ATR Inhibitor Elimusertib (BAY1895344) Plus Niraparib Phase 1b Study in Advanced Solid Tumors and Ovarian Cancer

• ClinicalTrials.gov Identifier: NCT04267939
• Recruitment Status: Terminated
• First Posted: February 13, 2020
• Last Update Posted: December 21, 2023
• Sponsor: Bayer
• Collaborator: GlaxoSmithKline
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: February 11, 2020
• First Posted Date: February 13, 2020
• Last Update Posted Date: December 21, 2023
• Actual Study Start Date: February 26, 2020
• Actual Primary Completion Date: December 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 24, 2022)

• Incidence of treatment emergent adverse events (TEAEs) [ Time Frame: Up to 30 days after the last administration of study intervention ]
• Severity of treatment emergent adverse events (TEAEs) [ Time Frame: Up to 30 days after the last administration of study intervention ]
• Incidence of treatment emergent serious adverse events (TESAEs) [ Time Frame: Up to 30 days after the last administration of study intervention ]
• Severity of treatment emergent serious adverse events (TESAEs) [ Time Frame: Up to 30 days after the last administration of study intervention ]
• Maximum tolerated dose (MTD): Frequency of Dose Limiting Toxicities (DLTs) at each dose level during the DLT observation period for Cycle 1 [ Time Frame: Cycle 1, 28 days after first administration of study intervention ]
• Recommended Phase II dose (RP2D) of elimusertib [ Time Frame: Up to 30 days after last administration of study Intervention ]

Original Primary Outcome Measures (submitted: February 11, 2020)

• Maximum tolerated dose (MTD) and / or recommended Phase II dose (RP2D) of BAY1895344 [ Time Frame: Up to 28 days after last administration of study Intervention ]
  The MTD is defined as the highest dose level that can be given so that the toxicity probability is closest to the target toxicity PT=30% or as the maximum tested dose, whichever is achieved first during Cycle 1. Estimation of the MTD will be based on the estimation of the observed dose-dependent incidence rate of DLT in Cycle 1.
• Incidence of treatment emergent adverse events (TEAEs) [ Time Frame: Up to 28 days after the last administration of study intervention ]
• Severity of treatment emergent adverse events (TEAEs) [ Time Frame: Up to 28 days after the last administration of study intervention ]
• Incidence of treatment emergent serious adverse events (TESAEs) [ Time Frame: Up to 28 days after the last administration of study intervention ]
• Severity of treatment emergent serious adverse events (TESAEs) [ Time Frame: Up to 28 days after the last administration of study intervention ]
• Frequency of Dose Limiting Toxicities at each dose level during the DLT observation period for Cycle 1 [ Time Frame: 28 days after first administration of study intervention (Cycle 1) ]
  Maximum tolerated dose (MTD)

Current Secondary Outcome Measures (submitted: August 24, 2022)

• Incidence of participants with complete response (CR) [ Time Frame: At baseline and at the start of every 2nd cycle (each cycle is 28 days) starting with Cycle 3, and at the start of every 4th cycle after Cycle 11 up to 24 months. ]
• Incidence of participants with partial response (PR) [ Time Frame: At baseline and at the start of every 2nd cycle (each cycle is 28 days) starting with Cycle 3, and at the start of every 4th cycle after Cycle 11 up to 24 months. ]
• Incidence of participants with stable disease (SD) [ Time Frame: At baseline and at the start of every 2nd cycle (each cycle is 28 days) starting with Cycle 3, and at the start of every 4th cycle after Cycle 11 up to 24 months. ]
• Incidence of participants with progressive disease (PD) [ Time Frame: At baseline and at the start of every 2nd cycle (each cycle is 28 days) starting with Cycle 3, and at the start of every 4th cycle after Cycle 11 up to 24 months. ]
• Objective response rate (ORR) [ Time Frame: At baseline and at the start of every 2nd cycle (each cycle is 28 days) starting with Cycle 3, and at the start of every 4th cycle after Cycle 11 up to 24 months. ]
• Disease control rate (DCR) [ Time Frame: At baseline and at the start of every 2nd cycle (each cycle is 28 days) starting with Cycle 3, and at the start of every 4th cycle after Cycle 11 up to 24 months. ]
• Cmax (Maximal plasma exposure) of elimusertib after single dose administration [ Time Frame: Cycle 1 Day 5 and Cycle 1 Day 21, each cycle is 28 days. ]
• AUC(0-8) of elimusertib after single dose administration [ Time Frame: Cycle 1 Day 5 and Cycle 1 Day 21, each cycle is 28 days. ]
• Cmax,md of elimusertib after multiple dose administration [ Time Frame: Cycle 1 Day 5 and Cycle 1 Day 21, each cycle is 28 days. ]
• AUC(0-8)md of elimusertib after multiple dose administration [ Time Frame: Cycle 1 Day 5 and Cycle 1 Day 21, each cycle is 28 days. ]
  AUC: Area under the curve

Original Secondary Outcome Measures (submitted: February 11, 2020)

• Incidence of participants with complete response (CR) [ Time Frame: Up to 24 months ]
• Incidence of participants with partial response (PR) [ Time Frame: Up to 24 months ]
• Incidence of participants with stable disease (SD) [ Time Frame: Up to 24 months ]
• Incidence of participants with progressive disease (PD) [ Time Frame: Up to 24 months ]
• Objective response rate (ORR) [ Time Frame: Up to 24 months ]
• Disease control rate (DCR) [ Time Frame: Up to 24 months ]
• Cmax (Maximal plasma exposure) of BAY1895344 after single dose administration [ Time Frame: Pre-dose, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours post-dose on Cycle 1, Day 1 ]
• AUC(0-12) of BAY1895344 after single dose administration [ Time Frame: Pre-dose, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours post-dose on Cycle 1, Day 1 ]
• Cmax,md of BAY1895344 after multiple dose administration [ Time Frame: Pre-dose, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours post-dose on Cycle 1, Day 17 ]
• AUC(0-12)md of BAY1895344 after multiple dose administration [ Time Frame: Pre-dose, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours post-dose on Cycle 1, Day 17 ]
  AUC: Area under the curve

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: ATR Inhibitor Elimusertib (BAY1895344) Plus Niraparib Phase 1b Study in Advanced Solid Tumors and Ovarian Cancer
• Official Title: An Open-label Phase 1b Study to Determine the Maximum Tolerated and/or Recommended Phase 2 Dose of the ATR Inhibitor Elimusertib (BAY 1895344) in Combination With PARP Inhibitor Niraparib, in Participants With Recurrent Advanced Solid Tumors and Ovarian Cancer
• Brief Summary: The purpose of the study is to test how well patients with advanced solid tumors and ovarian cancer respond to treatment with elimusertib in combination with niraparib. In addition researchers want to find for patients the optimal dose of elimusertib in combination with niraparib, 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 produced by the body (ATR Kinase) which is important for the growth of tumor cells. Niraparib works by blocking a substance produced by the body (PARP enzymes) in a way that tumor cells can be killed, or made more susceptible to chemotherapy.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Other

Condition

• Advanced Solid Tumors (Excluding Prostate Cancer)
• Ovarian Cancer

Intervention

• Drug: Elimusertib (BAY1895344)
  Elimusertib will be administered in 28-day cycles.
• Drug: Niraparib
  Niraparib will be administered in 28-day cycles.

Study Arms

• Experimental: Dose escalation of elimusertib_Part A.1
  Dose escalation will initiate with Part A.1 in which niraparib is used at a lower fixed dose.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Niraparib
• Experimental: Dose escalation of elimusertib_Part A.2
  If the starting dose level in Part A.1 is tolerated, dose escalation in Part A.2 may be initiated on an optional basis. In Part A.2, niraparib is used at a higher fixed dose.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Niraparib
• Experimental: Dose expansion_sub-population 1_lower dose of niraparib

  MTDs and/or candidate RP2Ds for elimusertib used in combination with niraparib at a lower fixed dose.

  MTD: Maximum tolerated dose. RP2D: Recommended phase 2 dose.

  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Niraparib
• Experimental: Dose expansion_sub-population 2_lower dose of niraparib
  MTDs and/or candidate RP2Ds for elimusertib used in combination with niraparib at a lower fixed dose.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Niraparib
• Experimental: Dose expansion_sub-population 1_higher dose of niraparib
  MTDs and/or candidate RP2Ds for elimusertib used in combination with niraparib at a higher fixed dose.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Niraparib
• Experimental: Dose expansion_sub-population 2_higher dose of niraparib
  MTDs and/or candidate RP2Ds for elimusertib used in combination with niraparib at a higher fixed dose.
  Interventions:

  • Drug: Elimusertib (BAY1895344)
  • Drug: Niraparib

• Publications *: Smith G, Alholm Z, Coleman RL, Monk BJ. DNA Damage Repair Inhibitors-Combination Therapies. Cancer J. 2021 Nov-Dec 01;27(6):501-505. doi: 10.1097/PPO.0000000000000561.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: October 11, 2023): 14
• Original Estimated Enrollment (submitted: February 11, 2020): 56
• Actual Study Completion Date: December 1, 2023
• Actual Primary Completion Date: December 1, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participant must be ≥ 18 years of age, at the time of signing the informed consent.

• Participants must have histologically confirmed diagnosis of the following indications as described below:

  • Dose escalation (Part A): recurrent advanced solid tumors, excluding prostate cancer, who experienced disease progression after treatment with standard of care therapy for metastatic disease.

  • Dose expansion (Part B): recurrent EOC, fallopian tube or primary peritoneal cancer

    • Sub-population 1: participants PARPi naïve and with a platinum-resistant/refractory disease (recurrence with a PFI < 6 months from last platinum-based regimen). Participants may not have had more than 3 prior therapies since the development of platinum resistance.
    • Sub-population 2: participants with disease progression on PARPi (including niraparib), administered as maintenance as well active line of therapy. Participants must have not received further line of therapy after disease progression on PARPi.

• Participants in dose escalation (Part A) of the study will need to have tumor-associated DDR deficiency and/or CCNE1 gene amplification.

  -- A homozygous deletion and/or a deleterious mutation in a gene reported to be involved in DNA repair and/or sensitive to ATRi's and/or PARPi's.

• Participants in dose expansion (Part B) of the study will need to have tumor associated DDR deficiency (Sub-population 1). Participants in Part B (Sub-population 2) are not enrolled based on the presence or absence of a particular biomarker.
• Participants must have disease progression and measurable disease, as defined by RECIST 1.1.
• Available archival tumor tissue ≤ 12 months old, otherwise a fresh baseline tumor biopsy should be obtained.
• ECOG PS of 0 to 1
• Life expectancy of at least 12 weeks

• Adequate bone marrow function as assessed by the following laboratory tests to be conducted within 7 (±2) days before the first dose of study intervention:

  • Hemoglobin (Hb) ≥ 10 g/dL
  • Platelet count ≥ 150 x 10^9/L
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
• Participants must have adequate organ function.
• Participants must have adequate coagulation.
• Adequate cardiac function per institutional normal measured by echocardiography (recommended) or cardiac MRI per institutional guidelines.
• A female participant is eligible to participate if she is not pregnant (confirmed by a negative serum pregnancy test within 7 (±2) days of first study intervention), not breastfeeding, or is not a woman of childbearing potential (WOCBP). WOCBP must agree to use highly effective contraception during the intervention period and for at least 6 months (180 days) after the last dose of study intervention.

Exclusion Criteria:

• Inability to swallow oral medication
• Known hypersensitivity to elimusertib and/or niraparib or excipients of the preparations or any agent given in association with this study
• History of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) diagnosis
• Ongoing or active uncontrolled infection (bacterial, fungal, or viral; e.g. hepatitis viral) of CTCAE grade ≥ 2 that requires systemic treatment
• Participants with HIV may be be ineligible depending on various parameters, but are not automatically excluded.
• Immunocompromised participants (e.g. diagnosis of immunodeficiency or ongoing immunosuppressive therapy)
• Pleural effusion or ascites that causes respiratory compromise (CTCAE grade ≥ 2 dyspnea)
• Active HBV or HCV infection that requires treatment.
• Moderate or severe hepatic impairment, i.e. Child Pugh Class B or C

• Participants with significant cardiovascular disease and/or relevant findings meeting the below criteria are excluded:

  • History of cardiac disease: congestive heart failure 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).
  • Clinically relevant findings in the ECG such as a second- or third-degree atrioventricular block, prolongation of the QRS complex ≥ 120 ms, or prolongation of the of the QTc interval (Fridericia) over 450 ms unless agreed otherwise between the investigator and the sponsor's medically responsible person. QTc > 450 ms detected in 2 or more time points within a 24-hour period are excluded.
  • Clinically significant arterial hypertension despite optimal medical management (per investigator´s opinion). Clinically significant hypertension defined as systolic blood pressure above 150 mmHg and/or diastolic blood pressure above 90 mmHg, despite optimal medical management. For participants taking antihypertensive medication, blood pressure should be stable/ controlled for more than 7 days before first dose of study medication.
• Previous treatment with an ATR Inhibitor
• Participants in Part A and Part B (Sub-population 2): Previous treatment with known or putative PARPi, if discontinued for CTCAE grade ≥ 3 AEs or CTCAE grade ≥ 3 hypersensitivity to PARPi. Participants in Part B Sub-population 1 must not have received prior PARPi treatment.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States
• Removed Location Countries: Switzerland

Administrative Information

• NCT Number: NCT04267939
• Other Study ID Numbers: 18595; 2018-003930-34 ( 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

• Plan to Share IPD: No

Plan Description

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

• Current Responsible Party: Bayer
• Original Responsible Party: Same as current
• Current Study Sponsor: Bayer
• Original Study Sponsor: Same as current
• Collaborators: GlaxoSmithKline

Investigators

• Study Director: Bayer Study Director; Bayer

• PRS Account: Bayer
• Verification Date: December 2023