Phase 2 Study of Daratumumab (DARA) Plus Bortezomib, Cyclophosphamide, and Dexamethasone (D-VCd) in a Diverse Patient Population with Newly Diagnosed Amyloid Light Chain (AL) Amyloidosis: Aquarius

Background: AL amyloidosis is a rare disorder in which deposition of insoluble amyloid fibrils composed of misfolded light chains in vital organs, such as the heart or kidney, leads to serious and life-threatening organ dysfunction. Cardiac involvement is the primary determinant of clinical outcomes for patients with AL amyloidosis, and survival expectations decrease with increasing cardiac stage. Subcutaneous DARA (DARA SC) in combination with VCd recently became the first and only approved treatment for newly diagnosed AL amyloidosis based on results of the phase 3 ANDROMEDA study. In the ANDROMEDA study, a higher hematologic complete response rate was consistently achieved with D-VCd versus VCd in patients with newly diagnosed AL amyloidosis, regardless of baseline cardiac stage (Kastritis E, et al. N Engl J Med. 2021;385[1]:46-58). However, cardiac involvement leads to challenges in the attribution of cardiac events to underlying disease and/or treatments. Additionally, among patients randomized to receive D-VCd in the ANDROMEDA study, 15.4% were Asian, 4.6% were Hispanic or Latino, and 3.1% were Black or African American, limiting the interpretation of safety, efficacy, and pharmacokinetic results among patients of different racial and ethnic backgrounds.

Therefore, the ongoing phase 2 AQUARIUS (AMY2009) study will characterize the cardiac safety of different D-VCd treatment regimens in patients with newly diagnosed AL amyloidosis with cardiac involvement to identify potential mitigation strategies for cardiac toxicity, as well as better characterize the safety, efficacy, and pharmacokinetics of D-VCd among racial and ethnic minorities.

Study Design and Methods: This ongoing multicenter, multicohort, open-label phase 2 study will enroll ~150 patients aged ≥18 years with newly diagnosed systemic AL amyloidosis and measurable disease from ~45 sites across 10 countries. Patients in Cohort 1 (n = ~120) will have cardiac involvement (AL amyloidosis Mayo Cardiac Stage II and Stage IIIa) with or without other organ involvement. Patients in Cohort 2 (n = ~30) will be of racial or ethnic minority (including ≥15 Black or African American patients) and have ≥1 organ affected by systemic AL amyloidosis.

Patients in Cohort 1 will be stratified by baseline cardiac stage (Stages II and IIIa) and randomly assigned (2:1) to receive DARA SC plus immediate VCd (Arm A) or DARA SC plus deferred VCd (Arm B; Figure 1). In both arms, DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE ® drug delivery technology, Halozyme, Inc., San Diego, CA, USA]) will be administered QW during Cycles 1-2, Q2W during Cycles 3-6, and Q4W thereafter until a maximum of 24 cycles or the start of subsequent therapy. In Arm A, starting at Cycle 1 Day 1, VCd will be administered weekly in every 28-day cycle for a maximum of 6 cycles. In Arm B, starting at Cycle 4 Day 1, VCd will be administered weekly in every 28-day cycle for a maximum of 6 cycles. Patients in Cohort 2 will receive DARA SC plus immediate VCd.

Several unique initiatives were incorporated into the study to enhance enrollment of patients of racial or ethnic minority in Cohort 2, including selecting sites from the ANDROMEDA study that enrolled racially/ethnically diverse patients, targeting new sites in diverse communities, raising awareness of AL amyloidosis and the AQUARIUS study among minority patients at the local and national levels, and educating sites on engagement of patients from diverse backgrounds.

The first primary endpoint is incidence of any toxicity grade cardiac events for the different D-VCd treatment regimens (DARA SC + immediate VCd and DARA SC + deferred VCd). The second primary endpoint is trough serum concentration (C _trough) of DARA at the end of QW dosing (Cycle 3 Day 1 predose). Efficacy evaluations include assessment of hematologic response and organ response. Data will be summarized using descriptive statistics. The first patient was enrolled on March 17, 2022. As of July 10, 2023, the study has enrolled 75 patients; 71 in Cohort 1 and 4 in Cohort 2. In the US, 2 of the 8 patients enrolled were of racial minority ( Figure 2). Efforts to increase enrollment of minorities continue to be optimized and new collaborative initiatives explored to ensure representative and diverse enrollment in clinical trials. The ClinicalTrials.gov Identifier is NCT05250973.