First-in-human Study of ATR Inhibitor BAY1895344 in Patients With Advanced Solid Tumors and Lymphomas

Advanced Solid Tumor Clinical Trial

Official title:

An Open-label, First-in-human, Dose-escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Maximum Tolerated Dose and / or Recommended Phase II Dose of the ATR Inhibitor BAY1895344 in Patients With Advanced Solid Tumors and Lymphomas

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03188965
• Other study ID #: 18594
• Secondary ID: 2016-004484-39
• Status: Completed
• Phase: Phase 1
• Start date: July 6, 2017
• Est. completion date: September 13, 2023

Study information

• Verified date: October 2023
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The ATR (ataxia-telangiectasia and Rad3 related protein) inhibitor BAY1895344 is developed for the treatment of patients with advanced solid tumors and lymphomas. The purpose of the proposed trial is to evaluate the safety and tolerability of BAY1895344, and to identify the maximum tolerated dose of BAY1895344 that could be safely given to cancer patients. Further, the response of the cancer to the treatment will be determined.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 229
• Est. completion date: September 13, 2023
• Est. primary completion date: December 2, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Part A - single-agent dose-escalation:

• Patients with histologically confirmed solid tumors or NHL. Patients with tumors known to be positive for deoxyribonucleic acid damage repair (DDR) defects (such as ataxia-telangiectasia mutated [ATM] deleterious mutation or low ATM expression) can be included.

J-arm of Part A - single-agent dose-escalation in Japanese:

• Japanese patients with histologically confirmed solid tumors. Patients with tumors known to be positive for DDR defects (such as ATM deleterious mutation or low ATM expression) can be included.

Part A.1 - single-agent dose-escalation with alternative dosing schedule:

• Patients with histologically confirmed solid tumors or NHL known to be positive for ATM loss and/or ATM deleterious mutations will be included. The biomarker status of patients in Part A.1 will be evaluated before general screening and only patients with the presence of the putative biomarkers of DDR deficiency will be recruited into general screening.

Part B - single-agent expansion:

• Patients with DDR deficiency biomarker-positive advanced solid tumors of the following histologies: i) CRPC; ii) HER2-negative BC that is hormone-receptor positive (estrogen-receptor positive, progesterone-receptor positive, or both) or TNBC; iii) CRC, and iv) gynecological tumors (ovarian, primary peritoneal, and fallopian tube cancers, endometrial cancer, or cervical cancer).
• Patients with histologically confirmed advanced solid cancer, regardless of the cancer type, or NHL and loss of ATM protein by IHC.
• The biomarker status of patients in Part B will be evaluated before general screening and only patients with the presence of the putative biomarkers of DDR deficiency will be recruited into general screening.

Part A.1 And Part B:

• Patients must be able to provide either samples of archival tumor tissue not older than 6 months or a fresh tumor biopsy during general screening.

Part B.1 - single-agent expansion with alternative dosing schedule:

• Patients with histologically confirmed R/R MCL. These patients do not undergo biomarker testing to determine eligibility. The provision of baseline tumor tissue (archival or fresh) is strongly encouraged. If archival tissue = 6 months old is unavailable, a fresh baseline biopsy may be obtained if safe and feasible.

The following inclusion criteria apply to ALL (dose-escalation and expansion) patients:

• Patients with tumors resistant or refractory to standard treatment and in which, in the opinion of the investigator, experimental treatment with BAY1895344 may be of benefit. Furthermore, no standard therapy would confer clinical benefit to the patient. Patients in the MCL cohort of Part B.1 are to be relapsed or refractory to standard treatments.
• Patients must have measurable disease (as per Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1] or the Lugano classification as applicable, with the exception of prostate cancer patients who must have measurable or evaluable disease per the recommendations of the Prostate Cancer Clinical Trial Working Group 3 [PCWG3]).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. For MCL patients: ECOG of 0 to 2.
• Patients must have adequate bone marrow function as assessed by the following laboratory tests to be conducted within 7 (+2) days before the first dose of study drug. Note that the below values are to be independent of red blood cell transfusions or granulocytes colony-stimulating factor (G-CSF) (i.e., no red blood cell or platelets transfusion within 28 days prior to the screening complete blood count [CBC] result, or administration of G-CSF is to occur within 14 days prior to the CBC result). Requirements for MCL patients are indicated below.
• a. Hemoglobin = 9 g/dL. Patients with chronic erythropoietin treatment consistent with institutional guidelines can be included. For MCL patients: = 8 g/dL; red blood cell transfusions during the screening period are allowed, and patients with chronic erythropoietin treatment consistent with institutional guidelines can be included
• b. Absolute neutrophil count (ANC) = 1.5 X 10^9/L (= 1500/mm^3). For MCL patients: ANC = 1.0 X 10^9/L. Patients with ANC = 1.0 X 10^9/L due to marrow infiltration may receive G-CSF during screening to bring pretreatment ANC levels to = 1.0 X 10^9/L
• c. Platelet count = 100 X 10^9/L (=100,000/mm^3). For MCL patients: = 75 X 10^9/L

Exclusion Criteria:

• Known hypersensitivity to the study drugs or excipients of the preparations or any agent given in association with this study
• 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)
• Moderate or severe hepatic impairment, i.e. Child-Pugh class B or C
• Known human immunodeficiency virus (HIV)-infected persons are not eligible if any of

the following criteria apply:

• CD4+ T-cell count less than 350 cells/µL
• History of AIDS-defining opportunistic infection within the past 12 months
• On established antiretroviral therapy (ART) for less than 4 weeks or presenting with a viral load of more than 400 copies/mL prior to enrollment
• On ART or prophylactic antimicrobials that are expected to cause significant drug-drug interactions or overlapping toxicities with study intervention
• Patients who have an active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection requiring treatment. Patients with chronic HBV or HCV infection are eligible at the investigator's discretion provided that the disease is stable and sufficiently controlled under treatment.
• Infections of Common Terminology Criteria for Adverse Events Version (CTCAE) Grade 2 not responding to therapy or active clinically serious infections of CTCAE Grade > 2
• Metastatic solid brain, spinal, or meningeal tumors or central nervous system (CNS) lymphoma manifestations (including meningeosis lymphomatosa and parenchymal lymphoma lesions) unless the patient is > 3 months from definitive therapy, has a stable imaging study within 4 weeks prior to the first dose of study drug and is clinically stable with respect to the tumor at the time of study entry. Patients with asymptomatic brain metastases must not be on steroid therapy. Patients with neurological symptoms should undergo a CT / MRI scan of the brain or spinal column to exclude new or progressive brain, meningeal, or spinal metastases or CNS lymphoma manifestations.
• History of organ allograft transplantation. For MCL patients: Those who received an allogeneic stem cell transplant may participate provided that engraftment has occurred, there is no evidence of GVHD, and the patient is not taking immune suppressants. MCL patients who received an autologous stem cell transplant may participate once they have recovered from the procedure.
• Treatment with anticancer chemotherapy or immunotherapy during the study or within 3 weeks before the first dose of study drug. For small-molecule drugs, a period of at least 3 half-lives before the first dose of study drug is acceptable. Mitomycin C or nitrosoureas should not be given within 6 weeks before the first dose of study drug.
• Treatment with systemic steroids (methylprednisolone dose =10 mg/day or equivalent dose). For MCL patients: Treatment with systemic corticosteroids > 20 mg/day prednisone equivalent (unless patient has been taking a stable dose for >3 weeks and has shown tumor progression).

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Lymphoma
• Lymphoma, Mantle-Cell
• Mantle Cell Lymphoma
• Non-Hodgkin's Lymphoma

Intervention

Drug:
• Elimusertib (BAY1895344)
Solution or tablet, oral, to be administered until evidence of tumor progression, unacceptable toxicity, consent withdrawal, or withdrawal from the study at the discretion of the investigator.

Locations

Country	Name	City	State
Canada	Cross Cancer Institute	Edmonton	Alberta
Canada	OHRI - The Ottawa Hospital	Ottawa	Ontario
Canada	Integrated Cancer Center of the CHU de Québec	Quebec
China	Beijing Cancer Hospital	Beijing
Japan	National Cancer Center Hospital	Chuo-ku	Tokyo
Japan	National Cancer Center Hospital East	Kashiwa	Chiba
Japan	Shizuoka Cancer Center	Sunto	Shizuoka
Singapore	National Cancer Center Singapore	Singapore
Singapore	National University Hospital	Singapore
Switzerland	Oncology Institute of Southern Switzerland	Bellinzona
Switzerland	Hôpital Cantonal Universitaire de Genève	Geneva	Genève
Switzerland	Kantonsspital St. Gallen	St. Gallen	Sankt Gallen
United Kingdom	Velindre Hospital	Cardiff	South Glamorgan
United Kingdom	Freeman Hospital	Newcastle Upon Tyne	Tyne And Wear
United Kingdom	Royal Marsden NHS Trust (Surrey)	Sutton	Surrey
United States	Emory University	Atlanta	Georgia
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Gabrail Cancer Center	Canton	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	City of Hope National Medical Center	Duarte	California
United States	US Oncology / Eugene	Eugene	Oregon
United States	Fairfax-Northern Virginia Hematology/Oncology, PC	Fairfax	Virginia
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	Weill Cornell Medical College	New York	New York
United States	Jefferson Medical College	Philadelphia	Pennsylvania
United States	University of Utah - Oncology	Salt Lake City	Utah
United States	Texas Oncology- San Antonio Northeast	San Antonio	Texas
United States	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Canada,  China,  Japan,  Singapore,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The maximum tolerated dose (MTD) and / or recommended Phase II dose (RP2D) of BAY1895344	MTD and/or R2PD will be determined in Cycle 1 of Part A, Part A.1 and J-arm of Part A.; The MTD is defined as the maximum dose at which the incidence of dose-limiting toxicities (DLTs) during Cycle 1 is below 30%, or the maximum dose tested, whichever is achieved first during dose-escalation.	Up to 6 months, minimum: 1 cycle (= 21days)
Primary	Incidence of DLTs during Cycle 1 in dose-escalation cohorts during Part A of the study		During Cycle 1, 1 cycle=21 days
Primary	Incidence of DLTs during Cycle 1 in dose-escalation cohorts during Part A.1 of the study		During Cycle 1, 1 cycle=28 days
Primary	Incidence of DLTs during Cycle 1 in dose-escalation cohorts during J-arm of the study		During Cycle 1, 1 cycle=21 days
Primary	The incidence of serious and nonserious treatment-emergent adverse events (TEAEs)		After first administration of study drug up to 30 days after the last dose of study drug
Primary	Area under the plasma concentration of BAY1895344 vs. time curve from zero to 12 hours after single-dose (AUC[0-12]) and multiple-dose administrations (AUC[0-12]md) in Cycle 1	AUC(0-12) and AUC(0-12)md will be evaluated in Part A, A.1 and J-arm of Part A.	Pre-dose and up to 12 hours post-dose at Day 1 of Cycle 1 and Day 10 (Part A and J-arm) or Day 17 (Part A.1) of Cycle 1
Primary	Maximum observed drug concentration in plasma of BAY1895344 after single-dose (Cmax) and multiple-dose administrations (Cmax,md) in Cycle 1	Cmax and Cmax,md will be evaluated in Part A, A.1 and J-arm of Part A.	Pre-dose and up to 12 hours post-dose at Day 1 of Cycle 1 and Day 10 (Part A and J-arm) or Day 17 (Part A.1) of Cycle 1
Secondary	Incidence of solid tumor responses (except CRPC) consistent with the RECIST 1.1 criteria	Responses include: CR (complete response), PR (partial response), SD (stable disease), PD (progressive disease). CRPC: castration resistant prostate cancer; RECIST: Response Evaluation Criteria in Solid Tumors	Through study completion, an average of 4 months
Secondary	Incidence of lymphoma responses consistent with the Lugano Classification	Responses include: CR (complete response), PR (partial response), SD (stable disease), PD (progressive disease).	Through study completion, an average of 4 months
Secondary	Incidence of CRPC tumor responses consistent with the recommendations of the PCWG3	Responses include: CR (complete response), PR (partial response), SD (stable disease), PD (progressive disease).; PCWG3: Prostate Cancer Working Group 3	Through study completion, an average of 4 months

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