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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03188965
Recruitment Status : Recruiting
First Posted : June 16, 2017
Last Update Posted : July 16, 2020
Sponsor:
Information provided by (Responsible Party):
Bayer

Tracking Information
First Submitted Date  ICMJE June 14, 2017
First Posted Date  ICMJE June 16, 2017
Last Update Posted Date July 16, 2020
Actual Study Start Date  ICMJE July 6, 2017
Estimated Primary Completion Date February 25, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 27, 2019)
  • The maximum tolerated dose (MTD) and / or recommended Phase II dose (RP2D) of BAY1895344 [ Time Frame: Up to 6 months, minimum: 1 cycle (= 21days) ]
    Dose-escalation cohort during 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 in the dose-escalation cohorts during Part A of the study.
  • Incidence of DLTs during Cycle 1 in dose-escalation cohorts during Part A of the study [ Time Frame: During cycle 1, 1 cycle=21 days ]
  • Incidence of DLTs during Cycle 1 in dose-escalation cohorts during Part A.1 of the study [ Time Frame: During cycle 1, 1 cycle=28 days ]
  • Incidence of DLTs during Cycle 1 in dose-escalation cohorts during J-arm of the study [ Time Frame: During cycle 1, 1 cycle=21 days ]
  • The incidence of serious and nonserious treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 30 days after end of treatment ]
  • AUC (area under the plasma concentration of BAY1895344 vs. time curve) from zero to 12 hours after single-dose (C1D1) and multiple-dose administrations (C1D10) [ Time Frame: At day 1 and day 10 of first cycle ]
    In Part A, A.1, J-arm of Part A and Part B. Analysis of drug exposure and pharmacokinetic parameters in patients over a course of time
  • Cmax of BAY1895344 in cycle 1 after single-dose (C1D1) and multiple-dose administrations (C1D10) [ Time Frame: At day 1 and day 10 of first cycle ]
    In Part A, A.1, J-arm of Part A and Part B. To support profiling pharmacokinetic of study drug in patients
Original Primary Outcome Measures  ICMJE
 (submitted: June 14, 2017)
  • The maximum tolerated dose (MTD) and / or recommended Phase II dose (RP2D) of BAY1895344 [ Time Frame: Up to 6 months, minimum: 1 cycle (= 21days) ]
    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 in the dose-escalation cohorts during Part A of the study.
  • The incidence of serious and nonserious treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 23 months, minimum: 1 cycle (=21days) ]
    Assessment of safety parameters (such as ECG, vital signs… etc.) which is deemed relating to study drug.
  • AUC (area under the plasma concentration of BAY1895344 vs. time curve) from zero to 12 hours after single (first) dose of BAY1895344 [ Time Frame: At day 1 and day 10 of first cycle ]
    Analysis of drug exposure and pharmacokinetic parameters in patients over a course of time
  • Cmax of BAY1895344 in cycle 1 after single-dose (C1D1) and multiple-dose administrations (C1D10) [ Time Frame: At day 1 and day 10 of first cycle ]
    To support profiling pharmacokinetic of study drug in patients
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 27, 2019)
  • Incidence of patients with CR, PR, SD or PD (except for patients with castration resistant prostate cancer) consistent with the RECIST 1.1 criteria [ Time Frame: Through study completion, an average of 4 months ]
    CR (complete response) PR (partial response) SD (stable disease) PD (progressive disease) RECIST (Response Evaluation Criteria in Solid Tumors)
  • Incidence of lymphoma patients with CR, PR, SD or PD consistent with the Lugano Classification [ Time Frame: Through study completion, an average of 4 months ]
    CR (complete response) PR (partial response) SD (stable disease) PD (progressive disease)
  • Incidence of castration resistant prostate cancer patients with CR, PR, SD or PD consistent with the recommendations of the Prostate Cancer Working Group 3 (PCWG3) [ Time Frame: Through study completion, an average of 4 months ]
    CR (complete response) PR (partial response) SD (stable disease) PD (progressive disease)
Original Secondary Outcome Measures  ICMJE
 (submitted: June 14, 2017)
  • Incidence of patients with CR, PR, SD or PD (except for patients with castration resistant prostate cancer) consistent with the RECIST 1.1 criteria [ Time Frame: Up to 23 months or until discontinuation of study, whichever comes first ]
    CR (complete response) PR (partial response) SD (stable disease) PD (progressive disease) RECIST (Response Evaluation Criteria in Solid Tumors)
  • Incidence of lymphoma patients with CR, PR, SD or PD consistent with the Lugano Classification [ Time Frame: Up to 23 months or until discontinuation of study, whichever comes first ]
    CR (complete response) PR (partial response) SD (stable disease) PD (progressive disease)
  • Incidence of castration resistant prostate cancer patients with CR, PR, SD or PD consistent with the recommendations of the Prostate Cancer Working Group 3 (PCWG3) [ Time Frame: Up to 23 months or until discontinuation of study, whichever comes first ]
    CR (complete response) PR (partial response) SD (stable disease) PD (progressive disease)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE First-in-human Study of ATR Inhibitor BAY1895344 in Patients With Advanced Solid Tumors and Lymphomas
Official Title  ICMJE 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
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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms
Intervention  ICMJE Drug: BAY1895344
Study drug will be administered as scheduled.
Study Arms  ICMJE
  • Experimental: Dose escalation of BAY1895344 in Part A
    Single-agent dose-escalation part. Part A has the objective to define the MTD and / or RP2D.
    Intervention: Drug: BAY1895344
  • Experimental: J-arm of Part A
    Single-agent dose-escalation part in Japanese patients. J-arm has the objective to confirm the MTD (or RP2D) dose is safe and tolerable in Japanese patients.
    Intervention: Drug: BAY1895344
  • Experimental: Dose expansion of BAY1895344 in Part B
    Single-agent expansion part. Once the MTD has been defined, safety, PK profile, PD of target engagement, and preliminary efficacy will be further evaluated in Part B of the study. Once the MTD dose has been confirmed is safe and tolerable in Japanese patients, safety, PK profile, PD of target engagement, and preliminary efficacy will be further evaluated in Part B of the study.
    Intervention: Drug: BAY1895344
  • Experimental: Part A.1: Single-agent dose escalation part
    Part A.1 - single-agent dose escalation part 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.
    Intervention: Drug: BAY1895344
Publications * Lücking U, Wortmann L, Wengner AM, Lefranc J, Lienau P, Briem H, Siemeister G, Bömer U, Denner K, Schäfer M, Koppitz M, Eis K, Bartels F, Bader B, Bone W, Moosmayer D, Holton SJ, Eberspächer 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 27, 2019)
276
Original Estimated Enrollment  ICMJE
 (submitted: June 14, 2017)
210
Estimated Study Completion Date  ICMJE March 25, 2022
Estimated Primary Completion Date February 25, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Part A - single-agent dose-escalation part:

- Patients with histologically confirmed solid tumors or non-Hodgkin's lymphoma (NHL).

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 (deoxyribonucleic acid damage repair) defects (such as ATM (ataxia-telangiectasia mutated) deleterious mutation or low ATM expression) can be included.

Part A.1 - single-agent dose escalation part 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.

Part B - single-agent expansion part:

  • Patients with DDR deficiency biomarker-positive advanced solid tumors of the following histologies: i) CRPC (castration-resistant prostate cancer); ii) HER2-negative BC that is hormone-receptor positive (estrogen-receptor positive, progesterone-receptor positive, or both) or TNBC (triple negative BC); iii) CRC (colorectal cancer), and iv) gynecological tumors (ovarian, primary peritoneal, and fallopian tube cancers, endometrial cancer, or cervical cancer).
  • 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.
  • Patients with histologically confirmed advanced cancer, regardless of the cancer type, or NHL and loss of ATM protein by IHC.

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.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
  • 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:

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):

  1. Hemoglobin ≥ 9 g/dL; patients with chronic erythropoietin treatment consistent with institutional guidelines can be included.
  2. Absolute neutrophil count (ANC) ≥ 1.5X10* 9/L (≥ 1500/mm*3)
  3. Platelet count ≥ 100X10*9/L (≥100,000/mm*3)

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
  • Patients with known human immunodeficiency virus (HIV) infection
  • 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 CTCAE(Common Terminology Criteria for Adverse Events Version) Grade 2 not responding to therapy or active clinically serious infections of CTCAE Grade >2
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Bayer Clinical Trials Contact (+) 1-888-8422937 clinical-trials-contact@bayer.com
Listed Location Countries  ICMJE Canada,   China,   France,   Germany,   Japan,   Singapore,   Switzerland,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03188965
Other Study ID Numbers  ICMJE 18594
2016-004484-39 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Bayer
Study Sponsor  ICMJE Bayer
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Bayer Study Director Bayer
PRS Account Bayer
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP