Phase 2/3 Evaluation of Evorpacept with Trastuzumab, Ramucirumab, and Paclitaxel in Metastatic HER2-Overexpressing Gastric/GEJ Adenocarcinoma

The primary objective of this study is to evaluate the effect of **ALX148** in combination with trastuzumab, ramucirumab, and paclitaxel on the objective response rate (ORR) in patients with metastatic HER2-overexpressing gastric or gastroesophageal junction (GEJ) adenocarcinoma. This is compared to a historical control using ramucirumab and paclitaxel. Additionally, the study aims to assess the contribution of ALX148 to the treatment regimen by measuring the difference in ORR between the two randomized treatment arms. In Phase III, the primary objective extends to assessing the impact of ALX148 on overall survival (OS) compared to ramucirumab and paclitaxel alone. These objectives are clinically relevant as they aim to improve treatment outcomes in a patient population with limited therapeutic options.

Secondary objectives include:

• Assessing the effect of ALX148 plus trastuzumab, ramucirumab, and paclitaxel on ORR using blinded independent central review (BICR).
• Evaluating secondary measures of efficacy for ALX148 in combination with trastuzumab, ramucirumab, and paclitaxel versus the combination without ALX148.
• Assessing the safety and tolerability of ALX148 in combination with trastuzumab, ramucirumab, and paclitaxel.
• Characterizing the pharmacokinetics (PK) and evaluating the immunogenicity of ALX148.
• In Phase III, assessing the impact on patient-reported outcomes of quality of life when ALX148 is added to the treatment regimen.

The clinical trial involves a total of **332 participants** diagnosed with **HER2-overexpressing advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma**. The study population includes both male and female subjects aged 18 years and older, with the exception of regions where the minimum age for participation is higher. Participants were selected based on their progression on or after a prior HER2-directed agent and fluoropyrimidine- or platinum-containing chemotherapy, specifically in the 2nd-line or 3rd-line treatment setting. The trial includes individuals with adequate bone marrow, renal, liver, cardiac, and clotting function, as well as an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Participants must have at least one measurable lesion as defined by RECIST version 1.1 and must have resolved acute effects of any prior therapy. The study population is characterized by a requirement for non-pregnant status in individuals of childbearing potential, who must agree to use a highly effective method of contraception throughout the study. The trial also includes a vulnerable population, and all participants have provided consent to the study and its procedures.

The clinical trial is designed to evaluate the efficacy and safety of **ALX148** in combination with **trastuzumab**, **ramucirumab**, and **paclitaxel** in patients with advanced HER2-overexpressing gastric or gastroesophageal junction adenocarcinoma. This study is structured as a randomized, double-blind, controlled trial with two phases: Phase II and Phase III. The primary objective in Phase II is to assess the objective response rate (ORR) of the combination therapy compared to a historical control, while Phase III focuses on overall survival (OS) as the primary endpoint. The trial is expected to run from September 2021 to November 2028, with a maximum treatment period of 60 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, HER2 overexpression, and adequate organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment response and safety, including assessments of ORR, OS, and adverse events. The end-of-study visit will conclude the participant's involvement, during which final evaluations will be conducted. The expected length of participant involvement is approximately 60 days, with conditions for early termination including significant adverse events or disease progression.

Key elements of the research methodology include the use of **RECIST version 1.1** for evaluating tumor response, and the assessment of pharmacokinetic exposure and immunogenicity of ALX148. Secondary endpoints will explore additional efficacy measures such as progression-free survival (PFS) and quality of life assessments. The trial will ensure rigorous monitoring of laboratory abnormalities and adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v. 5.0). Participants will be required to provide informed consent and adhere to study procedures, including the use of effective contraception if applicable.

The clinical trial involves the administration of **ALX148**, an investigational medication developed by ALX Oncology. ALX148 is formulated as an **injection** and is administered via **intravenous use**. The dosing schedule for ALX148 is determined based on the study protocol, with a maximum treatment period of 60 days. The specific dosage in milligrams is not provided, and participant compliance is monitored throughout the trial to ensure adherence to the dosing regimen.

In addition to ALX148, the trial includes the administration of **trastuzumab**, marketed as Herceptin, which is provided as a **powder for concentrate for solution for infusion**. This medication is also administered intravenously. Trastuzumab is a protein-based therapeutic agent, and its role in the trial is as a comparator treatment. The dosing schedule and compliance monitoring are aligned with the study's requirements, with a maximum treatment period of 60 days.

**Paclitaxel**, marketed as a 6 mg/mL concentrate for solution for infusion, is another comparator treatment used in the trial. It is a chemical-based therapeutic agent administered via **intravenous use**. The dosing schedule is consistent with the trial protocol, and the maximum treatment period is 60 days. Participant compliance is monitored to ensure proper administration.

**Ramucirumab**, marketed as Cyramza, is included in the trial as a concentrate for solution for infusion. This protein-based therapeutic agent is administered intravenously and serves as a comparator treatment. The dosing schedule and compliance monitoring are conducted according to the study protocol, with a maximum treatment period of 60 days.

Normal Saline (Sodium Chloride) is used as a placebo in the trial. It does not have a specific pharmaceutical form or active substance designation. The administration details, including route and frequency, are determined by the study protocol, and it serves as a control to evaluate the effects of the investigational and comparator treatments.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. In Phase II, the primary endpoint is the **Objective Response Rate (ORR)**, which includes Complete Response (CR) or Partial Response (PR) as determined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, based on investigator assessment. In Phase III, the primary endpoint is **Overall Survival (OS)**. Secondary endpoints for Phase II include ORR based on blinded independent central review (BICR), Duration of Response (DoR), Disease Control Rate (DCR), Time to Tumor Progression (TTP), Progression-Free Survival (PFS), and OS. Additionally, adverse events, laboratory abnormalities, pharmacokinetic exposure of ALX148, and immunogenicity will be evaluated. In Phase III, secondary endpoints include ORR, DCR, DoR, TTP, PFS, adverse events, laboratory abnormalities, pharmacokinetic exposure, immunogenicity, and quality of life measurements using the EORTC QLQ-C30 and QLQ-STO22 questionnaires.

The efficacy parameters will be measured and collected at specified timepoints throughout the trial. The ORR will be assessed using RECIST version 1.1 criteria, and the OS will be monitored over the course of the study. Adverse events and laboratory abnormalities will be characterized by type, frequency, severity, timing, seriousness, and relationship to study therapy, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v. 5.0). Pharmacokinetic exposure will be determined by measuring trough (pre-infusion) and peak (post-infusion) serum concentrations of ALX148. Immunogenicity will be assessed by the presence or absence of serum anti-ALX148 antibodies. Quality of life will be evaluated using validated questionnaires. These assessments will provide comprehensive data on the efficacy and safety of the treatment regimen in patients with metastatic HER2-overexpressing gastric/gastroesophageal junction adenocarcinoma.