ATR Inhibitor BAY 1895344 Plus Niraparib Phase 1b Study in Advanced Solid Tumors and Ovarian Cancer
Study Details
Study Description
Brief Summary
The purpose of the study is to test how well patients with advanced solid tumors and ovarian cancer respond to treatment with BAY1895344 in combination with niraparib. In addition researchers want to find for patients the optimal dose of BAY1895344 in combination with niraparib, how the drug is tolerated and the way the body absorbs, distributes and discharges the drug. The study medication BAY1895344 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Dose escalation of BAY1895344 and fixed dose of Niraparib In participants with all solid tumor(excluding prostate cancer) and positive for DDR deficiency. DDR: DNA-Damage Repair |
Drug: BAY1895344
BAY1895344 will be administered BID (twice daily) in a 28 day-cycle.
Drug: Niraparib
Niraparib will be administered orally once daily continuously throughout the cycle.
|
| Experimental: Participants PARPi naïve Participants with ovarian cancer, PARPi naïve and with a platinum resistant/refractory disease and DDR deficiency. DDR: DNA-Damage Repair |
Drug: BAY1895344
BAY1895344 will be administered BID (twice daily) in a 28 day-cycle.
Drug: Niraparib
Niraparib will be administered orally once daily continuously throughout the cycle.
|
| Experimental: Participants with disease progression on PARPi Participants with ovarian cancer and disease progression on PARPi |
Drug: BAY1895344
BAY1895344 will be administered BID (twice daily) in a 28 day-cycle.
Drug: Niraparib
Niraparib will be administered orally once daily continuously throughout the cycle.
|
Outcome Measures
Primary Outcome Measures
- Maximum tolerated dose (MTD) and / or recommended Phase II dose (RP2D) of BAY1895344 [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) [Up to 28 days after the last administration of study intervention]
- Severity of treatment emergent adverse events (TEAEs) [Up to 28 days after the last administration of study intervention]
- Incidence of treatment emergent serious adverse events (TESAEs) [Up to 28 days after the last administration of study intervention]
- Severity of treatment emergent serious adverse events (TESAEs) [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 [28 days after first administration of study intervention (Cycle 1)]
Maximum tolerated dose (MTD)
Secondary Outcome Measures
- Incidence of participants with complete response (CR) [Up to 24 months]
- Incidence of participants with partial response (PR) [Up to 24 months]
- Incidence of participants with stable disease (SD) [Up to 24 months]
- Incidence of participants with progressive disease (PD) [Up to 24 months]
- Objective response rate (ORR) [Up to 24 months]
- Disease control rate (DCR) [Up to 24 months]
- Cmax (Maximal plasma exposure) of BAY1895344 after single dose administration [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 [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 [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 [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
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Participant must be ≥ 18 years of age, at the time of signing the informed consent.
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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 all available standard of care therapies for metastatic disease Participants must have DDR deficiency in their tumors. -- Dose expansion (Part B): recurrent EOC, fallopian tube or primary peritoneal cancer
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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.
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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.
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Participants in Part A and sub-population 1of part B of the study will need to have DDR deficiency in their tumors.Sub-population 2 of Part B will be BM unselected (BM analysis only retrospective).
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Participants must have disease progression and measurable disease, as defined by RECIST 1.1.
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Archival tissue must not be older than 12 months, otherwise fresh tumor tissue samples at baseline are mandatory.
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ECOG PS of 0 to 1
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Life expectancy of at least 12 weeks
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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:
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Hemoglobin (Hb) ≥ 10 g/dL
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Platelet count ≥ 150 x 109/L ( ≥150,000/mm*3)
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Absolute neutrophil count (ANC) ≥ 2.0 x 109/L ( ≥ 2000/mm*3)
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Participants must have adequate organ function.
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Participants must have adequate coagulation.
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Adequate cardiac function per institutional normal measured by echocardiography (recommended) or MUGA scan/cardiac MRI per institutional guidelines.
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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). Participants must agree to use highly effective contraception during the intervention period and for at least 6 months (180 days) after intervention
Exclusion Criteria:
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Inability to swallow oral medication
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Known hypersensitivity to BAY1895344 and/or niraparib or excipients of the preparations or any agent given in association with this study
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History of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) diagnosis
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Ongoing or active uncontrolled infection (bacterial, fungal, or viral; e.g. hepatitis viral) of CTCAE grade ≥ 2 that requires systemic treatment
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Known history of HIV infection (HIV 1/2 antibodies)
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Immunocompromised participants (e.g. diagnosis of immunodeficiency or ongoing immunosuppressive therapy)
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Pleural effusion or ascites that causes respiratory compromise (CTCAE grade ≥ 2 dyspnea)
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Active HBV or HCV infection that requires treatment.
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Moderate or severe hepatic impairment, i.e. Child Pugh Class B or C
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Participants with significant cardiovascular disease and/or relevant findings are excluded:
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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).
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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.
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Previous treatment with an ATR Inhibitor
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Previous treatment with known or putative PARPi, if discontinued for CTCAE grade ≥ 3 AEs or CTCAE grade ≥ 3 hypersensitivity to PARPi
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Dana-Farber Cancer Institute | Boston | Massachusetts | United States | 02215 |
| 2 | Memorial Sloan-Kettering Cancer Center | New York | New York | United States | 10065 |
| 3 | Cleveland Clinic Foundation | Cleveland | Ohio | United States | 44195 |
| 4 | University of Texas MD Anderson Cancer Center | Houston | Texas | United States | 77030 |
Sponsors and Collaborators
- Bayer
Investigators
- Study Director: Bayer Study Director, Bayer
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 18595
- 2018-003930-34