A Phase 2, Multicohort Study of Daratumumab-Based Therapies in Participants with
Amyloid Light Chain (AL) Amyloidosis

Daratumumab is a human IgG1* monoclonal antibody (mAb) that binds with high
affinity to a uniqueepitope on CD38, a transmembrane glycoprotein. It is a
targeted immunotherapy directed towards tumor cells that express high levels of
CD38, such as plasma cells from participants with AL amyloidosis.

No formal statistical hypothesis will be tested in this study. The goal of the
study is to generate descriptive data:
Cohort 1: To characterize the cardiac safety profile that may support deferred
administration of VCd (Cohort 1 Arm B) as a potential mitigation strategy for
cardiac events vs immediate administration of VCd (Cohort 1 Arm A) in
participants with newly diagnosed systemic AL amyloidosis with cardiac
involvement treated with SC daratumumab.

Cohort 2: To verify that SC daratumumab (given in combination with VCd)
demonstrates a pharmacokinetic (PK), immunogenicity, safety, and efficacy
profile among racial and ethnic minorities, including Black or African American
participants, consistent with that of the overall population of participants
with newly diagnosed AL amyloidosis.

This study has been transitioned to CTIS with ID 2023-507069-25-00 check the CTIS register for the current data.

The primary objectives for the study are:
Cohort 1, to characterize cardiac safety of different Daratumumab,
cyclophosphamide, bortezomib, and dexamethasone (D-VCd) treatment regimens (Arm
A: immediate daratumumab + VCd treatment and Arm B: daratumumab + deferred VCd)
in newly diagnosed systemic AL amyloidosis with cardiac involvement and to
identify potential mitigation strategies (monitoring of cardiac
health/performance via electrocardiogram (ECG), echocardiography (ECHO), 6 min
walk test, biomarkers [TroponinT, HS TroponinT, and N-terminal pro-brain
natriuretic peptide [NT proBNP]] to inform clinical mitigation strategies
alongside comparison of different treatment schedules) for cardiac toxicity.

Cohort 2, to characterize the pharmacokinetics of subcutaneous (SC)
daratumumab, among racial and ethnic minorities, including Black or African
American, with newly diagnosed AL amyloidosis treated with SC daratumumab in
combination with VCd.

Key secondary objectives are to evaluate overall efficacy and to assess the
safety profile, including cardiac events.

This is a multicenter, multicohort, open-label, Phase 2 study in participants
with newly diagnosed systemic AL amyloidosis to characterize the following:
• Cohort 1: safety of SC daratumumab + VCd (Arm A) vs daratumumab with deferred
administration of VCd (Arm B) in newly diagnosed systemic AL amyloidosis with
Mayo Cardiac Stage II and IIIa cardiac involvement.
• Cohort 2: PK, immunogenicity, safety, and efficacy of SC daratumumab among
racial and ethnic minorities, including Black or African American participants,
with newly diagnosed systemic AL amyloidosis treated with D-VCd.
Cardiac safety and function (ECG, ECHO, 6 min walk test, biomarkers [TroponinT,
HS TroponinT, and NT-proBNP]), PK and immunogenicity will be evaluated for both
cohorts. Data obtained from this study will provide information about the
pharmacokinetic profile of SC daratumumab in participants with newly diagnosed
systemic AL amyloidosis with cardiac involvement and in racial and ethnic
minorities with AL amyloidosis .
During the Screening Phase, all participants will provide written consent for
study participation and will be screened for study eligibility within 28 days
of Cycle 1 Day 1 (for participants requiring mass spectrometry typing, the
screening period will be extended to 42 days). All eligibility criteria must be
met prior to enrollment. Waivers will not be allowed. Participants should start
treatment within 7 days of enrollment approval.
All treatment cycles are 28 days (± 5-day window) in length. Participant will
receive study treatment until intolerable toxicity, start of subsequent
therapy, withdrawal of consent, or completion of 24 cycles, whichever occurs
first. Cardiac events and clinical signs and symptoms of cardiac AL amyloidosis
will be collected for 12 months from Cycle 1 Day 1 regardless of treatment
discontinuation or start of subsequent treatment. In addition, clinical signs
and symptoms of cardiac AL amyloidosis will also be collected at the EOT visit.
In addition to efficacy and safety assessments, samples for PK, immunogenicity,
exploratory biomarkers, and patient reported outcomes (PROs) will be collected
for all participants. All study evaluations will be conducted according to the
Schedule of Activities.

Study treatment will be administered on 28 day cycles (± 5 days) for all
treatment groups.

Cohort 1 Arm A and Cohort 2: Dosing will be initiated with the first dose of SC
daratumumab (1800 mg) on Cycle 1 Day 1. SC daratumumab will be administered
weekly during Cycles 1 and 2, every 2 weeks (Q2W) (Days 1 and 15) during Cycles
3 to 6, and every 4 weeks (Q4W) (Day 1 of each cycle) thereafter until a
maximum of 24 cycles of treatment or start of subsequent therapy. Starting at
Cycle 1 Day 1, VCd will be administered weekly (Days 1, 8, 15, 22) in every
28-day cycle for a maximum of 6 cycles (Cycle 6 Day 22).

Cohort 1 Arm B: Dosing will be initiated with the first dose of SC daratumumab
(1800 mg) on Cycle 1 Day 1. SC daratumumab will be administered weekly during
Cycles 1 and 2, Q2W (Days 1 and 15) during Cycles 3 to 6, and Q4W (Day 1 of
each cycle) thereafter until a maximum of 24 cycles of treatment or start of
subsequent therapy. Starting at Cycle 4 Day 1, VCd will be administered weekly
(Days 1, 8, 15, 22) in every 28-day cycle for a maximum of 6 cycles (Cycle 9
Day 22).

If participants complete the study in full, they have to visit the study
location about 48 times in two years. In total, participants will receive a
subcutaneous injection 34 times. Chances of side effects and risks are listed
in the ICF in section 5 (p. 9-13) and in appendix D (p. 29-34). Also check the
answers on questions E9 and E9a.