Phase 1/2 Study of DF6002 Monotherapy and DF6002 with Nivolumab in Patients with Advanced Solid Tumors

The primary objective of this study is to assess the **safety** and tolerability of DF6002 as a monotherapy and in combination with nivolumab in patients with advanced solid tumors. This includes determining the maximum tolerated dose (MTD) of subcutaneous DF6002, both as a standalone treatment and in combination with intravenous nivolumab. Additionally, the study aims to evaluate the Objective Response Rate (ORR) according to RECIST 1.1 criteria, as assessed by an Independent Endpoint Review Committee (IERC), for all efficacy expansion cohorts testing the clinical activity of DF6002.

Secondary objectives include: - Characterizing the safety of DF6002 as a monotherapy and in combination with nivolumab. - Characterizing the pharmacokinetics (PK) of DF6002 and the PK profiles of DF6002 and nivolumab when given in combination. - Evaluating the immunogenicity of DF6002 and nivolumab. - Assessing the Overall Response Rate (ORR), Duration of Response (DOR), and Clinical Benefit Rate (CBR) using RECIST 1.1 criteria. - Evaluating progression-free survival (PFS) and median overall survival (OS) time. - Investigating potential correlations between exposure and clinical activity.

The clinical trial involves a total of **60 participants** diagnosed with **advanced solid tumors**, including conditions such as melanoma and non-small cell lung cancer (NSCLC). The study population comprises both male and female subjects aged **18 years and older**. Participants were selected based on their diagnosis of locally advanced or metastatic solid tumors for which no standard therapy exists or where standard therapy has failed. The trial includes individuals with an **ECOG performance status** of 0 or 1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants are required to have a measurable disease and an estimated life expectancy of at least three months. The trial population includes a vulnerable population, and lifestyle factors such as diet and physical activity are not specified. Key inclusion criteria include histologically or cytologically proven disease and the ability to provide informed consent. The trial does not specify any exclusion criteria related to lifestyle habits such as smoking or alcohol consumption.

The clinical trial is designed as a **Phase 1/2**, first-in-human, multi-part, open-label, multiple-ascending dose study. It aims to investigate the safety, tolerability, pharmacokinetics, biological, and clinical activity of **DF6002** as a monotherapy and in combination with **nivolumab** in patients with locally advanced or metastatic solid tumors. The trial is structured to include several phases, with Phase 1 focusing on assessing the safety and tolerability of DF6002 as a monotherapy and determining the maximum tolerated dose (MTD) of subcutaneous DF6002. Phase 1b will evaluate the safety and tolerability of DF6002 in combination with intravenous nivolumab, also determining the MTD for this combination. Phase 2 will assess the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for all efficacy expansion cohorts.

The trial is expected to run from July 2021 to August 2025. Participants will be involved in the study for varying durations depending on their response to treatment and the specific phase of the trial they are enrolled in. The study includes an initial screening visit to confirm eligibility based on inclusion criteria such as age, histologically confirmed advanced solid tumors, and ECOG performance status. Follow-up visits will be scheduled to monitor safety, tolerability, and response to treatment, with assessments including laboratory tests, electrocardiograms, and imaging studies. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination.

Participants may be withdrawn from the study early if they experience dose-limiting toxicities (DLTs) during the first three weeks of treatment, as these are primary endpoints in Phase 1/1b. Other conditions for early termination include significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous safety monitoring and data collection protocols to ensure the integrity of the study and the well-being of participants.

The clinical trial involves the administration of two experimental medications: **Nivolumab** and **DF6002**. **Nivolumab**, marketed under the name **OPDIVO**, is a **concentrate for solution for infusion** with a concentration of 10 mg/mL. It is administered via **intravenous use**. The pharmaceutical form is a **solution for infusion**, and it is classified as a biological medicinal product. The active substance, **Nivolumab**, is a protein of other origin, and it is produced by Bristol-Myers Squibb Pharma EEIG. The administration schedule and dosage are determined based on the study protocol, with compliance monitored throughout the trial.

**DF6002** is another investigational product used in this study. It is provided as a **solution for injection/infusion** and is administered via **subcutaneous use**. The active substance, also named **DF6002**, is a protein of other origin, developed by Dragonfly Therapeutics, Inc. This product is also classified as a biological medicinal product. The dosing schedule and administration frequency are outlined in the study protocol, with participant compliance being closely monitored to ensure adherence to the treatment regimen.

In this trial, **DF6002** is evaluated both as a monotherapy and in combination with **Nivolumab**. The primary objective is to assess the safety, tolerability, and maximum tolerated dose of **DF6002** when used alone and in combination with **Nivolumab** in patients with advanced solid tumors. The study also aims to evaluate the objective response rate according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) for all efficacy expansion cohorts. No non-experimental treatments, such as standard-of-care therapy or placebo, are mentioned in the trial documentation.

Efficacy in this clinical trial will be assessed using several parameters, primarily focusing on the **Objective Response Rate (ORR)** according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). This will be evaluated by an Independent Endpoint Review Committee (IERC) for all efficacy expansion cohorts testing the clinical activity of DF6002 as a monotherapy or in combination with nivolumab. The primary endpoints in Phase 1/1b include the occurrence of dose-limiting toxicities (DLTs) during the first three weeks of treatment. In Phase 2, the primary endpoint is the confirmed ORR, per RECIST 1.1, as adjudicated by an IERC.

Secondary endpoints will include the number, severity, and duration of treatment-emergent adverse events (TEAEs) for all dose groups and indications, assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. Additional secondary endpoints involve changes from baseline in laboratory parameters, electrocardiograms (ECGs), vital signs, and Eastern Cooperative Oncology Group (ECOG) performance status. The duration of response (DOR), best overall response (BOR), and clinical benefit rate (CBR) will also be evaluated according to RECIST 1.1, per investigator assessment and IERC. Pharmacokinetic (PK) parameters for DF6002 and nivolumab, including AUC, Cmax, tmax, and t½, will be measured. These assessments will be conducted at specified timepoints throughout the trial to ensure comprehensive data collection and analysis.