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

NCT03188965 | Completed Phase 1 FDA Drug

• 2 other identifiers: 185942016-004484-39
• Study Type: interventional
• Target: 229
• Locations: 7 countries
• Sites: 29

Brief 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.

Conditions

Advanced Solid Tumor; Non-Hodgkin's Lymphoma; Mantle Cell Lymphoma

Keywords

First in human; Solid tumors; Lymphomas; Dose escalation; Dose expansion

Outcome Measures

Primary Outcomes (7)

• 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)

• Incidence of DLTs during Cycle 1 in dose-escalation cohorts during Part A of the study

  During Cycle 1, 1 cycle=21 days

• Incidence of DLTs during Cycle 1 in dose-escalation cohorts during Part A.1 of the study

  During Cycle 1, 1 cycle=28 days

• Incidence of DLTs during Cycle 1 in dose-escalation cohorts during J-arm of the study

  During Cycle 1, 1 cycle=21 days

• 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

• 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

• 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 Outcomes (3)

• Incidence of solid tumor responses (except CRPC) consistent with the RECIST 1.1 criteria

  Through study completion, an average of 4 months

• Incidence of lymphoma responses consistent with the Lugano Classification

  Through study completion, an average of 4 months

• Incidence of CRPC tumor responses consistent with the recommendations of the PCWG3

  Through study completion, an average of 4 months

Study Arms (5)

Part A: single-agent dose-escalation

EXPERIMENTAL

Patients with histologically confirmed solid tumors or non-Hodgkin's lymphoma (NHL) receive BAY1895344 in a 21-day cycle.

Drug: Elimusertib (BAY1895344)

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

EXPERIMENTAL

Patients with histologically confirmed solid tumors or NHL known to be positive for ATM loss and/or ATM deleterious mutations receive BAY1895344 in a 28-day cycle.

Drug: Elimusertib (BAY1895344)

J-arm of Part A: dose escalation cohort in Japanese patients

EXPERIMENTAL

Japanese patients with histologically confirmed solid tumors receive BAY1895344 at two dose levels: MTD-1 and MTD.

Drug: Elimusertib (BAY1895344)

Part B: single-agent expansion

EXPERIMENTAL

Patients with a) DDR deficiency biomarker-positive advanced solid tumors: castration-resistant prostate cancer (CRPC), HER2-negative breast cancer (BC), colorectal cancer (CRC), and gynecological tumors; OR b) histologically confirmed advanced cancer and loss of ATM regardless of the cancer type receive BAY1895344 at MTD determined at the end of dose escalation.

Drug: Elimusertib (BAY1895344)

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

EXPERIMENTAL

Patients with histologically confirmed relapsed or refractory MCL receive BAY1895344 at a dose determined after evaluation of multiple BAY1895344 doses in Part A.1

Drug: Elimusertib (BAY1895344)

Interventions

Elimusertib (BAY1895344) DRUG

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.

J-arm of Part A: dose escalation cohort in Japanese patients; Part A.1: Single-agent dose escalation with alternative dosing schedule; Part A: single-agent dose-escalation; Part B.1: single-agent expansion with alternative dosing schedule; Part B: single-agent expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Bayer: lead

Study Sites (29)

City of Hope National Medical Center

Duarte, California, 91010, United States

Location

H. Lee Moffitt Cancer Center & Research Institute

Tampa, Florida, 33612, United States

Location

Emory University

Atlanta, Georgia, 30322, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114-2696, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Weill Cornell Medical College

New York, New York, 10021, United States

Location

Gabrail Cancer Center

Canton, Ohio, 44718, United States

Location

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

US Oncology / Eugene

Eugene, Oregon, 97401, United States

Location

Jefferson Medical College

Philadelphia, Pennsylvania, 19107, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030-4009, United States

Location

Texas Oncology- San Antonio Northeast

San Antonio, Texas, 78217, United States

Location

University of Utah - Oncology

Salt Lake City, Utah, 84112, United States

Location

Fairfax-Northern Virginia Hematology/Oncology, PC

Fairfax, Virginia, 22031, United States

Location

Cross Cancer Institute

Edmonton, Alberta, T6G 1Z2, Canada

Location

OHRI - The Ottawa Hospital

Ottawa, Ontario, K1H 8L6, Canada

Location

Integrated Cancer Center of the CHU de Québec

Québec, G1J 1Z4, Canada

Location

Beijing Cancer Hospital

Beijing, 100142, China

Location

National Cancer Center Hospital East

Kashiwa, Chiba, 277-8577, Japan

Location

Shizuoka Cancer Center

Sunto, Shizuoka, 411-8777, Japan

Location

National Cancer Center Hospital

Chuo-ku, Tokyo, 104-0045, Japan

Location

National University Hospital

Singapore, 119228, Singapore

Location

National Cancer Center Singapore

Singapore, 168583, Singapore

Location

Hôpital Cantonal Universitaire de Genève

Geneva, Canton of Geneva, 1205, Switzerland

Location

Kantonsspital St. Gallen

Sankt Gallen, Canton of St. Gallen, 1009, Switzerland

Location

Oncology Institute of Southern Switzerland

Bellinzona, 6500, Switzerland

Location

Velindre Hospital

Cardiff, South Glamorgan, CF14 2TL, United Kingdom

Location

Royal Marsden NHS Trust (Surrey)

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Freeman Hospital

Newcastle upon Tyne, Tyne and Wear, NE7 7DN, United Kingdom

Location

Related Publications (1)

• Lucking U, Wortmann L, Wengner AM, Lefranc J, Lienau P, Briem H, Siemeister G, Bomer U, Denner K, Schafer M, Koppitz M, Eis K, Bartels F, Bader B, Bone W, Moosmayer D, Holton SJ, Eberspacher U, Grudzinska-Goebel J, Schatz C, Deeg G, Mumberg D, von Nussbaum F. Damage Incorporated: Discovery of the Potent, Highly Selective, Orally Available ATR Inhibitor BAY 1895344 with Favorable Pharmacokinetic Properties and Promising Efficacy in Monotherapy and in Combination Treatments in Preclinical Tumor Models. J Med Chem. 2020 Jul 9;63(13):7293-7325. doi: 10.1021/acs.jmedchem.0c00369. Epub 2020 Jun 28.

  PMID: 32502336 DERIVED

Related Links

• Click here to find information for studies related to Bayer products. To find this study enter the ClinicalTrials.gov identifier (NCT) number or Bayer Study Identifier (ID) in the search field.

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin; Lymphoma, Mantle-Cell; Lymphoma

Interventions

BAY 1895344

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 14, 2017
• First Posted: June 16, 2017
• Study Start: July 6, 2017
• Primary Completion: December 2, 2022
• Study Completion: September 13, 2023
• Last Updated: October 11, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1); CH (3); CA (3); SG (2); US (14); JP (3); GB (3)