A Phase 2, Randomized, Open-Label Study of Two Dose Levels of Vobramitamab Duocarmazine in Participants with Metastatic Castration-Resistant Prostate Cancer (TAMARACK)

The primary objective of this study is to evaluate the **efficacy** of vobramitamab duocarmazine at two dose levels, as measured by Radiographic Progression-Free Survival (rPFS) by investigator assessment using Prostate Cancer Working Group 3 (PCWG3) criteria. This is clinically relevant as it aims to determine the potential of vobramitamab duocarmazine in delaying disease progression in patients with Metastatic Castration-resistant Prostate Cancer, a condition characterized by resistance to conventional hormonal therapies and associated with poor prognosis.

Secondary objectives include:

• Characterizing the frequency and severity of adverse events (AEs) and overall tolerability of vobramitamab duocarmazine at doses of 2.0 mg/kg and 2.7 mg/kg administered intravenously every four weeks.
• Evaluating the efficacy of vobramitamab duocarmazine as measured by prostate-specific antigen (PSA) levels.
• Assessing the efficacy in participants with RECIST-evaluable disease, as measured by objective response rate (ORR) and Duration of Response (DoR) by investigator assessment.
• Evaluating the effect of vobramitamab duocarmazine on skeletal-related events (SSEs).
• Characterizing the pharmacokinetics (PK) of vobramitamab duocarmazine.
• Characterizing the immunogenicity of vobramitamab duocarmazine.

The clinical trial involves a total of **59 participants** diagnosed with **Metastatic Castration-resistant Prostate Cancer**. The study population consists exclusively of male subjects, with an age range that includes both middle-aged and older adults. Participants were selected based on specific criteria, including a histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell, or small cell features, and the presence of at least one metastatic lesion detectable via MRI, CT, or bone scan. The trial does not include a vulnerable population. Participants are required to have documented tumor progression at study entry and must have received at least one prior androgen receptor axis-targeted therapy (ARAT) for prostate cancer. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants are in an acceptable physical condition with appropriate laboratory values, and they must provide an archival or formalin-fixed paraffin-embedded tumor tissue sample if metastasis to internal organs is present.

The clinical trial is a **Phase 2**, randomized, open-label study designed to evaluate the efficacy of **vobramitamab duocarmazine** at two dose levels in participants with **metastatic castration-resistant prostate cancer**. The primary objective is to assess radiographic progression-free survival (rPFS) by investigator assessment using Prostate Cancer Working Group 3 (PCWG3) criteria. Secondary endpoints include PSA response rate, time to PSA progression, duration of PSA response, and overall response rate (ORR) by investigator assessment, among others. The trial is expected to commence on April 1, 2023, and conclude by February 28, 2025, with a maximum treatment period of 104 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed adenocarcinoma of the prostate and the presence of metastatic lesions. Following the screening, participants will be randomized to receive one of the two dose levels of vobramitamab duocarmazine, administered intravenously. The study will include regular follow-up visits to monitor treatment response and safety, with assessments conducted according to PCWG3 criteria. The end-of-study visit will occur at the conclusion of the treatment period or upon early termination.

Participant involvement is anticipated to last up to 104 weeks, contingent upon individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous safety monitoring protocols to ensure participant well-being throughout the study duration.

The clinical trial involves the administration of **Prednisone**, marketed as Prednison acis 20 mg, which is provided in **tablet** form. This medication is manufactured by ACIS ARZNEIMITTEL GMBH and is authorized under the marketing authorization number 46168.00.00 in Germany. Prednisone is a chemically derived active substance classified under the ATC code H02AB07. The maximum daily dose for participants is 80 mg, administered orally. The treatment period is set for a maximum of 104 weeks. The commercial packaging of Prednisone will be relabeled with a clinical trial label, which includes a tamper-evident seal to ensure the integrity of the medication. The clinical label will cover only the bottom portion of the front panel of the commercial carton, ensuring that the label cannot be removed.

The experimental treatment in this trial is **Vobramitamab Duocarmazine**, also known as MGC018, which is an antibody-drug conjugate. This investigational product is provided as a **concentrate for solution for infusion** and is manufactured by MACROGENICS INC. The active substance, Vobramitamab Duocarmazine, is a protein-based compound. The maximum dose administered is 2.7 mg/kg, delivered intravenously. The treatment duration is also set for a maximum of 104 weeks. This investigational product is not yet assigned an ATC code and is currently under clinical evaluation for its efficacy in treating metastatic castration-resistant prostate cancer.

The efficacy of vobramitamab duocarmazine in the treatment of **metastatic castration-resistant prostate cancer** will be assessed primarily through Radiographic Progression Free Survival (rPFS) as evaluated by investigator assessment using the Prostate Cancer Working Group 3 (PCWG3) criteria. This primary endpoint will provide a measure of the time during and after the treatment that the patient lives with the disease without it getting worse.

Secondary endpoints will include a variety of measures to further evaluate the efficacy of the treatment. These will encompass the Prostate-Specific Antigen (PSA) response rate, time to PSA progression, duration of PSA response, PSA percent change over time, and best PSA percent change, all assessed per PCWG3 criteria. Additionally, the Objective Response Rate (ORR) and Duration of Response (DoR) will be evaluated by investigator assessment using the same criteria. Other secondary endpoints will include the time to the first symptomatic skeletal event (SSE), the number of participants experiencing adverse events (AEs), serious adverse events (SAEs), and AEs leading to study treatment discontinuation. Pharmacokinetic parameters for vobramitamab duocarmazine and the incidence of anti-drug antibodies (ADA) formation against the drug will also be assessed.