Trial Condition(s):

Advanced solid tumor, Non-Hodgkin’s lymphoma, Mantle cell lymphoma

First-in-human study of ATR inhibitor BAY1895344 in patients with advanced solid tumors and lymphomas

Bayer Identifier:

18594

ClinicalTrials.gov Identifier:

NCT03188965

EudraCT Number:

2016-004484-39

Recruiting

Trial Purpose

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.

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.
- 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).

Trial Summary

Enrollment Goal
239
Trial Dates
black-arrow
Phase
1
Could I receive a placebo?
No
Products
Elimusertib (BAY1895344)
Accepts Healthy Volunteers
No

Where to Participate

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Locations
Status
LocationsStatus
Locations

National University Hospital

Singapore, Singapore, 119228

Status
Recruiting
 
Locations

University of Texas MD Anderson Cancer Center

Houston, United States, 77030-4009

Status
Active, not recruiting
 
Locations

Royal Marsden NHS Trust (Surrey)

Sutton, United Kingdom, SM2 5PT

Status
Active, not recruiting
 
Locations

Freeman Hospital

Newcastle Upon Tyne, United Kingdom, NE7 7DN

Status
Active, not recruiting
 
Locations

Kantonsspital St. Gallen

St. Gallen, Switzerland, 9007

Status
Completed
 
Locations

Oncology Institute of Southern Switzerland

Bellinzona, Switzerland, 6500

Status
Recruiting
 
Locations

Hôpital Cantonal Universitaire de Genève

Genève, Switzerland, 1205

Status
Completed
 
Locations

National Cancer Center Singapore

Singapore, Singapore, 169610

Status
Recruiting
 
Locations

Fairfax-Northern Virginia Hematology/Oncology, PC

Fairfax, United States, 22031

Status
Completed
 
Locations

Emory University

Atlanta, United States, 30322

Status
Completed
 
Locations

Weill Cornell Medical College

New York, United States, 10021

Status
Completed
 
Locations

University of Utah - Oncology

Salt Lake City, United States, 84112

Status
Completed
 
Locations

University Hospitals Cleveland Medical Center

Cleveland, United States, 44106

Status
Completed
 
Locations

H. Lee Moffitt Cancer Center & Research Institute

Tampa, United States, 33612

Status
Active, not recruiting
 
Locations

Gabrail Cancer Center

Canton, United States, 44718

Status
Completed
 
Locations

Jefferson Medical College

Philadelphia, United States, 19107

Status
Completed
 
Locations

National Cancer Center Hospital

Chuo-ku, Japan, 104-0045

Status
Completed
 
Locations

Shizuoka Cancer Center

Sunto, Japan, 411-8777

Status
Completed
 
Locations

National Cancer Center Hospital East

Kashiwa, Japan, 277-8577

Status
Recruiting
 
Locations

Velindre Hospital

Cardiff, United Kingdom, CF14 2TL

Status
Completed
 
Locations

Cross Cancer Institute

Edmonton, Canada, T6G 1Z2

Status
Recruiting
 
Locations

Integrated Cancer Center of the CHU de Québec

QUEBEC, Canada, G1J 1Z4

Status
Completed
 
Locations

OHRI - The Ottawa Hospital

Ottawa, Canada, K1H 8L6

Status
Completed
 
Locations

Dana-Farber Cancer Institute

Boston, United States, 02215

Status
Active, not recruiting
 
Locations

Beijing Cancer Hospital

Beijing, China, 100142

Status
Completed
 
Locations

Texas Oncology- San Antonio Northeast

San Antonio, United States, 78217

Status
Completed
 
Locations

Massachusetts General Hospital

Boston, United States, 02114-2696

Status
Completed
 
Locations

US Oncology / Eugene

Eugene, United States, 97401

Status
Completed
 
Locations

City of Hope National Medical Center

Duarte, United States, 91010

Status
Completed
 

Trial Design