A Phase 3, Double-Blind, Multicenter Study to Evaluate the Efficacy and Safety of CAEL-101 and Plasma Cell Dyscrasia Treatment Versus Placebo and Plasma Cell Dyscrasia Treatment in Plasma Cell Dyscrasia Treatment-Naïve Patients with Mayo Stage IIIb AL Amyloidosis

2.1 Background
Amyloidosis is a rare and serious heterogeneous group of diseases characterized
by fibrillar
protein deposits and amyloids localized in a single organ or systemically in
many organs
(Hemminki 2012). AL amyloidosis is the most common form of systemic amyloid
disease,
accounting for approximately 70% of all patients suffering from the disease
(Milani 2018). All
organs, except for the brain, can be affected in AL amyloidosis leading to
irreversible organ
dysfunction and death if unrecognized or treated ineffectively (Milani 2018).
The disease is
inevitably progressive and accumulating amyloid protein deposits interfere with
the tissue or
organ*s healthy function causing clinical symptoms, organ failure and death.
Thirty to 40% of
patients die within 12 months of diagnosis (Dispenzieri 2015). The prognosis is
very poor, with
less than 5% of all patients with AL amyloidosis surviving more than 10 years
after diagnosis
(Kyle 1986, Palladini 2015, Palladini 2017). The prognosis of patients with AL
amyloidosis
depends on the burden of the amyloid in the tissues, especially the heart, and
the size of the
plasma cell clone and its biology, which predict the ability to achieve a
hematologic response.
Current treatment regimens are largely derived from anti-myeloma therapies and
autologous
stem cell transplants. Both therapies seek to reduce abnormal bone
marrow-resident plasma cells.
Daratumumab, an anti-CD38 antibody which binds to plasma cells, is the only
therapy approved
by the United States Food and Drug Administration (FDA), under accelerated
approval, for the
treatment of AL amyloidosis. There are currently no approved treatments for AL
amyloidosis
that directly target the removal of deposited amyloid fibrils.

3. STUDY OBJECTIVES
3.1. Primary Objectives
The primary objectives are:
• To determine if CAEL-101 and treatment for PCD improves overall survival in
Mayo stage IIIb AL amyloidosis patients who are treatment naïve compared to
treatment for PCD alone
• To evaluate the safety and tolerability of CAEL-101 in combination with
treatment for PCD
3.2. Key Secondary Objectives
The key secondary objectives in this study are:
• To assess quality of life as measured by the KCCQ-OS
• To assess cardiac improvement as measured GLS%
• To assess functional improvement as measured by the distance walked in the
6MWT
• To assess quality of life as measured by the SF-36v2® PCS
3.3. Exploratory Objectives
Additional objectives in this study include:
• To assess improvement in cardiac amyloidosis as measured by changes in
NT-proBNP, cTnT, dFLC, and CRP
• To assess cardiac response, defined as a decrease of > 30% in NT-proBNP
levels AND a decrease of NT-proBNP > 300 ng/L
• To assess composite cardiac response when both of the following are satisfied:
* a decrease of > 30% in NT-proBNP levels AND a decrease of NT-proBNP > 300
ng/L;
* GLS improvement of >= 2%
• To assess the composite endpoint for cardiac deterioration defined as:
* death (cardiac transplant and left ventricular assist device implantation are
treated as death), OR
* > 30% increase in NT-proBNP levels (in the absence of eGFR decline of >= 25%)
AND >= 300 ng/L increase in NT-proBNP (in the absence of eGFR decline of >= 25%),
OR
* <= 2% improvement in GLS
• To assess renal response, defined as 30% decrease in proteinuria or drop of
proteinuria below 0.5 g/24 h in the absence of >= 25% decrease in eGFR.
(Palladini 2014) Renal response will be assessed in patients with renal
involvement, defined as those with a baseline urinary protein excretion of more
than 0.5 g per day
• To assess changes in effects on liver function including AST, ALT, ALP and GGT
• To assess changes in effects on renal function including eGFR, serum
creatinine and 24-hour urine protein
• To assess QoL as measured by the KCCQ domain scores, SF-36v2® scaled domain
scores and EQ-5D-5L*
• To assess change in NYHA Functional Classification
• To describe the PK profile based on plasma levels of CAEL-101
• To assess the immunogenicity of CAEL-101

4. STUDY DESIGN
This is a double-blind, randomized, multicenter, international Phase 3 study of
CAEL-101 combined with SoC PCD treatment versus placebo combined with SoC PCD
treatment in Mayo stage IIIb PCD treatment-naïve AL amyloidosis patients. As
this is an event-driven study, the study will enroll until at least 101 deaths
have been observed (see Section 10.1).
Approximately 124 patients will be enrolled using a 2:1 randomization ratio and
stratification will be based on geographic region across investigator sites. An
interim analysis (IA) with stopping rules for early efficacy may be performed
when approximately 75% (76/101) of the expected deaths have been observed (see
Section 11).
Patients in both study intervention groups will be followed from randomization
until death from any cause or until the end of study.
A schematic of the study design is presented in Figure 1 while the Schedule of
Assessments is presented in Table 1.

6. TREATMENT PLAN
The study is divided into a Screening period, Treatment period, End of
Treatment period and Survival Follow-up period.
During the Treatment period, patients will be seen in the clinic every 7 (+/-
1) days for 4 weeks then approximately every 14 (+/- 2) days to receive study
drug infusions. Approximately every 28 (+/- 2) days, patients will be assessed
for changes in NT-proBNP, cTnT, FLC, PK, and safety measurements including
immunogenicity assessments at Weeks 1, 10, 26, and 50. Approximately every 12
weeks (starting at Week 14), patients will be assessed for changes in 6MWT and
QoL questionnaires. After week 50, the 6MWT and QoL questionnaires are only
required every 6 months +/- 30 days. Patients will undergo echocardiography for
GLS% and collection of 24-hour urine for assessment of protein, CRP, and
assessment of NYHA Functional Classification (Section 8.9) at approximately
Weeks 14, 26, and 50 then approximately every 6 months while on study treatment.
During the End of Treatment period, patients who discontinue study drug therapy
for reason other than death will be seen in the clinic at approximately every
14 (+/- 1) days following the last dose of study drug twice, then approximately
every 28 (+/-1) days for 4 more visits for efficacy and safety assessments.
During the Survival Follow-up period, patients who discontinue study drug
therapy for reasons other than death will be contacted approximately every 12
weeks (+/- 7 days) until death or end of the study to assess for survival and
PCD therapies received.
Every effort should be made to schedule assessments within the
protocol-specified windows. Refer to the Schedule of Assessments in Table 1 for
the list and timing of assessments.

6.2.1. Administration of Study Drug
Patients randomized to receive CAEL-101 will receive 1000 mg/m2. The total dose
will be based on the patient*s BSA in meters squared which is calculated using
the height and weight obtained during the Screening period. See the Pharmacy
Manual for instructions on calculation of BSA. It is not necessary to
recalculate the BSA for subsequent dosing unless the patient experiences weight
change of >= 20%. Patients randomized to receive placebo will receive 0.9%
normal saline in an equivalent volume to a CAEL-101 infusion (approximately 250
cc). When administered on the same day, the study drug will be administered
first before PCD therapy. (Patient may take dexamethasone prior to receiving
study drug). Patients will receive study drug by an IV infusion over
approximately 2 hours. Patients will be observed for infusion reactions,
injection site reactions and overall well-being in the clinic for approximately
90 minutes, or as long as the Investigator deems appropriate, following the
completion of the study drug infusion for the first 4 infusions. (Observations
may include vital signs at the Investigator*s discretion.) (Section 6.2.2)
Patients will receive study drug every 7 (+/- 1) days for 4 infusions then
every 14 (+/- 2) days. Doses may be delayed due to patient care requirements
(e.g., hospitalization, side effects) (Section 6.2.3).
Additional details for study drug administration are included in the Pharmacy
Manual.

2.3. Benefit-Risk Analysis
Treatment options for patients with AL amyloidosis are limited and there are no
approved therapies that have the potential to remove or reduce amyloid burden
in the organs. CAEL-101 studies to date have provided evidence of the potential
for CAEL-101 to have an organ response impact that is additive to hematologic
response benefit from current plasma cell dyscrasia (PCD) treatments.
Patients enrolled in this trial have a very poor prognosis and, despite
improvements in overall survival over the past 15 years, early mortality in
this population represents an unmet medical need.
All patients enrolled in this study will receive standard of care (SoC) PCD
treatment and will be randomized in a 2:1 ratio. For every three patients
enrolled, two will receive CAEL-101 in addition to their PCD treatment and one
will receive placebo in addition to their PCD treatment.
Common side effects (>= 10% of total population) observed in patients who have
received any dose of CAEL-101 included nausea, constipation, vomiting,
diarrhea, peripheral edema, fatigue, rash, and dyspnea.
The benefit to risk assessment favors initial and continuing treatment for AL
amyloidosis. If new evidence becomes available that would impact this risk
assessment, it will be revised and communicated accordingly.