Phase 2 Study of ATR Inhibitor Tuvusertib with PARP Inhibitor Niraparib or ATM Inhibitor Lartesertib in BRCA Mutant/HRD Positive Epithelial Ovarian Cancer

The primary objective of this Phase 2 study is to assess the **efficacy** and **safety** of the ATR inhibitor tuvusertib in combination with either the PARP inhibitor niraparib or the ATM inhibitor lartesertib in participants with BRCA mutant and/or homologous recombination deficiency (HRD) positive epithelial ovarian cancer that has progressed following prior PARP inhibitor therapy. The study aims to determine the objective response (OR) rates for these combinations to support the selection of the most effective combination for further investigation in Part B of the study. Evaluating the safety and tolerability of these combinations is crucial for ensuring patient safety and optimizing therapeutic strategies in this patient population.

The clinical trial involves a total of **55 participants** diagnosed with **epithelial ovarian cancer** that has progressed following prior **PARP inhibitor therapy**. The study population is exclusively female, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific criteria, including a histologically or cytologically confirmed diagnosis of high-grade serous or high-grade endometrioid ovarian, primary peritoneal, and/or fallopian tube cancer that is recurrent. The trial population includes individuals whose tumors carry germline or somatic deleterious mutations in the **BRCA1** and **BRCA2** genes, or tumors with positive homologous recombination deficiency (HRD) status. Participants must have radiologically confirmed disease progression while on PARP inhibitors therapy and demonstrate measurable disease per RECIST v1.1. The trial requires an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and a life expectancy of at least six months. The study does not include male subjects and involves a vulnerable population. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as an open-label, multicenter, randomized Phase 2 study to evaluate the efficacy and safety of the ATR inhibitor **tuvusertib** in combination with the PARP inhibitor **niraparib** or the ATM inhibitor **lartesertib** in participants with epithelial ovarian cancer that has progressed following prior PARP inhibitor therapy. The trial aims to assess the objective response and treatment-emergent adverse events to determine the optimal combination for further study. The trial is expected to commence recruitment on December 12, 2024, and conclude by January 25, 2028.

Participants will be involved in the study for a maximum treatment period of 42 days, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as histologically confirmed high-grade serous or endometrioid ovarian cancer, BRCA mutations, and disease progression on prior PARP inhibitors. Follow-up visits will monitor the participants' response to treatment and any adverse events. The end-of-study visit will assess the final outcomes and gather data on the primary endpoints, including confirmed objective response and the number of treatment-emergent adverse events.

Participants will be randomly assigned to receive either the combination of tuvusertib with niraparib or tuvusertib with lartesertib, administered orally. The trial will not include a placebo group, and both the participants and investigators will be aware of the treatment assignments. The study will adhere to rigorous safety monitoring protocols to ensure participant well-being throughout the trial duration. The inclusion criteria require participants to have measurable disease per RECIST v1.1 and an ECOG performance status of 0 or 1, with a life expectancy of at least six months. The trial's design and procedures are structured to provide robust data on the efficacy and safety of the investigational drug combinations in this specific patient population.

The clinical trial involves the administration of **Zejula 100 mg film-coated tablets**, which contain the active substance **niraparib tosilate monohydrate**. This medication is provided in the form of film-coated tablets and is administered orally. The treatment period for this medication is set to a maximum of 42 days. The tablets are manufactured by GlaxoSmithKline (Ireland) Limited and have been authorized for use in the European Union under the marketing authorization number EU/1/17/1235/004. The product has undergone modifications for the study, including the removal of the commercial package insert, relabeling, and release specifically for the trial.

Another experimental medication used in the trial is **M1774**, which is provided in the form of hard capsules. The active substance in M1774 is **2-amino-6-fluoro-N-(5-fluoro-4-(1-methyl-1H-imidazol-5-yl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide**. This medication is also administered orally, with a maximum treatment period of 42 days. M1774 is produced by Merck Healthcare KGaA and is identified by the sponsor product code MSC2584415A. The product is classified as a chemical medicinal product and is not designated as an orphan drug.

The trial also includes the administration of **M4076**, which is available as film-coated tablets. The active substance in M4076 is **8-(1,3-dimethylpyrazol-4-yl)-1-(3-fluoro-5-methoxypyridin-4-yl)-7-methoxy-3-methylimidazo[4,5-c]quinolin-2-one**. Like the other medications, M4076 is administered orally, with a treatment period not exceeding 42 days. This product is also manufactured by Merck Healthcare KGaA and is identified by the sponsor product code MSC2585823A. It is classified as a chemical medicinal product and is not designated as an orphan drug.

All medications in this trial are administered orally, and the study does not specify a maximum daily or total dose amount, indicating that dosing may be adjusted based on individual participant needs or study protocol requirements. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment regimen.

Efficacy in the clinical trial will be assessed using the primary endpoint of **Confirmed Objective Response (OR)** according to RECIST v1.1, as evaluated by the investigator. This endpoint will measure the proportion of participants who achieve a predefined level of tumor size reduction, indicating a response to the treatment. The trial involves the combination of the ATR inhibitor tuvusertib with either the PARP inhibitor niraparib or the ATM inhibitor lartesertib in participants with BRCA mutant and/or homologous recombination deficiency (HRD) positive epithelial ovarian cancer that has progressed on prior PARP inhibitor therapy.

The efficacy assessments will be conducted at specified intervals throughout the study, with the schedule for these assessments aligned with the trial protocol. The use of RECIST v1.1 criteria ensures a standardized and validated approach to evaluating tumor response, which is critical for determining the efficacy of the treatment combinations being tested. The trial aims to support the selection of the best combination for further study in Part B, based on the efficacy and safety data collected.