Phase 2 Randomized, Blinded, Placebo-Controlled Study of INBRX-109 in Adults with Unresectable or Metastatic Conventional Chondrosarcoma

The primary objective of this study is to evaluate the **anticancer efficacy** of INBRX-109 in patients with unresectable or metastatic conventional chondrosarcoma. This is measured by **Progression Free Survival (PFS)** according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECISTv1.1), assessed by central real-time independent radiology review (IRR), comparing INBRX-109 and placebo. This objective is clinically relevant as it aims to determine the potential of INBRX-109 to delay disease progression in a patient population with limited treatment options.

The secondary objectives include:

• Evaluating the anticancer efficacy of INBRX-109 as measured by overall survival (OS), overall response rate (ORR), and disease control rate (DCR) per RECISTv1.1, assessed by central real-time IRR, comparing INBRX-109 and placebo.
• Assessing the quality of life (QoL) using the European Organization for Research and Treatment of Cancer quality of life questionnaire C30 (EORTC QLQ-C30) Pain and Physical Functioning scales.
• Evaluating the duration of response (DOR) per RECISTv1.1, assessed by central real-time IRR.
• Assessing the safety and tolerability of INBRX-109.
• Characterizing the pharmacokinetics (PK) of INBRX-109.
• Evaluating the frequency of anti-drug antibodies (ADAs) and neutralizing ADAs (NAbs) against INBRX-109, and exploring their potential relationship with safety, PK, and efficacy.

The clinical trial involves a total of **104 participants** diagnosed with **unresectable or metastatic conventional chondrosarcoma**. The study population comprises both male and female subjects, aged between 18 and 85 years. Participants were selected based on specific criteria, including the presence of measurable disease as per RECISTv1.1 and confirmed radiographic disease progression within six months prior to the study. All participants are required to have adequate hematologic, coagulation, hepatic, and renal function, and an ECOG performance status of 0 or 1, with exceptions for non-frail, physically active individuals with mobility issues due to prior cancer surgery. The trial includes a vulnerable population, and participants must have an estimated life expectancy of at least 12 weeks. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **blinded**, placebo-controlled, Phase 2 study to evaluate the efficacy of INBRX-109 in patients with unresectable or metastatic conventional **chondrosarcoma**. The primary objective is to assess the anticancer efficacy of INBRX-109 by measuring Progression Free Survival (PFS) using the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECISTv1.1), with assessments conducted by central real-time independent radiology review (IRR). The trial is expected to run from February 1, 2022, to June 27, 2025, with a maximum treatment period of 150 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, disease measurability, and adequate organ function. Following randomization, participants will receive either INBRX-109 or a placebo. The study includes regular follow-up visits to monitor treatment response and safety, with assessments of primary and secondary endpoints such as Overall Survival (OS), Objective Response Rate (ORR), and Quality of Life (QoL) metrics. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of treatment outcomes and any adverse events.

Participant involvement is expected to last up to 150 days, with conditions for early termination including significant adverse events or disease progression that necessitates discontinuation of the study treatment. The trial's methodology ensures rigorous data collection and analysis, adhering to ethical standards and regulatory requirements to provide reliable and valid results.

The clinical trial involves the administration of **INBRX-109**, an experimental medication formulated as a lyophilized powder for preparation for injection. The active substance in INBRX-109 is **ozekibart**, a humanized IgG1 tetravalent monoclonal antibody targeting death receptor 5. The medication is administered intravenously at a dosage of 3 mg/kg, with a maximum total dose of 150 mg/kg over a treatment period of 150 days. This investigational drug is designated as an orphan drug and is provided by INHIBRX, INC.

**Diphenhydramine** is used as an auxiliary treatment in the study. It is administered intravenously in a pharmaceutical form coded as PHF00245MIG. The maximum daily dose is 50 mg, with a total maximum dose of 2500 mg over the course of the study, which spans 150 days.

**Glucose** is also included as an auxiliary treatment, provided as a solution for infusion. The active substance is glucose, administered via intravenous infusion. The maximum daily dose is 250 ml, with a total maximum dose of 12.5 liters over the 150-day treatment period.

Another auxiliary treatment is **dexamethasone**, which is administered orally. The pharmaceutical form is coded as PHF00043MIG, and it contains active substances including cinchocaine hydrochloride, dexamethasone, and 1,3-butylene glycol. The maximum daily dose is 8 mg, with a total maximum dose of 400 mg over the 150-day period.

**Acetylcysteine** is also used as an auxiliary treatment, administered orally in a pharmaceutical form coded as PHF00169MIG. The maximum daily dose is 1200 mg, with a total maximum dose of 60 g over the 150-day treatment period.

The trial includes a placebo group to compare the efficacy of INBRX-109. The placebo is administered intravenously, matching the administration route of the experimental drug. Participant compliance is monitored throughout the study to ensure adherence to dosing schedules and to evaluate the efficacy and safety of the treatments.

The efficacy of the investigational product **INBRX-109** in the treatment of unresectable or metastatic conventional chondrosarcoma will be assessed primarily through the measurement of **Progression Free Survival (PFS)**. This will be evaluated using the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECISTv1.1) and assessed by a central real-time independent radiology review (IRR). The primary endpoint focuses on comparing the PFS between the treatment group receiving INBRX-109 and the placebo group within the Intention To Treat (ITT) population.

Secondary endpoints include **Overall Survival (OS)**, **Objective Response Rate (ORR)**, and **Disease Control Rate (DCR)**, all assessed per RECISTv1.1 by central real-time IRR. Additionally, **Quality of Life (QoL)** will be evaluated using the EORTC QLQ-C30, focusing on pain and physical function. The study will also monitor treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs), and perform pharmacokinetic (PK) characterization, estimating parameters such as AUC, Cmax, and Tmax using a standard non-compartmental method. The frequency of anti-drug antibodies (ADAs) and neutralizing antibodies (Nabs) will also be assessed.