Phase 2 Multicohort Evaluation of Daratumumab, Bortezomib, Cyclophosphamide, and Dexamethasone in Systemic AL Amyloidosis with Cardiac Involvement

The primary objective of this study is to **characterize cardiac safety** of different D-VCd treatment regimens in newly diagnosed systemic **Amyloid Light Chain (AL) Amyloidosis** with cardiac involvement. This is clinically relevant as cardiac involvement is a significant complication in AL amyloidosis, often leading to increased morbidity and mortality. Identifying potential mitigation strategies for cardiac toxicity is also a primary focus, aiming to improve patient outcomes by reducing adverse cardiac events. Additionally, the study seeks to characterize the pharmacokinetics (PK) of subcutaneous (SC) daratumumab among racial and ethnic minorities with newly diagnosed systemic AL amyloidosis treated with D-VCd, which is crucial for understanding drug behavior in diverse populations.

Secondary objectives include: - Evaluating efficacy measures to determine the therapeutic impact of the treatment regimens. - Assessing the safety profile, including cardiac events, to ensure comprehensive safety monitoring. - Characterizing the PK of SC daratumumab to provide detailed insights into its pharmacological profile. - Assessing the immunogenicity of SC daratumumab to understand potential immune responses. - Monitoring the clinical signs and symptoms of cardiac AL amyloidosis to identify possible predictive factors for cardiac events, which could lead to improved risk stratification and management strategies.

The clinical trial involves a total of **72 participants** diagnosed with **Amyloid Light Chain Amyloidosis**. The study population includes both male and female subjects, aged 18 years and older, with a focus on newly diagnosed individuals with systemic AL amyloidosis, particularly those with cardiac involvement. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of systemic AL amyloidosis and measurable disease at screening. The trial also emphasizes the inclusion of racial and ethnic minorities, such as Black or African American individuals, to ensure diverse representation. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2, indicating they are ambulatory and capable of self-care. The trial population is characterized by a range of pre-treatment clinical laboratory values, ensuring participants meet specific health criteria. Lifestyle considerations, such as diet and physical activity, are not explicitly detailed in the trial data provided. The study does not specify any particular habits or lifestyle factors that may influence participation.

The clinical trial is a Phase 2, multicohort study designed to evaluate the safety and pharmacokinetics of **daratumumab**-based therapies in participants with **amyloid light chain amyloidosis**. 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 June 2022 to February 2028, with participant involvement expected to last up to 24 months. The study aims to characterize cardiac safety, identify mitigation strategies for cardiac toxicity, and assess the pharmacokinetics of subcutaneous daratumumab, particularly among racial and ethnic minorities.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, diagnosis, and laboratory values. Following the screening, participants will be randomized into treatment cohorts. Regular follow-up visits will be scheduled to monitor safety, efficacy, and any adverse events. These visits will include assessments of cardiac events, overall hematologic complete response rates, and organ response rates at specified intervals, such as 6 and 12 months. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial will adhere to strict ethical guidelines, ensuring that all participants provide informed consent and that their health and well-being are prioritized throughout the study. The trial's primary endpoints include the incidence of cardiac events and the pharmacokinetic profile of daratumumab, while secondary endpoints focus on response rates, overall survival, and time to next treatment.

The clinical trial involves the administration of **VELCADE** (bortezomib), a **powder for solution for injection**. This experimental medication is administered via **subcutaneous use**. The maximum daily dose is 3.5 mg, with a total dose not exceeding 3.5 mg per administration. The treatment period is set for a maximum of 24 weeks. VELCADE is of chemical origin and is produced by Janssen-Cilag International NV. Participant compliance with the dosing schedule will be monitored throughout the trial.

**DARATUMUMAB** is another experimental medication used in this study. It is provided as a **solution for injection** and is administered subcutaneously. The maximum daily dose is 1800 mg, with a total dose not exceeding 1800 mg per administration. The treatment duration is also capped at 24 weeks. Daratumumab is a protein of other origin, and its administration will be closely monitored to ensure adherence to the dosing regimen.

**CYCLOPHOSPHAMIDE** is utilized as an auxiliary treatment in the trial. It is available as a **powder for solution for infusion** and is administered intravenously. The maximum daily dose is 500 mg, with a total dose not exceeding 500 mg per administration. The treatment period is limited to 24 weeks. Cyclophosphamide is of chemical origin, and participant compliance will be tracked to ensure proper administration.

**DEXAMETHASONE SODIUM PHOSPHATE** is also used as an auxiliary treatment. It is provided as a **solution for infusion** and administered intravenously. The maximum daily dose is 40 mg, with a total dose not exceeding 40 mg per administration. The treatment duration is set for a maximum of 24 weeks. Dexamethasone sodium phosphate is a corticosteroid, and adherence to the dosing schedule will be monitored throughout the study.

Efficacy in this clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoints include the incidence of any toxicity grade of cardiac events and the **C[trough]** levels. Secondary endpoints encompass a variety of measures such as the overall hematologic complete response (HemCR) and HemCR rate at 6 months, the rate of very good partial response (VGPR) or better, time to HemCR or VGPR, and the duration of response for HemCR and VGPR or better. Additionally, organ response rates at 6 and 12 months for kidney, heart, and liver will be evaluated, along with overall survival (OS), time to next treatment (TNT), and the incidence and severity of adverse events (AEs). The pharmacokinetic profile and immunogenicity of daratumumab, as well as clinical signs and symptoms of cardiac AL amyloidosis, will also be assessed.

The efficacy parameters will be measured and collected at specified timepoints, including 6 and 12 months, using validated scales and laboratory tests. The analysis will focus on both the hematologic and organ-specific responses, providing a comprehensive evaluation of the treatment's impact on systemic AL amyloidosis. The trial aims to characterize the cardiac safety and pharmacokinetics of subcutaneous daratumumab, particularly among racial and ethnic minorities with newly diagnosed systemic AL amyloidosis.