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
Overview
- Phase
- Phase 1
- Intervention
- Elimusertib (BAY1895344)
- Conditions
- Advanced Solid Tumors (Excluding Prostate Cancer)
- Sponsor
- Bayer
- Enrollment
- 14
- Locations
- 3
- Primary Endpoint
- Recommended Phase II dose (RP2D) of elimusertib
- Status
- Terminated
- Last Updated
- 2 years ago
Overview
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.
Investigators
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.
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:
Arms & Interventions
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.
Intervention: Elimusertib (BAY1895344)
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.
Intervention: Niraparib
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.
Intervention: Elimusertib (BAY1895344)
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.
Intervention: Niraparib
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.
Intervention: Elimusertib (BAY1895344)
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.
Intervention: Niraparib
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.
Intervention: Elimusertib (BAY1895344)
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.
Intervention: Niraparib
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.
Intervention: Elimusertib (BAY1895344)
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.
Intervention: Niraparib
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.
Intervention: Elimusertib (BAY1895344)
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.
Intervention: Niraparib
Outcomes
Primary Outcomes
Recommended Phase II dose (RP2D) of elimusertib
Time Frame: Up to 30 days after 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
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
Secondary Outcomes
- Incidence of participants with complete response (CR)(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)(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)(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)(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)(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)(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,md of elimusertib after multiple dose administration(Cycle 1 Day 5 and Cycle 1 Day 21, each cycle is 28 days.)
- Cmax (Maximal plasma exposure) of elimusertib after single dose administration(Cycle 1 Day 5 and Cycle 1 Day 21, each cycle is 28 days.)
- AUC(0-8) of elimusertib after single dose administration(Cycle 1 Day 5 and Cycle 1 Day 21, each cycle is 28 days.)
- AUC(0-8)md of elimusertib after multiple dose administration(Cycle 1 Day 5 and Cycle 1 Day 21, each cycle is 28 days.)