S1702 Isatuximab in Treating Patients With Relapsed or Refractory Primary Amyloidosis

PRIMARY OBJECTIVES:

I. To assess the efficacy as measured by the confirmed overall hematologic response rate
(partial response or better) of isatuximab in relapsed/refractory systemic light chain (AL)
amyloidosis.

SECONDARY OBJECTIVES:

I. To evaluate toxicities in the treatment of relapsed/refractory AL amyloidosis with
isatuximab.

II. To evaluate time to hematologic response. III. To evaluate duration of response. IV. To
evaluate progression-free survival (PFS). V. To evaluate overall survival (OS).

TERTIARY OBJECTIVES:

I. To evaluate efficacy of isatuximab in relapsed/refractory immunoglobulin amyloid light
chain (AL) amyloidosis as measured by organ specific response rates (cardiac, renal,
gastrointestinal [GI], liver, soft tissue, nerve), in the subset of patients that can be
evaluated for organ response.

II. To evaluate time to organ response in the subset of patients that can be evaluated for
organ response.

OUTLINE:

Patients receive isatuximab intravenously (IV) on days 1, 8, 15, and 22 of course 1 and on
days 1 and 15 of subsequent courses. Treatment repeats every 28 days for 24 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up within 30 days and then every
at least every 6 months for up to 4 years.

Inclusion Criteria:

- Patient must have relapsed or refractory primary systemic AL amyloidosis,
histologically-confirmed by positive Congo red stain with green by birefringence on
polarized light microscopy, OR characteristic appearance by electron microscopy AND
confirmatory AL amyloid typing (mass spectrometry-based proteomic analysis or
immunofluorescence)

- Patient must have measurable disease within 28 days prior to registration; serum beta2
microglobulin, serum quantitative immunoglobulins (immunoglobulin [Ig]G, IgA, and
IgM), serum free kappa and lambda, and serum protein electrophoresis (SPEP) with
M-protein quantification must be obtained within 14 days prior to registration

- Patient must demonstrate a difference in the involved serum free light chains (kappa
or lambda) versus the uninvolved serum free light chain of >= 4.5 mg/dL within 14 days
prior to registration

- Patient must have objective organ involvement defined by ONE (or more) of the
following; all disease for involved organs must be assessed and documented on the AL
baseline tumor assessment form

- Kidney: albuminuria greater than or equal to 500 mg per day on a 24-hour urine
specimen within 35 days prior to registration, OR prior kidney biopsy (at time of
diagnosis) showing amyloid deposition

- Heart: mean left ventricular wall thickness on echocardiogram greater than or
equal to 12 mm in the absence of hypertension or valvular heart disease, OR
N-terminal fragment brain natriuretic protein (NT-pro) brain natriuretic peptide
(BNP) greater than 332 ng/mL provided that patient does not have impaired renal
function (as defined by calculated creatinine clearance less than 25 mL/min)
within 14 days prior to registration, OR prior cardiac biopsy (at time of
diagnosis) showing amyloid deposition with past documented or presently noted
clinical symptoms and signs supportive of a diagnosis of heart failure in the
absence of an alternative explanation for heart failure

- Liver: hepatomegaly (total liver span > 15 cm) as demonstrated by computed
tomography (CT) or magnetic resonance imaging (MRI) within 35 days prior to
registration OR elevated alkaline phosphatase (ALP) greater than 1.5 times the
upper limit of normal within 14 days prior to registration, OR prior liver biopsy
(at time of diagnosis) showing amyloid deposition

- Gastrointestinal tract: prior biopsy showing amyloid deposition AND symptoms such
as GI bleeding or persistent diarrhea (> 4 loose stools/day on most days over a
consecutive 28-day period)

- Autonomic or peripheral nervous system: orthostatic blood pressure, symptoms of
nausea, early satiety, diarrhea or constipation, abnormal sensory and/or motor
findings on neurologic exam, or gastric atony by gastric emptying scan; Note:
pulse and blood pressure must be recorded with the patient supine (lying down),
and then again after at least 1 minute, but less than 3 minutes of standing; this
assessment must be repeated on 2 separate occasions (at least 1 day apart; e.g.
day -3 and day -1) within a 28-day screening period

- Soft tissue: macroglossia, or soft tissue deposits (including lymphadenopathy,
recurrent peri-orbital purpura, peri-articular, skin or other soft tissue)
requiring therapy

- Patients must not have active symptomatic multiple myeloma, as defined by 2015
International Myeloma Working Group (IMWG) criteria (hypercalcemia, renal failure,
anemia, and bone [CRAB] criteria; bone marrow plasmacytosis > 60%); kappa: lambda
ratio > 100 is acceptable only if the clinical symptoms and sign are attributable only
to amyloidosis and not multiple myeloma (hemoglobin [Hgb] < 8 g/dL)

- Patient must be relapsed or refractory to at least one prior line of therapy (such as:
transplant, radiation, or chemotherapy)

- Patients must have completed other systemic therapy >= 14 days or investigational drug
>= 28 days prior to registration, surgery (other than biopsies) >= 21 days prior to
registration, and any autologous stem cell transplant (ASCT) >= 100 days prior to
registration

- Patients must not have received any or supplements which have been known to have some
anti-amyloidogenic effect (such as: doxycycline; curcumin; prednisone; dexamethasone;
epigallocatechin gallate [EGCG]) within 14 days prior to registration

- Patients must not have any known allergies to isatuximab or other monoclonal antibody
therapies

- Patients must not have received daratumumab within 56 days prior to registration nor
have been refractory to daratumumab

- Patients must not be eligible for autologous stem cell transplantation

- Patients must have a complete medical history and physical exam within 14 days prior
to registration

- Within 14 days prior to registration: Total bilirubin =< 2.0 x IULN (institutional
upper limit of the norm) AND

- Within 14 days prior to registration: Serum glutamic-oxaloacetic transaminase
(SGOT)/aspartate aminotransferase (AST) and serum glutamate pyruvate transaminase
(SGPT)/alanine aminotransferase (ALT) =< 4.0 x IULN

- Creatinine clearance (CrCl) >= 25 mL/min, as measured by a 24-hour urine collection or
as estimated by the Cockcroft and Gault formula; the serum creatinine value used in
the calculation must have been obtained within 35 days prior to registration

- Patients must have bone marrow aspirate, including fluorescence in situ hybridization
(FISH) (including: del 17p; t11;14; t4;14, t14;16; and del 13q) and cytogenetic
testing (normal ? XY; and all abnormalities) within 35 days prior to registration;
central pathology analysis will not be required, however the local pathology report
and FISH/cytogenetic data must be submitted in Medidata RAVE

- Within 14 days prior to registration: Absolute neutrophil count (ANC) >= 1,000
cells/mcl without growth factor support, AND

- Within 14 days prior to registration: Platelets >= 75,000 cells/mcl

- Patients must have hemoglobin >= 8 g/dL within 14 days prior to registration; patients
may have received transfusion if greater than 7 days prior to registration

- New York Heart Association (NYHA) < class IV heart failure

- Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) >= 35% within 35
days prior to registration; and

- NT-proBNP =< 8500 ng/L within 14 days prior to registration

- Patients must have a Zubrod performance status =< 2

- Patients must not have any clinically significant uncontrolled systemic illness,
including but not limited to uncontrolled, active infection requiring intravenous
antibiotics, unstable angina pectoris, myocardial infarction within the past 6 months,
uncontrolled cardiac arrhythmias, uncontrolled hypertension, or uncontrolled diabetes
mellitus

- Uncontrolled diabetes: patients who have a diagnosis of diabetes must have an
glycosylated hemoglobin (HbA1C) < 7% within 14 days prior to registration; the
same criterion will be used in patients with confirmed diagnosis of diabetes
mellitus who have been on a stable dietary or therapeutic regimen for this
condition in the last three months

- Uncontrolled blood pressure and hypertension: all blood pressure measurements
within the 14 days prior to registration must be systolic blood pressure (SBP) =<
160 and diastolic blood pressure (DBP) =< 100; an exception can be made by a
healthcare provider for a patient with a single blood pressure elevation who upon
rechecking has a normal blood pressure

- Females of childbearing potential must have a negative baseline pregnancy test within
14 days prior to registration; this may be either a serum or urine pregnancy test,
with a sensitivity of at least 50 mIU/mL; females of childbearing potential (FCBP)
must also agree: (1) to have a pregnancy test prior to the start of each treatment
cycle and (2) to either commit to continued abstinence from heterosexual intercourse
or to use effective contraception while receiving study drug and for at least 12 weeks
after receiving the last dose of study drug; females are considered to be of
?childbearing potential? if they have had menses at any time in the preceding 24
consecutive months; in addition to routine contraceptive methods, ?effective
contraception? also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, she is responsible
for beginning contraceptive measures

- Patients with evidence of hepatitis B virus (HBV) are eligible provided there is
minimal hepatic injury and the patient has undetectable HBV on suppressive HBV
therapy; patient must be willing to maintain adherence to HBV therapy; patients with
previously treated and eradicated hepatitis C virus (HCV) who have minimal hepatic
injury are eligible

- Patients who are known to be human immunodeficiency virus (HIV)-positive at
registration are eligible if at time of registration they meet all other protocol
eligibility criteria in addition to the following:

- Patient has undetectable HIV viral load by standard polymerase chain reaction
(PCR) clinical assay

- Patient is willing to maintain adherence to combination antiretroviral therapy

- Patient has no history of acquired immunodeficiency syndrome (AIDS) defining
condition (other than CD4 cell count < 200 mm^3)

- Patient is otherwise likely to have a near normal lifespan if not for the
presence of relapsed/refractory amyloid

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease free for at least two years