 months
measure: Incidence of stable disease (SD)
timeFrame: Up to 24 months
measure: Incidence of progressive disease (PD)
timeFrame: Up to 24 months
measure: Objective Response Rate (ORR)
timeFrame: Up to 24 months
measure: Disease control rate (DCR)
timeFrame: Up to 24 months
Other outcomes:
Locations:
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Baltimore
country: United States
facility: Johns Hopkins Hospital/Health System
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Charlotte
country: United States
facility: Levine Cancer Institute
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
state: Baden-Württemberg
city: Tübingen
country: Germany
facility: Eberhard-Karls-Universität Tübingen
state: Baden-Württemberg
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz (Clinica de la Concepcion)
city: Madrid
country: Spain
facility: Hospital Madrid Norte Sanchinarro
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
state: Sankt Gallen
city: Bellinzona
country: Switzerland
facility: Ospedale Regionale di Bellinzona e Valli
state: Ticino
city: Sutton
country: United Kingdom
facility: Royal Marsden NHS Trust (Surrey)
state: Surrey
city: Newcastle
country: United Kingdom
facility: Freeman Hospital
state: Tyne And Wear
Study officials:
References: