Phase I/IIa Study of AZD3470 Monotherapy and Combination Therapy in MTAP-Deficient Advanced Solid Tumors

The primary objective of this study is to assess the **safety** and tolerability of AZD3470, a PRMT5 inhibitor, as monotherapy and in combination with anticancer agents in participants with MTAP deficient advanced solid tumors. Additionally, the study aims to determine the recommended Phase 2 dose (RP2D) of AZD3470. This is clinically relevant as it helps establish a safe and effective dosage regimen for patients with these specific tumor characteristics, potentially improving therapeutic outcomes.

Secondary objectives include:

• Estimating the antitumor activity of AZD3470 both as a monotherapy and in combination with other anticancer agents, which is crucial for understanding its efficacy in reducing tumor burden.
• Characterizing the pharmacokinetics (PK) following multiple oral doses of AZD3470 administered as monotherapy, providing insights into the drug's absorption, distribution, metabolism, and excretion.
• Evaluating the effect of multiple doses of AZD3470 on the pharmacokinetics of a single oral dose of midazolam and/or dextromethorphan, which is important for assessing potential drug-drug interactions.

The clinical trial involves a total of **160 participants** diagnosed with **advanced/metastatic solid tumors** that are MTAP deficient. The study population includes both male and female subjects, aged 18 years and older, who are capable of providing informed consent. Participants were selected based on their medical condition, specifically those who have received and progressed, are refractory, or are intolerant to standard therapy for their specific tumor type. All participants have had at least one prior line of treatment in the recurrent or metastatic setting. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have a minimum life expectancy of 12 weeks and at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Adequate organ and bone marrow reserve function is required, and contraceptive use must align with local regulations. The trial population also includes vulnerable populations, ensuring comprehensive representation in the study.

The clinical trial is designed to evaluate the safety and tolerability of **AZD3470**, a PRMT5 inhibitor, as monotherapy and in combination with anticancer agents in patients with advanced or metastatic solid tumors that are MTAP deficient. This is a Phase I/IIa, multi-center, dose escalation, and expansion study. The trial employs a **randomized, double-blind, controlled** design to ensure the reliability and validity of the results. The estimated duration of the trial is from March 2024 to February 2026, with participant involvement expected to last up to 999 days, depending on individual response and progression.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, tumor sample availability, and previous treatment history. The screening will also assess the presence of MTAP deficiency and the participant's performance status. Following successful screening, participants will enter the treatment phase, which includes regular follow-up visits to monitor safety, tolerability, and efficacy. These visits will involve assessments such as adverse event monitoring, radiological evaluations, and laboratory tests. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to gather comprehensive data on the primary and secondary endpoints.

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 adverse events, serious adverse events, and dose-limiting toxicities. Secondary endpoints focus on radiological response, duration of response, disease control rate, progression-free survival, and overall survival. The study will also measure pharmacokinetic parameters to understand the drug's behavior in the body. The trial aims to determine the recommended Phase II dose (RP2D) of AZD3470, providing critical data for future research and potential therapeutic applications.

The clinical trial involves the administration of **AZD3470**, a film-coated tablet developed by AstraZeneca AB. This experimental medication is a synthetic chemical compound, administered orally. The dosage and frequency of administration are determined based on the study protocol, with a maximum treatment period of 999 days. The active substance in AZD3470 is chemically derived and is identified by the synonym AZ14218739. The trial aims to assess the safety and tolerability of AZD3470 as a monotherapy and in combination with other anticancer agents in patients with advanced or metastatic solid tumors that are MTAP deficient.

Another treatment used in the study is **DEXTROMETHORPHANE ELERTE 1.5 mg/ml**, a syrup formulation produced by Laboratoire des Realisations Therapeutiques Elerte. This non-experimental treatment contains the active substance **dextromethorphan hydrobromide**, a chemical compound classified under the ATC code R05DA09. The syrup is administered orally, with the dosage and administration schedule adhering to standard guidelines. The role of this treatment in the study is to serve as a comparator or supportive therapy, depending on the specific study arm.

The study also includes the use of **Midazolam-ratiopharm® 2 mg/ml oral solution**, manufactured by Ratiopharm GmbH. This oral solution contains the active substance **midazolam**, a chemical compound with the ATC code N05CD08. The solution is administered orally, with dosing schedules tailored to the study's requirements. Midazolam is utilized in the trial to evaluate its effects in combination with AZD3470, providing insights into potential interactions and therapeutic outcomes.

Efficacy in the clinical trial of AZD3470, a **PRMT5 inhibitor**, will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on safety and tolerability, including the incidence of adverse events (AEs), serious adverse events (SAEs), and dose-limiting toxicities (DLTs). These will be determined by the number of patients experiencing such events, categorized by system organ class and preferred term.

Secondary endpoints will evaluate the radiological response using the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Key measures include the Objective Response Rate (ORR), which is the percentage of patients with a confirmed complete or partial response, and the Duration of Response (DOR), defined as the time from the first documented response to disease progression or death. The Disease Control Rate (DCR) at 12 weeks will also be assessed, representing the percentage of participants with a confirmed complete response (CR), partial response (PR), or stable disease (SD) for at least 11 weeks post-first dose.

Additional secondary endpoints include the percentage change in tumour size from baseline, Progression-Free Survival (PFS), and Overall Survival (OS). Pharmacokinetic parameters such as the area under the concentration-time curve (AUC), maximum observed plasma concentration (Cmax), and terminal elimination half-life (t1/2) will be measured. The trial will also evaluate the plasma geometric mean ratio of Midazolam and Dextromethorphan with and without AZD3470. These assessments will be conducted at specified intervals throughout the trial to ensure comprehensive data collection and analysis.