Evaluation of ART0380 Mesilate Monotherapy and Combination Therapy with Gemcitabine Hydrochloride or Irinotecan Hydrochloride in Advanced or Metastatic Solid Tumors

The primary objective of this study is to evaluate the **safety** and **tolerability** of ART0380, an ATR kinase inhibitor, when administered orally to patients with advanced or metastatic solid tumors. The study aims to determine the maximum tolerated doses (MTDs) and recommended Phase II doses/schedules (RP2Ds) of ART0380 as monotherapy or in combination with gemcitabine or irinotecan. This is clinically relevant as it helps establish the appropriate dosing regimen for ART0380, which is crucial for optimizing therapeutic outcomes and minimizing adverse effects in patients with these challenging cancer types.

Secondary objectives include:

• Assessing the safety and tolerability of ART0380 at the RP2D in combination with gemcitabine versus gemcitabine alone.
• Determining the pharmacokinetics (PK) of ART0380 following single and multiple dosing in patients with advanced or metastatic solid tumors.
• Evaluating signs of efficacy with ART0380 monotherapy and in combination with gemcitabine or irinotecan in various tumor types, including those with ATM gene alterations.
• Assessing efficacy signs for ART0380 with gemcitabine versus gemcitabine alone in patients with high-grade serous ovarian, primary peritoneal, or fallopian tube carcinoma resistant to platinum.
• Identifying markers in tumor samples that may predict ART0380 activity.
• Determining the PK of irinotecan and its metabolite SN38 following single and multiple dosing of ART0380 in combination with irinotecan.

The clinical trial involves a total of **352 participants** diagnosed with **advanced or metastatic solid tumors**. The study population includes both male and female subjects, with an age range encompassing adults and older adults. Participants were selected based on specific inclusion criteria, including the requirement for a signed informed consent and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, indicating they are ambulatory and capable of all self-care. The trial does not include a vulnerable population. Participants are required to have acceptable hematologic, renal, hepatic, and coagulation functions, independent of transfusions and granulocyte colony-stimulating factor. Lifestyle considerations such as diet and physical activity are not specified, but participants must have discontinued all previous cancer treatments for at least 21 days or 5 half-lives, whichever is shorter, and recovered from acute effects of therapy to CTCAE Grade ≤1. Additionally, female patients of childbearing potential and male patients with female partners of childbearing potential are required to use highly effective contraception plus one barrier method during their participation in the study and for a specified period following the last dose. The trial does not involve any vulnerable populations, and participants are expected to have an estimated life expectancy of at least 12 weeks.

The clinical trial is designed as a **Phase I/IIa**, open-label, multi-center study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of the ATR kinase inhibitor **ART0380**. The study involves administering ART0380 orally as monotherapy and in combination with **gemcitabine hydrochloride** or **irinotecan hydrochloride** to patients with advanced or metastatic solid tumors. The trial is structured to include several parts, each with specific objectives and treatment regimens. The trial is not categorized as low intervention and is expected to conclude by June 2025, with recruitment having commenced in March 2023.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as having advanced or metastatic solid tumors and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Following the screening, eligible participants will enter the treatment phase, which includes regular follow-up visits to monitor safety, tolerability, and efficacy. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination. The expected duration of participant involvement varies depending on the treatment arm and response to therapy, but it generally spans several months.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The primary endpoints include the incidence of dose-limiting toxicities in Part A and the incidence and severity of adverse events in Parts B1/B3/B4/B5, with progression-free survival being a key endpoint in Part B2. Secondary endpoints involve pharmacokinetic assessments and objective response rates. The trial aims to determine the maximum tolerated doses and recommended Phase II doses/schedules of ART0380, both as monotherapy and in combination with other agents, to inform future studies and potential therapeutic applications.

The clinical trial involves the administration of several treatments, including the experimental medication **ART0380**, which is an ATR kinase inhibitor. **ART0380** is provided in a **tablet** form and is administered orally. The dosing schedule for **ART0380** is determined based on the study phase, with the primary objective being to assess its safety, tolerability, and pharmacokinetics in patients with advanced or metastatic solid tumors. The trial aims to establish the maximum tolerated doses (MTDs) and recommended Phase II doses/schedules (RP2Ds) for **ART0380** as monotherapy and in combination with other agents. Participant compliance with the dosing regimen is monitored throughout the study.

In addition to **ART0380**, the trial includes the administration of **gemcitabine hydrochloride**, a chemotherapeutic agent. **Gemcitabine hydrochloride** is administered intravenously, with the pharmaceutical form designated as PHF00230MIG. The frequency and dosage of **gemcitabine hydrochloride** are tailored to the specific study arm and patient condition, particularly in combination therapy settings. The trial evaluates the efficacy of **ART0380** in combination with **gemcitabine hydrochloride** versus **gemcitabine hydrochloride** alone in patients with high-grade serous ovarian, primary peritoneal, or fallopian tube carcinoma resistant to platinum-based therapies.

Another treatment used in the trial is **irinotecan hydrochloride**, also administered intravenously in the PHF00230MIG form. **Irinotecan hydrochloride** is used in combination with **ART0380** to further assess the safety and tolerability of the combination therapy. The dosing schedule for **irinotecan hydrochloride** is aligned with the study's objectives to determine the RP2Ds when used in conjunction with **ART0380**. Monitoring of participant compliance and adverse events is conducted to ensure the safety and efficacy of the treatment regimen.

The trial does not include any placebo or standard-of-care therapy as a comparator treatment. All substances used in the trial are of chemical origin, and none of the formulations are pediatric. The study is designed to provide comprehensive data on the safety and potential therapeutic benefits of the investigational treatments in the specified patient population.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the incidence of dose-limiting toxicities (DLTs) in Part A, and the incidence and severity of adverse events (AEs) as per CTCAE v5.0 in Parts B1, B3, B4, and B5. For Part B2, the primary endpoint is **Progression Free Survival** (PFS) evaluated using RECIST v1.1 criteria.

Secondary endpoints for Part B2 include the incidence and severity of AEs, as well as the objective response rate and duration of response based on RECIST v1.1. Additionally, ART0380 plasma concentration and renal clearance data will be collected, along with irinotecan and its metabolite SN-38 plasma concentration data. For Parts A and B1, B3, B4, and B5, secondary endpoints also include objective response rate, duration of response, and progression-free survival. Furthermore, archival tumor or pre-dose tumor biopsy samples will be analyzed to correlate lesions in DNA repair pathways.

The efficacy parameters will be measured and collected at various timepoints throughout the study, with specific methods such as RECIST v1.1 being employed for radiological evaluations. The data collected will be analyzed to determine the efficacy of ART0380 as monotherapy and in combination with gemcitabine or irinotecan in patients with advanced or metastatic solid tumors.