A Phase II Study of Isatuximab (SAR650984) (NSC-795145) for Patients With Previously Treated AL Amyloidosis
Phase: PHASE2
Conditions: Amorphous, Eosinophilic, and Acellular Deposit, Constipation, Diarrhea, Early Satiety, Gastrointestinal Hemorrhage, Hepatomegaly, Lymphadenopathy, Macroglossia, Nausea, Primary Systemic Amyloidosis, Purpura, Recurrent Primary Amyloidosis, Refractory Primary Amyloidosis
Sponsor: SWOG Cancer Research Network

 
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PRIVILEGED COMMUNICATION 
FOR INVESTIGATIONAL USE ONLY 
 
 
SWOG 
TITLE 
A PHASE II STUDY OF ISATUXIMAB (SAR650984) (NSC-795145) FOR PATIENTS WITH 
PREVIOUSLY TREATED AL AMYLOIDOSIS  
 
NCT#03499808 
 
STUDY CHAIRS: 
AGENTS: 
 
Terri Parker, M.D. (Medical Oncology) 
SWOG-Held IND Agents: 
Yale School of Medicine 
Isatuximab (SAR650984) (NSC#795145)  
333 Cedar Street 
 
(IND-138083) 
P.O. Box 208028 
New Haven, CT 06520 
Phone: 203/737-7059 
 
FAX: 203/737-3401 
E-mail: terri.parker@yale.edu  
BIOSTATISTICIANS: 
 
Vaishali Sanchorawala, M.D. (Medical Oncology) 
Antje Hoering, Ph.D. (Biostatistics) 
Boston Medical Center 
Kari Chansky, M.S. (Biostatistics) 
820 Harrison Ave, FGH-1 
Cancer Research and Biostatistics 
Boston, MA  02118 
1730 Minor Avenue, Suite 1900 
Phone:  617/638-8265 
Seattle, WA 98101-1468 
FAX:  617/638-6518 
Phone:  206/652-2267 
E-mail:  vaishali.sanchorawala@bmc.org  
FAX:  206/652-4612 
 
E-mail:  antjeh@crab.org  
ALLIANCE CHAMPION: 
E-mail:  karic@crab.org  
 
Heather J. Landau, M.D. 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, NY 10065 
Phone: 212/639-8808 
E-mail: landauh@mskcc.org  
 
ECOG-ACRIN CHAMPION: 
 
Erica Campagnaro, M.D. 
E-mail:  ericam@umich.edu  
PARTICIPANTS 
 
U.S. Only 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
TITLE  ......................................................................................................................................................... 1 
PARTICIPANTS ............................................................................................................................................ 1 
TABLE OF CONTENTS ............................................................................................................................... 2 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 4 
1.0 
OBJECTIVES .................................................................................................................................. 5 
1.1 
Primary Objective ............................................................................................................................. 5 
1.2 
Secondary Objectives ...................................................................................................................... 5 
1.3 
Other Objectives .............................................................................................................................. 5 
2.0 
BACKGROUND ............................................................................................................................... 5 
2.1  
Study Population .............................................................................................................................. 5 
2.2  
Current Standard of Care ................................................................................................................. 6 
2.3  
Isatuximab ........................................................................................................................................ 6 
2.4  
TED 10893 Phase I Study ............................................................................................................... 7 
2.5  
Hypothesis ....................................................................................................................................... 8 
2.6 
Response Criteria ............................................................................................................................ 8 
2.7 
Inclusion of Women and Minorities .................................................................................................. 9 
3.0 
DRUG INFORMATION .................................................................................................................... 9 
3.1 
Isatuximab (SAR650984) (NSC #795145, IND-138083) ................................................................. 9 
4.0 
STAGING CRITERIA ..................................................................................................................... 16 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 16 
5.1 
Disease Related Criteria ................................................................................................................ 16 
5.2 
Prior/Concurrent Therapy Criteria .................................................................................................. 17 
5.3 
Clinical/Laboratory Criteria ............................................................................................................. 18 
5.4 
Specimen Submission Criteria ....................................................................................................... 20 
5.5 
Regulatory Criteria ......................................................................................................................... 20 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 20 
7.0 
TREATMENT PLAN ...................................................................................................................... 21 
7.1 
General Treatment Instructions ..................................................................................................... 21 
7.2 
Pre-Medication ............................................................................................................................... 22 
7.3 
Treatment ....................................................................................................................................... 23 
7.4 
Organ Evaluation Guidelines ......................................................................................................... 23 
7.5 
Criteria for Removal from Protocol Treatment ............................................................................... 24 
7.6 
Discontinuation of Treatment ......................................................................................................... 24 
7.7 
Follow-Up Period ............................................................................................................................ 24 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 25 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 25 
8.2 
Supportive Care ............................................................................................................................. 25 
8.3 
Dose Delays ................................................................................................................................... 25 
8.4 
White Blood Cell Growth Factors ................................................................................................... 26 
8.5 
Guidelines for the Management of Infusion Reactions (IRs) ......................................................... 26 
8.6 
Dose Delay Contacts ..................................................................................................................... 27 
8.7 
Adverse Event Reporting ............................................................................................................... 27 
9.0 
STUDY CALENDAR ...................................................................................................................... 28 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 33 
10.1 
Measurable disease ....................................................................................................................... 33 
10.2 
Hematologic Response and Progression ....................................................................................... 33 
10.3 
Organ Response () ......................................................................................................................... 33 
10.4 
Criteria for Organ Progression ....................................................................................................... 35 
10.5 
Time to Hematologic Response ..................................................................................................... 36 
10.6 
Overall Survival .............................................................................................................................. 36 
10.7 
Progression-Free Survival.............................................................................................................. 36 
10.8 
Performance Status ....................................................................................................................... 36 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 36 
11.1 
Two-Stage Design .......................................................................................................................... 36 
11.2 
Sample size and Power Justification ............................................................................................. 37 

 
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11.3 
Analysis of Primary Endpoint ......................................................................................................... 37 
11.4 
Analysis of Secondary and Other Endpoints ................................................................................. 37 
11.5 
Safety Analysis ............................................................................................................................... 38 
12.0 
DISCIPLINE REVIEW .................................................................................................................... 38 
13.0 
REGISTRATION GUIDELINES ..................................................................................................... 39 
13.1 
Registration Timing ........................................................................................................................ 39 
13.2 
Investigator/Site Registration ......................................................................................................... 39 
13.3 
OPEN Registration Requirements ................................................................................................. 42 
13.4 
Registration Procedures................................................................................................................. 43 
13.5 
Exceptions to SWOG registration policies will not be permitted. ................................................... 44 
14.0 
DATA SUBMISSION SCHEDULE ................................................................................................ 44 
14.1 
Data Submission Requirement ...................................................................................................... 44 
14.2 
Master Forms ................................................................................................................................. 44 
14.3 
Data Submission Procedures ........................................................................................................ 44 
14.4 
Data Submission Overview and Timepoints .................................................................................. 45 
15.0 
SPECIAL INSTRUCTIONS............................................................................................................ 46 
15.1 
Translational Medicine and Banking (OPTIONAL) ........................................................................ 46 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................... 50 
16.1 
Adverse Event Reporting Requirements........................................................................................ 50 
17.0 
BIBLIOGRAPHY ............................................................................................................................ 56 
18.0 
APPENDIX ..................................................................................................................................... 58 
18.1 
New York Heart Association Classifications .................................................................................. 59 
18.2 
Neuropathy Impairment Scale – Lower Limbs ............................................................................... 60 
18.3 
SWOG Biospecimen Bank Appendix ............................................................................................. 61 
18.4 
Sanofi-Direct Pregnancy Reporting Consent ................................................................................. 62 
18.5 
Sanofi Exposure During Pregnancy (EDP) Form .......................................................................... 66 
18.6 
Isatuximab Type and Screen Card ................................................................................................ 69 
18.7 
Measuring Orthostatic Blood Pressure .......................................................................................... 70 
 
 
 

 
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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
 
For regulatory requirements: 
 
For patient enrollments: 
For study data submission: 
Regulatory documentation must be 
submitted to the CTSU via the 
Regulatory Submission Portal: 
 
(Sign in at www.ctsu.org, and 
select the Regulatory Submission 
sub-tab under the Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory Help 
Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient 
enrollment section of the 
protocol for instructions on 
using the Oncology Patient 
Enrollment Network (OPEN) 
which can be accessed at  
 
https://www.ctsu.org/OPEN_S
YSTEM/  
 
or  
 
https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related 
questions at: 
 
ctsucontact@westat.com. 
 
 
Data collection for this study will 
be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
Do not submit study data or 
forms to CTSU Data Operations. 
Do not copy the CTSU on data 
submissions. 
 
Other Tools and Reports: 
Institutions participating through 
the CTSU continue to have 
access to other tools and reports 
available on the SWOG 
Workbench. Access this by 
using your active CTEP-IAM 
userid and password at the 
following url: 
 
https://crab.crab.org/TXWB/ctsul
ogon.aspx  
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password.    
For patient eligibility or data submission questions contact the SWOG Data Operations Center by 
phone or email: 
 
206/652-2267 
myelomaquestion@crab.org   
 
For treatment or toxicity related questions contact the Study Chair by phone or email:  
Dr. Terri Parker at 203/737-7059 or terri.parker@yale.edu or  
Dr. Vaishali Sanchorawala at 617/638-8265 or vaishali.sanchorawala@bmc.org    
 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.   
 
All calls and correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 

 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
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. 
 
1.2 
Secondary Objectives 
 
a. 
To evaluate toxicities in the treatment of relapsed/ refractory AL amyloidosis with 
isatuximab. 
 
b. 
To evaluate time to hematologic response. 
 
c. 
To evaluate duration of response. 
 
d. 
To evaluate progression-free survival (PFS). 
 
e. 
To evaluate overall survival (OS). 
 
1.3 
Other Objectives 
 
a. 
To evaluate efficacy of isatuximab in relapsed/ refractory immunoglobulin amyloid 
light chain (AL) amyloidosis as measured by organ specific response rates 
(cardiac, renal, GI, liver, soft tissue, nerve), in the subset of patients that can be 
evaluated for organ response. 
 
b. 
To evaluate time to organ response in the subset of patients that can be evaluated 
for organ response. 
 
 
2.0 
BACKGROUND 
 
2.1  
Study Population 
 
Systemic light chain (AL) amyloidosis is a monoclonal plasma cell disease in which 
misfolded light chains spontaneously aggregate into soluble oligomers and insoluble fibrils.  
Extracellular fibril deposition in different organs leads to organ dysfunction and symptoms. 
Historically, survival after a diagnosis of AL amyloidosis has been short, particularly in 
patients with advanced cardiac involvement (with a median survival of 3-6 months). (1)  
Current therapy for AL amyloidosis generally targets the small light chain-producing 
monoclonal plasma cell population in the bone marrow. Therapeutic regimens have been 
adapted from myeloma therapy.  
 
Approximately 1/3 of AL patients are eligible for high-dose melphalan and autologous stem 
cell transplantation (ASCT), with the remaining patients generally being treated with 
alkylator and/or bortezomib-based regimens. The outcomes of 421 subjects treated with 
HDM-SCT from July 1994 to December 2008 revealed the median event-free survival 
(EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Of 340 subjects, who 
were evaluable at 1 year beyond HDM-SCT, 43% achieved a complete response (CR) and 
78% of them experienced an organ response. For CR subjects, median EFS and OS were 
8.3 and 13.2 years, respectively. Among the 195 subjects who did not obtain CR, 52% 
reached an organ response, and the median EFS and OS were 2 and 5.9 years, 
respectively. (2)  Cardiac involvement at diagnosis and response to therapy are the two 
main determinants of survival in both ASCT and non-ASCT patients. 
 
 

 
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2.2  
Current Standard of Care 
 
The optimal treatment for relapsed or refractory patients remains unclear. In general, 
treatment strategies that have been successful in the context of myeloma have proven to 
be beneficial in AL amyloidosis as well. To this end, both the immunomodulatory drugs 
(IMiDs; thalidomide and lenalidomide) and the proteasome inhibitor bortezomib have been 
studied as treatments for AL amyloidosis with variable degrees of efficacy and toxicity often 
requiring dose reduction. There are no currently FDA-approved pharmacologic agents for 
relapsed AL amyloidosis. 
 
The immunomodulatory drugs (IMiDs), thalidomide and lenalidomide, in combination with 
dexamethasone are associated with overall hematologic response rates of 40-50% for 
relapsed AL, with some organ responses seen, though toxicities are significant and dose 
reductions are often needed. (3) Outcomes of AL patients with relapsed and refractory 
disease previously treated with bortezomib, lenalidomide and autologous stem cell 
transplant (40-80%) with pomalidomide and dexamethasone resulted in overall 
hematologic response rates of 48- 51% in two studies. Median time to hematologic 
response was 1.9 months (range, 0.9-11.3) and median duration of response 19 months. 
Organ improvement was documented in 18% overall (15% cardiac, 25% renal).  Median 
and 3 year PFS were 14 months and 17% respectively. Median and 3-year OS were 28 
months and 41%. (4,5) Bortezomib also has significant activity in the newly diagnosed and 
relapsed setting. (6,7) Median time to response with combination cyclophosphamide; 
bortezomib and dexamethasone (CyBorD) is 2 months. (8) 
 
Despite the availability of multiple IMiDs and bortezomib, there remains a desperate need 
for other treatment options that will be available to patients when they relapse or are 
intolerant to standard medications. The development of newer classes of drugs with less 
toxicity at standard doses and novel mechanisms of action for AL are certainly warranted, 
however, they should be tested cautiously and as single agents to establish preliminary 
data on efficacy and safety before considered in combination with other agents. Setting an 
estimated benchmark response rate for this novel drug for relapsed AL cannot be based 
on responses to other active agents such as the IMiDs or bortezomib as described above, 
as the class of drug (monoclonal antibody) has never been given to AL patients. Thus, the 
goal of this single arm open label study is to establish if there is a preliminary efficacy signal 
without serious toxicity as this is the first study using a CD38 monoclonal antibody in AL. 
A reasonable expectation for hematologic response may be based on the efficacy seen as 
a single agent in relapsed multiple myeloma (ORR 27%).  
 
2.3  
Isatuximab 
 
Isatuximab (SAR) is an IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a 
unique epitope on CD38. It is a targeted immunotherapy that attacks tumor cells that 
overexpress CD38, a transmembrane glycoprotein, in a variety of hematological 
malignancies including plasma cell malignancies. Isatuximb induces lysis of CD38-
expressing tumor cells, including malignant plasma cells by a wide spectrum of 
mechanisms including complement-dependent cytotoxicity (CDC) and antibody-dependent 
cell-mediated cytotoxicity (ADCC). The most common adverse reactions seen are infusion 
reactions that can be mitigated and managed with corticosteroids and antihistamines, both 
as prophylaxis and treatment.  
 
Isatuximab has been shown to be efficacious and well tolerated in relapsed and refractory 
multiple myeloma patients when used as a single agent as well as in various combinations 
with other agents. 
 
 

 
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2.4  
TED 10893 Phase I Study 
 
Final results are available for the Phase I study TED10893. Preliminary clinical activity 
results as of the cutoff dates are provided for Phase 2, Stage 1 of Study TED10893. 
 
In the Phase I study (TED10893), 89 patients with CD38-positive hematological 
malignancies have been treated with isatuximab at doses up to 10 mg/kg QW or 20 mg/kg 
QW. Six patients (5 with MM, 1 with NHL) were treated in the accelerated escalation cohort. 
Thirty-nine patients (35 with MM, 2 with NHL, and 2 with chronic lymphocytic leukemia 
[CLL]) were treated in the basic escalation cohorts. Nineteen and 18 patients with MM 
(standard or high risk) and high risk MM were treated in dose expansion cohorts 1 and 2, 
respectively. In an additional cohort, 7 patients with MM were treated with isatuximab, 20 
mg/kg QW. 
 
For all 89 treated patients, the median number of cycles administered was 5 (range, 1:56), 
the median duration of exposure was 10.1 weeks (range, 2:116), and the median relative 
dose intensity was 98.48%. 
Eighty-one patients discontinued treatment (69, due to disease progression (PD), 4 due to 
adverse events (AEs), 8 for reason recorded as “other,” Consent withdrawal [8 patients]) 
and 8 remain on treatment. The median time on treatment was 10.1 weeks (range, 2 to 16 
weeks). 
 
In 84 patients with MM, the median age was 64 years (range, 40 to 81 years). The median 
time from diagnosis to first isatuximab dosing was 5.8 years (range, 1.2 to 22.8 years). The 
median number of prior lines of therapies was 5.0 (range, 1 to 13). Prior therapy included 
lenalidomide (94.0%), pomalidomide (40.5%), bortezomib (98.8%), and carfilzomib 
(42.9%). 
 
Among the 89 patients enrolled, and across all the treatment cohorts, Grade ≥3 treatment-
emergent AEs (TEAEs) were reported in 53.9% of patients, serious TEAEs in 39.3%, 
TEAEs with fatal outcome in 2.2%, TEAEs leading to treatment discontinuation in 5.6%, 
and dose limiting toxicities (DLTs) in 2.2%. 
 
The most common were infusion-associated reaction (IARs) (in 49.4% of the patients, 
overall, including 2 patients with IARs to pre medication treatment and not related to 
isatuximab; Grade 3-4 in 2.2%), fatigue (in 37.1% of the patients, overall; Grade 3-4 in 
3.4%), nausea (in 32.6% of the patients, overall; Grade 3-4, none), anemia (in 28.1% of 
the patients, overall; Grade 3-4 in 16.9%), upper respiratory tract infection (in 22.5% of the 
patients, overall; Grade 3-4, none), cough (in 22.5% of the patients, overall; Grade 3-4, 
none), back pain (in 20.2% of the patients, overall; Grade 3-4 in 3.4%), and diarrhea (in 
20.2% of the patients, overall; Grade 3-4, none). 
 
Overall response rate (≥partial response (PR)) using the European Society for Blood and 
Marrow Transplantation criteria among the 84 treated MM patients was 20.2% (1 CR, 15 
PRs), all responses PR or better are confirmed with 2nd assessment. Clinical benefit rate 
(≥ minimal response (MR)) was 26.2% and best response was stable disease in 42.9% of 
the treated MM patients. The MR or better occurred at all dose levels ≥1 mg/kg. In patients 
treated at doses ≥10 mg/kg in the dose escalation and expansion cohorts (n=63), ORR 
was 23.8% (15 of 63 patients), and the CBR was 30.2% (19 of 63 patients). In patients 
treated at 10 mg/kg Q2W in the high-risk cohort (n=18), ORR was 16.7% (3 of 18 patients) 
and CBR was 27.8% (5 of 18 patients). 
 
In the Phase II, Stage 1 study TED10893, 97 patients were treated in Phase 2, Stage 1 of 
Study TED10893: 23 patients at 3 mg/kg Q2W, 24 patients at 10 mg/kg Q2W, 25 patients 
at 10 mg/kg Q2W/Q4W, and 25 patients at 20 mg/kg QW/Q2W. As of the cut-off date (29 

 
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February 2016), 85 patients discontinued treatment, 73 due to PD, 7 due to 
 
AEs, and 5 due to reason recorded as “other” (non-IMWG confirmed PD [2 patients], 
Consent withdrawal [2 patients], lack of response [1 patient]). Twelve patients remain on 
treatment. 
 
Patients received 1 of 4 different doses or schedules of administration. The median age 
was 62.0 years (range, 38 to 85 years). The median time from diagnosis to first isatuximab 
dosing was 5.85 years (range, 1.2 to 24.1 years). Patients were generally heavily 
pretreated and were exposed to most of the available anti-MM treatment. All patients 
received at least 1 immunomodulatory drug (IMiD) (ie, lenalidomide, pomalidomide) or 
proteasome inhibitors (ie, bortezomib, carfilzomib, ixazomib).  
 
For all 97 treated patients, the median number of cycles administered was 3 (range, 1:17), 
the median duration of exposure was 13.1 weeks (range, 4:69), and the median relative 
dose intensity was 98.85%.  
 
The ORR showed a dose response effect between the 3 mg/kg Q2W (ORR<10%) and 
doses of 10 mg/kg or higher (ORR ≥20% in all arms). At doses of 10 mg/kg or higher, the 
response rate ranged from 20% to 29% without a meaningful dose response between the 
10 mg/kg and the 20 mg/kg arms. 
 
The median duration of responses were: 12.9 months (3.7–14.8) at 10 mg/kg Q2W; 9.2 
months (3.7–13.8) at 10 mg/kg Q2W/Q4W; and 8.75 months (4.6–9.9) at 20 mg/kg 
QW/Q2W. 
 
The response rates are consistent cross all sub-groups. In patients treated at doses ≥10 
mg/kg, ORR was ≥20% in all sub-groups, including patients with high-risk cytogenetics 
(38% [8/21]). 
 
The median PFS was: 3.7 months (1.84–10.15) across all dose levels. The median OS for 
10 mg/kg Q2W group was 18.628 (9.9220 to NC) months, and has not been reached in 
the 10 mg/kg Q2W/Q4W and 20 mg/kg QW/Q2W arms. 
 
Among the 97 patients enrolled, and across all the treatment cohorts, Grade ≥3 TEAEs 
were reported in 63.9% of patients, serious TEAEs in 43.3%, TEAEs with fatal outcome in 
10.3% (and 5 because of disease progression), and TEAEs leading to treatment 
discontinuation in 8.2% of the patients (2 due to infusion-related reactions, 1 due to Grade 
3 thrombocytopenia, and 5 patients unrelated to toxicity). The most common TEAEs were 
nausea (35.1%; Grade 3-4, none), fatigue (30.9%; Grade 3-4, none), cough (28.9%; Grade 
3-4 in 1%), and dyspnea (26.8%; Grade 3-4 in 3.1%). 
 
Infusion-associated reactions were reported in 49 of 97 patients (50.5%) patients across 
all dose levels. The severity of the IARs was Grade 3 or higher in 3 (3.1%) patients. The 
symptoms of IARs with a severity of Grade 3-4 consisted of anaphylactic reaction, 
hypertension, dyspnea, bronchospasm (in 1 patient each). 
 
2.5  
Hypothesis 
 
Although isatuximab has never been used in AL amyloidosis patient, we expect that the 
efficacy and tolerability will be similar to that of daratumumab as seen in AL amyloidosis. 
(9,10,11) 
 
2.6 
Response Criteria 
 
The criteria for hematologic and organ responses have historically been based on the 
consensus opinion from the Xth International Symposium on Amyloidosis (ISA,2005); 

 
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cardiac and hematologic response was subsequently updated at the XIIth ISA (2012) and 
more recently the renal response criteria have been revised by Palladini et al (2014) which 
are now widely accepted. We will use these criteria for evaluating hematologic and organ 
response on this trial (See Section 10.0). (12,13,14) 
 
2.7 
Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to 
measure differences of intervention effects.  The anticipated accrual in the ethnicity/race 
and sex categories is shown in the table below.   
 
DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
1 
0 
0 
1 
Asian 
1 
0 
0 
0 
1 
Native Hawaiian or Other 
Pacific Islander 
0 
1 
0 
0 
1 
Black or African American 
3 
3 
0 
0 
6 
White 
10 
13 
2 
2 
27 
More Than One Race 
1 
2 
0 
0 
3 
Total 
15 
20 
2 
2 
39 
 
 
 
3.0 
DRUG INFORMATION 
 
Investigator Brochures  
 
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, isatuximab is investigational and is being provided under an IND held by SWOG.  
For INDs filed by SWOG, the protocol serves as the Investigator Brochure for the performance of 
the protocol.  In such instances submission of the protocol to the IRB should suffice for providing 
the IRB with information about the drug.  However, in cases where the IRB insists on having the 
official Investigator Brochure from the company, further information may be requested by contacting 
the SWOG Operations Office at 210/614-8808. 
 
Diphenhydramine, methylprednisolone, ranitidine and acetaminophen are commercially available 
and should therefore be purchased by a third party.  These drugs will not be supplied by the NCI 
or industry sponsor. 
 
3.1 
Isatuximab (SAR650984) (NSC #795145, IND-138083) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action:  
Isatuximab is an immunoglobulin G1 monoclonal antibody that selectively binds to 
the human cell surface antigen molecule CD38 expressed in a number of 
hematological malignancies from B-lymphocyte, T-lymphocyte, and myeloid origin. 
The agent works through antibody-dependent cellular-mediated cytotoxicity, 

 
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complement-dependent cytotoxicity, antibody dependent cellular phagocytosis, 
and induction of apoptosis. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Exposure increased more than proportionally with the dose 
from 0.03 to 20 mg/kg. Some accumulation was observed following 10 or 
20 mg/kg administered with qw or q2w schedule. Achievement of steady 
state has not been formally evaluated yet. Additionally, four doses of 20 
mg/kg QW showed that total clearance (sum of nonlinear and linear 
clearances) approached linear clearance (indicating target saturation) 
after which the 20 mg Q2W schedule appeared to maintain the total 
clearance close to the linear clearance. 
 
Isatuximab has a low clearance to those of non-specific endogenous IgG 
associated with a half-life of 18 days and the volume of distribution of 
central compartment (Vp) approached the blood volume. Because 
isatuximab is an antibody, it is expected to be eliminated by proteolytic 
catabolism. 
 
 
2. 
Distribution: The PK of isatuximab appeared to be nonlinear in the dose 
range investigated in studies.  More precisely, after the first administration, 
the exposure (AUC1week, AUC2weeks, or AUClast) appeared to increase 
more than proportionally with the dose up to 10 mg/kg, while no major 
deviation to the dose proportionality could be observed between 10 mg/kg 
and 20 mg/kg.  This nonlinearity suggests the presence of target-mediated 
drug disposition with isatuximab. 
 
3. 
Metabolism: No available data; being evaluated. 
 
4. 
Elimination: Some accumulation was observed following 10 or 20 mg/kg 
administered with every-week or every-2-week schedule. Achievement of 
steady state has not been formally evaluated yet. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Adverse Effects: 
 
Adverse Events with Possible  
Relationship to “Isatuximab” 
Likely (> 20%) 
Less Likely (4 – ≤ 
20%) 
Rare but Serious (≤ 
3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
Anemia 
Febrile neutropenia 
 
Leukopenia 
Hyperviscosity 
syndrome 
 
Thrombocytopenia 
 
 
Lymphopenia 
 
 
Neutropenia 
 
 
CARDIAC DISORDERS 
 
Atrial fibrillation 
Cardiopulmonary 
failure 
 
Acute coronary 
syndrome 
Stress 
cardiomyopathy 

 
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Adverse Events with Possible  
Relationship to “Isatuximab” 
Likely (> 20%) 
Less Likely (4 – ≤ 
20%) 
Rare but Serious (≤ 
3%) 
 
 
 
EYE DISORDERS 
 
Eye pain 
 
 
Photophobia 
 
 
Visual impairment 
 
GASTROINTESTINAL DISORDERS 
Nausea 
Constipation 
Small intestinal 
obstruction 
Diarrhea 
Abdominal pain 
Gastrointestinal 
amyloidosis 
Vomiting 
 
Gastrointestinal 
hemorrhage 
 
 
Ileus 
 
 
Intussusception 
 
 
Obstruction gastric 
 
 
Tongue edema 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue 
Performance 
decreased 
Device malfunction 
Pyrexia 
Non-Cardiac Chest 
Pain 
Disease progression 
Chills 
Asthenia 
Gait disturbance 
 
Pain 
 
 
Face edema 
 
HEPATOBILIARY DISORDERS 
AST increased 
Hyperbilirubinemia 
 
ALT increased 
 
 
Alkaline phosphatase 
increased 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
 Anaphylactic 
reaction 
INFECTIONS AND INFESTATIONS 
Upper respiratory tract 
infection 
Sepsis 
Pneumocystis 
jirovecii pneumonia 
Pneumonia 
Lung infection 
Bacterial sepsis 
 
Gastroenteritis 
Clostridium difficile 
colitis 
 
Herpes zoster 
Gastroenteritis 
rotavirus 
 
Otitis media 
Infectious colitis 
 
Bronchitis 
Abdominal sepsis 
 
Bronchitis viral 
Atypical pneumonia 
 
Influenza 
Infective aortitis  
 
Varicella 
Meningitis bacterial 
 
Upper respiratory 
tract infection 
Mengingococcal 
sepsis 
 
Urinary tract 
infection 
Parainfluenzae virus 
infection 

 
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Adverse Events with Possible  
Relationship to “Isatuximab” 
Likely (> 20%) 
Less Likely (4 – ≤ 
20%) 
Rare but Serious (≤ 
3%) 
 
 
Pneumococcal 
bacteremia 
 
 
Pneumonia 
respiratory syncytial 
viral 
 
 
Pneumonia 
streptococcal 
 
 
Pneumonia 
mycoplasmal 
 
 
Pneumonia viral 
 
 
Septic shock 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
Infusion related 
reaction 
Fall 
 
 
Hip fracture 
 
 
Humerus fracture 
 
 
Joint injury 
 
 
Procedural 
hemorrhage 
 
 
Traumatic fracture 
 
INVESTIGATIONS 
Blood bilirubin 
increased 
 
 
Blood creatinine 
increased 
 
 
METABOLISM AND NUTRITION DISORDERS 
Hypercalcemia 
Decreased appetite 
Pathological fracture 
 
Hypercalcemia 
 
 
Tumor lysis 
syndrome 
 
MUSCULOSKELETAL AND CONNECTIVE TISSURE DISORDERS 
Back pain 
Bone pain 
 
 
Fracture pain 
 
 
Musculoskeletal 
chest pain 
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (include 
cysts and polyps) 
 
 
Basal cell carcinoma 
 
 
Malignant 
melanoma 
 
 
Myelodysplastic 
syndrome 
 
 
Squamous cell 
carcinoma of the 
oral cavity 
 
NERVOUS SYSTEM DISORDERS 
Headache 
Dizziness 
Cerebral 
hemorrhage 

 
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Adverse Events with Possible  
Relationship to “Isatuximab” 
Likely (> 20%) 
Less Likely (4 – ≤ 
20%) 
Rare but Serious (≤ 
3%) 
 
Seizure 
Transient ischemic 
attack 
 
 
Spinal cord 
compression 
 
 
 
 
RENAL AND URINARY DISORDERS 
 
 
Acute kidney injury 
 
 
Renal failure 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
 
Pelvic pain 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
Cough 
Respiratory alkalosis 
Pleural effusion 
 
Bronchospasm 
Pulmonary 
embolism 
 
Apnoea 
Acute respiratory 
failure 
 
Atelectasis 
Hemoptysis 
 
Laryngeal oedema 
Pneumoia aspiration 
 
Laryngospasm 
Pulmonary edema 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Rash 
Angioedema 
VASCULAR DISORDERS 
 
 Hypotension 
Aortic aneurysm 
 
 
Extrinsic iliac vein 
compression 
 
 
Hypertensive crisis 
 
2. 
Pregnancy and Lactation: Reproductive toxicology studies have not yet 
been performed. 
 
Drug Interactions: No drug-interactions has been observed between 
isatuximab and lenalidomide. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
Isatuximab should be administered via a peristaltic pump using an administration 
set that is polyethylene (PE) or polyvinyl chloride (PVC) DEHP free or polyvinyl 
chloride (PVC) with DEHP with 0.2 micron in-line filter that is polyether sulfone 
(PES) or Nylon.  Isatuximab initial infusion rate should not exceed 175 mg of 
isatuximab per hour.  In the absence of infusion related reactions (IAR), after 1 
hour of infusion, the infusion rate can be increased by 50 mg/hour increments 
every 30 minutes, to a maximum of 400 mg/hour. Subsequent infusions should be 
initiated at 175 mg/hour.  In the absence of IARS, the rate may be increased by 
100 mg/hour every 30 minutes, to a maximum of 400 mg/hour.  Patients who do 
not experience an IAR during the first 4 isatuximab infusions may have their need 
for subsequent premedication reconsidered at the Investigator’s discretion in 
consultation with the Study Chairs to avoid unnecessary sedation.  

 
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e. 
HOW SUPPLIED 
 
1. 
Isatuximab vials will be provided by Sanofi and distributed by: 
 
Sanofi US Services Inc. 
55 Great Valley Parkway 
Malvern, PA 19355 
USA 
 
2. 
Isatuximab C1P2F2 (cell 1, process 2, formulation 2) drug product is 
presented as a concentrate for solution for infusion in vials containing 20 
mg/mL (500 mg/25 mL) isatuximab in 20 mM histidine, 10% (w/v) sucrose, 
0.02% (w/v) polysorbate 80, pH 6.0 buffer. 
 
3. 
Isatuximab is supplied for parenteral administration as a sterile, 
nonpyrogenic, injectable, 20 mg/mL concentrate for solution for infusion, 
essentially free of particulates, and is packaged in 30 mL glass vials fitted 
with elastomeric closure. Each vial contains a nominal content of 500 mg 
of isatuximab C1P2F2. The fill volume has been established to ensure 
removal of 25 mL. Isatuximab are single-use vials. Unused portion must 
be discarded. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
1. 
Isatuximab will be stored between +2 and +8°C and protected from light 
upon receipt. Shelf-life of isatuximab is currently 24 months. Refer to the 
S1702 training slides for temperature excursion information.  
 
2. 
Isatuximab concentrate for solution for infusion will be diluted in an infusion 
bag with 0.9% sodium chloride solution or 5% dextrose solution to achieve 
the appropriate drug concentration for infusion. 
 
Infusion via a central line is preferred if available. In case of patients with 
local intolerance after peripheral IV infusion, decision to use central line is 
left to investigator decision. The final infusion volume corresponding to the 
dose of isatuximab will be administered by IV infusion for the period of time 
that will depend on total dose administered. 
 
3. 
Dilution should be performed in an aseptic condition per local guidelines. 
Select appropriate diluent bag volume of NaCl 0.9% and/or Dextrose 5% 
solutions that are polyolefin (PO), polyethylene (PE) or polypropylene 
(PP), or polyvinyl chloride (PVC) with DEHP to ensure diluted product 
concentration is between 0.8 and 5.3 mg/mL. Doses ≥ 3,300 mg must be 
diluted in Dextrose 5% solution. Bag sizes between 250 mL and 1,000 mL 
can be used to prepare the infusion solutions; bags of 250 mL, 500 mL, or 
1,000 mL are recommended for this study. Add appropriate amount of 
isatuximab into the bag and gently homogenize by inverting the bag. 
Follow local procedures for priming of tubing and filter and for use of a 
secondary line. Prepared solutions for infusion are stable at room 
temperature for 16 hours. 
 
4. 
Prior to dosing, each patient's dose will be individually prepared by the 
study pharmacist and labeled with protocol number, patient number, and 
treatment description. The patient’s weight should be measured prior to 
each cycle; however dose should only be changed if the patient has > 10% 
change in weight. 

 
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5. 
To calculate the exact volume of concentrated solution needed for the 
dose, apply the following equation: 
 
Vdose (mL) = [Dose (mg/kg) x Body weight (kg)]/20 (mg/mL) 
 
Example: for a 70 kg patient dosed at 20 mg/kg:  
Vdose is (20 x 70)/20 = 70 mL of Isatuximab 
 
6. 
To calculate the number of vials needed for the dose follow these steps: 
 
1.   
Patient dose (vials) = Vdose (mL)/25 mL 
2.  
If result is obtained with decimals, it should be rounded up to the 
nearest upper unit 
 
Example: for a 70 kg patient dosed at 20 mg/kg the calculated patient dose 
is 2.8 vials, then 3 vials should be used to obtain the volume of 
concentrated solution. 
 
g. 
DRUG ORDERING & ACCOUNTABILITY 
 
1. 
Drug ordering: Isatuximab may be ordered by completing and submitting 
the S1702 Drug Order and Acknowledgment of Receipt Form per the 
instructions on the form. The form can be found on the protocol abstract 
page of the SWOG website (www.swog.org) or on the protocol abstract 
page of the CTSU website (www.ctsu.org). 
 
2. 
Drug Handling and Accountability 
 
a. 
Drug Accountability: The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of 
the receipt, disposition, and return or disposal of all drugs received 
from the supplier using the NCI Drug Accountability Record Form 
(DARF) available at http://ctep.cancer.gov. 
 
b. 
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI DARF. 
 
c. 
Sites must also document drug receipt (including temperature 
excursion information) and the acknowledgment must be returned 
to Sanofi per the instructions on the S1702 Drug Order and 
Acknowledgment of Receipt Form.  The form can be found on the 
protocol abstract page of the SWOG website (www.swog.org) or 
on 
the 
protocol 
abstract 
page 
of 
the 
CTSU 
website 
(www.ctsu.org). 
 
3. 
Drug Disposition Instruction 
 
a. 
Used vials and expired vials should be destroyed on site per 
institution SOP and documented accordingly on DARF in a timely 
manner.  Unused vials should be destroyed on site per institution 
SOP and documented accordingly on the DARF upon study 
closure and the last enrolled patient has completed treatment. 
 
b. 
Drug expiration: (If packaging does not have expiration date, 
check with insert from company when available. If packaging has 
expiration date, indicate drug expiration date on the DARF under 

 
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Manufacturer and Lot # and use the drug lots with shorter 
expiration date first). 
 
4. 
Contact Information  
 
Questions about drug orders or shipping should be directed to the Sanofi 
US Services Inc at CS-US-Shipment-Requests@sanofi.com. 
 
 
4.0 
STAGING CRITERIA 
 
Staging criteria not applicable. 
 
 
5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered 
eligible for registration.  For each criterion requiring test results and dates, please record this 
information on the Onstudy Form or on the AL Baseline Tumor Assessment Form and submit via 
Medidata Rave® (see Section 14.0).  Any potential eligibility issues should be addressed to the 
Data Operations Center in Seattle at 206/652-2267 or myelomaquestion@crab.org prior to 
registration. NCI policy does not allow for waiver of any eligibility criterion 
http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm. 
 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be 
considered Day 28.  This allows for efficient patient scheduling without exceeding the guidelines.  
If Day 14 or 28, or 35 falls on a weekend or holiday, the limit may be extended to the next 
working day. 
 
5.1 
Disease Related Criteria 
 
a. 
Patient must have relapsed or refractory primary systemic AL Amyloidosis, 
histologically-confirmed by positive Congo red stain with green birefringence on 
polarized light microscopy, OR characteristic appearance by electron microscopy 
AND confirmatory AL amyloid typing (mass spectrometry-based proteomic 
analysis or immunofluorescence).  If there is question regarding diagnosis, consult 
Study Chairs prior to submission via e-mail to terri.parker@yale.edu and 
vaishali.sanchorawala@bmc.org. Pathology report must be submitted as indicated 
in Section 14.4a. 
 
b. 
Patient must have measurable disease as defined in Section 10.1 within 28 days 
prior to registration. Serum β2 microglobulin, Serum Quantitative Immunoglobulins 
(IgG, IgA, and IgM), serum free kappa and lambda, SPEP with M-protein 
quantification, and urine immunofixation electrophoresis must be obtained within 
28 days prior to registration. 
 
c. 
Patient must demonstrate a difference in the involved serum free light chains 
(kappa or lambda) versus the uninvolved serum free light chain of ≥ 4.5mg/dL 
within 28 days prior to registration. 
 
d. 
Patient must have objective organ involvement defined by ONE (or more) of the 
following. All disease for involved organs must be assessed at baseline (defined 
as within 28 days prior to registration) and must be documented on the AL Baseline 
Tumor Assessment Form.  Note that the following organ disease assessments are 
required if there is suspected involvement of the organ(s). Only one organ is 
required to be involved for the patient to be eligible for the study.  Assessment of 

 
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each organ at baseline is not required if organ involvement is not suspected (see 
Section 9.0 for post-activation requirements). 
 
1. 
Kidney: Albuminuria greater than or equal to 500 mg per day on a 24-hour 
urine specimen, OR prior kidney biopsy (at time of diagnosis) showing 
amyloid deposition; 
 
2. 
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 NT-pro BNP greater than 332 pg/mL provided that patient 
does not have impaired renal function (as defined by calculated creatinine 
clearance less than 25 mL/min), 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; 
 
3. 
Liver 
involvement: Hepatomegaly (total 
liver 
span 
>15cm) as 
demonstrated by CT, ultrasound, or MRI OR elevated alkaline 
phosphatase (ALP) greater than 1.5 times the upper limit of normal, OR 
prior liver biopsy (at time of diagnosis) showing amyloid deposition; 
 
4. 
Gastrointestinal tract: For patients with suspected baseline GI involvement 
(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]), a 24-hour fecal fat test must be obtained at 
baseline. 
 
5. 
Autonomic or peripheral nervous system: Orthostatic symptoms including 
dizziness or light-headedness with standing, nausea, early satiety, 
diarrhea or constipation, abnormal sensory and/or motor findings on 
neurologic exam, or gastric atony by gastric emptying scan. Patients 
suspected to have neurologic involvement, must have neurologic 
assessment including orthostatic measurements at baseline.  NIS score at 
baseline is also suggested as a clinical tool for measurement of peripheral 
neuropathy, but it is not required.  NCS/EMG studies are not required and 
can be obtained as clinically indicated.  Orthostatic measurements must 
be repeated on 2 separate occasions (at least 1 day apart; e.g., Day -3 
and Day -1). 
 
6. 
Soft 
tissue: 
Macroglossia, 
or 
soft 
tissue 
deposits 
(including 
lymphadenopathy, recurrent peri-orbital purpura, peri-articular, skin or 
other soft tissue) requiring therapy. Imaging (CT, MRI, or ultrasound) is 
not required but may be performed as clinically indicated to measure soft 
tissue involvement. 
 
e. 
Patients must not have active symptomatic multiple myeloma, as defined by 2015 
IMWG criteria (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 (Hgb < 8g/dL).  (15) 
 
5.2 
Prior/Concurrent Therapy Criteria 
 
a. 
Patient must be relapsed or refractory to at least one prior line of therapy (such 
as: transplant, radiation, or chemotherapy). 
 

 
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b. 
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. 
 
c. 
Patients must not have received any supplements which have been known to have 
some anti-amyloidogenic effect (such as: doxycycline; curcuramin; prednisone; 
dexamethasone; epigallocatechin gallate [EGCG]) within 14 days prior to 
registration. 
 
d. 
Patients must not have any known allergies to isatuximab or other monoclonal 
antibody therapies. 
 
e. 
Patients must not have received daratumumab within 56 days prior to registration 
nor have been refractory to daratumumab. 
 
f. 
Patients must not be eligible for autologous stem cell transplantation as 
determined by the treating investigator or if the patient declined/refused.  
 
5.3 
Clinical/Laboratory Criteria 
 
a. 
Patients must have a complete medical history and physical exam within 28 days 
prior to registration. 
 
b. 
Patients must be ≥ 18 years of age. 
 
c. 
Patients must have adequate hepatic function within 28 days prior to registration, 
as defined by the following: 
 
Total bilirubin ≤ 2.0 x IULN (institutional upper limit of the norm) (patients with 
Gilbert's Syndrome must have a total bilirubin less than 3.0 mg/dL) 
 
AND 
SGOT/AST and SGPT/ALT ≤ 4.0 x IULN 
d. 
Patients must have adequate renal function, as defined by:  
 
• 
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 28 days prior to registration.   
Estimated creatinine clearance =  
(140 - age) x wt (kg) x 0.85 (if female) 
72 creatinine (mg/dl) 
e. 
Patients must have bone marrow aspirate and biopsy within 35 days prior to 
registration.  The following are required:  
• 
quantitative percent clonal plasma cell involvement,  
• 
standard immunophenotyping,  
• 
immunohistochemistry,  
• 
cytogenetics,  
• 
fluorescent in situ hybridization (FISH) (via participating site local 
laboratory) to assess for del 17p; t11;14; t4;14, t14;16; and del 13q.  
 

 
S1702 
 
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Additionally, FISH and cytogenetic testing (normal – XY; and all abnormalities) are 
required to have been performed and to be reported, even if “no results” was 
achieved (i.e. due to too few cells in specimen).  If FISH was performed, then the 
patient is eligible.  If FISH was not performed, then patient is not eligible. Central 
pathology analysis will not be required, however the local pathology report and 
FISH/Cytogenetic data must be submitted in Medidata RAVE. 
 
f. 
Patients must have adequate bone marrow function as defined by the following 
within 28 days prior to registration: ANC ≥ 1,000 cells/mcl without growth factor 
support, AND platelets ≥ 75,000 cells/mcl. 
 
g. 
Patients must have hemoglobin ≥ 8 g/dL within 28 days prior to registration. 
Patients may have received transfusion if greater than 7 days prior to registration. 
 
h. 
Patients must have adequate cardiac function as defined by the following:  
• 
New York Heart Association (NYHA) < Class IV heart failure (see Section 
18.2); and 
• 
LVEF by ECHO ≥ 35% within 28 days prior to registration; and 
• 
NT-proBNP ≤ 8500 pg/mL within 28 days prior to registration.  
 
i. 
Patients must have a Zubrod Performance Status ≤ 2. 
 
j. 
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 
Hb A1C < 7% within 28 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 28 days prior to registration must be SBP ≤ 160 and 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 blood pressure within 
the parameters above.  
• 
See ACCF/AHA.AMA-PCPI joint statement  
 
k. 
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. Men must agree to use a  
condom with either cap, diaphragm or sponge with spermicide (double barrier 

 
S1702 
 
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method) during sexual contact with a FCBP, even if they have had a successful 
vasectomy for the study duration and for 12 weeks after the discontinuation of 
treatment.   
 
l. 
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.   
 
m. 
Patients who are known to be HIV-positive at registration are eligible if at time of 
registration they meet all other protocol eligibility criteria in addition to the following: 
 
1. 
Patient has undetectable HIV viral load by standard PCR clinical assay; 
 
2. 
Patient is willing to maintain adherence to combination antiretroviral 
therapy; 
 
3. 
Patient has no history of AIDS defining condition (other than CD4 cell 
count < 200 mm3); 
 
4. 
Patient is otherwise likely to have a near normal lifespan if not for the 
presence of relapsed/refractory amyloid.   
 
n. 
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. 
 
5.4 
Specimen Submission Criteria 
 
Patients must be offered participation in specimen banking as outlined in Section 15.1. 
With patient consent, pretreatment specimens must be collected and submitted via the 
SWOG Specimen Tracking System as outlined in Section 15.1. 
 
Instructions for obtaining a SWOG Patient ID prior to patient registration are available in 
Section 15.1c.2. 
 
5.5 
Regulatory Criteria 
 
a. 
Patients must be informed of the investigational nature of this study and must sign 
and give written informed consent in accordance with institutional and federal 
guidelines. 
 
b. 
As a part of the OPEN registration process (see Section 13.4c for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study 
has been entered in the system. 
 
 
6.0 
STRATIFICATION FACTORS 
 
There are no stratification factors. 
 
 

 
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7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Terri Parker at 203/737-7059 or 
Dr. Vaishali Sanchorawala at 617/638-8265.   
 
For dosing principles or questions, please consult the SWOG Policy #38 "Dosing Principles for 
Patients on Clinical Trials". 
 
7.1 
General Treatment Instructions 
 
a. 
Infusion associated reactions (IARs) (mostly Grade 1-2 and manageable) are very 
common with the first isatuximab dose administration, even in patients who had 
received prophylaxis (see Section 7.1b).  Extensive clinical experience with 
approved monoclonal antibodies indicates that mild­to­moderate infusion reactions 
(either allergic, or consisting of cytokine release, which mimics hypersensitivity 
reactions) are common, particularly during the first infusion; the cytokine release 
syndrome associated with monoclonal antibodies consists of a pseudo allergic 
Type B (non-immunoglobulin E mediated) reaction.  The IARs associated with 
isatuximab have been occurring most commonly at the first administration, are not 
dose dependent, and the patients do not appear to sustain sequelae.  Infusion-
associated reactions generally do not cause therapy discontinuation and tend not 
to recur at subsequent administrations of isatuximab, but if an IAR is observed, the 
patient must also be informed of the potential risk of recurrent allergic reactions at 
subsequent infusions. 
 
b. 
In an attempt to mitigate the incidence and severity of IARs, it is recommended 
that the initial infusion rate should not exceed 175 mg of isatuximab per hour.  In 
the absence of an IAR after 1 hour of infusion, the infusion rate can be increased 
by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour.  
Subsequent infusions should be initiated at 175 mg/hour.  In the absence of IAR’s, 
the rate may be increased by 100 mg/hour every 30 minutes, to a maximum of 400 
mg/hour. 
 
NOTE:  This drug requires infusion mg/hour 
 
In the event of a Grade 2 hypersensitivity reaction, the isatuximab infusion should 
be interrupted and may subsequently resume after recovery, at a slower infusion 
rate, under close monitoring and with supportive care as needed.  See Section 8.5 
for guidelines for management of infusion-related reactions. 
 
Prior to restarting the infusion, patients may receive additional medication per the 
judgment 
of 
the 
Investigator. 
Recommended 
medications 
consist 
of 
diphenhydramine 25 mg IV and methylprednisolone 100 mg IV (or equivalent).  In 
the event of a Grade 3 or 4 hypersensitivity reaction, treatment with isatuximab is 
to be immediately and permanently discontinued. 
 
Vital Sign Monitoring 
Blood Pressure is collected at baseline.  Vitals below will be performed per drug 
safety monitoring.  
 
First infusion: Prior to infusion obtain vital signs (BP, HR, temp, oxygen saturation 
by pulse oximeter). Repeat every 15 minutes for the 1st hour, then every 30 minutes 
and with each rate change for the duration of the infusion and continue for 30 
minutes after the end of the infusion. 

 
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Second infusion: Prior to infusion obtain vital signs (BP, HR, temp, oxygen 
saturation by pulse oximeter). Repeat every 30 minutes and with each rate change 
for the duration of the infusion and continue for 30 minutes after the end of the 
infusion 
 
Third and subsequent infusions: Prior to infusion obtain vital signs (BP, HR, 
temp, oxygen saturation by pulse oximeter). Repeat every 30 minutes and with 
each rate change for the duration of infusion and at the end of infusion. 
 
c. 
Potential Interference with Blood Bank Serologic Tests: 
 
The CD38 protein is weakly expressed on the surface of red blood cells. Because 
of this, anti-CD38 antibodies in patients’ plasma can lead to pan-reactivity and thus 
interfere with various blood bank serologic tests. To avoid potential problems with 
blood transfusion, the American Association of Blood Banks recommends that 
patients being treated with anti-CD38 antibodies have blood type and screen tests 
performed at baseline, after treatment, and each time before blood infusion.   
 
Type and screen patients and notify institutional blood bank before the first 
administration of the drug and repeat prior to any blood product transfusion. RBC 
antigen screen is recommended but not required, as per institutional blood bank 
protocol, and a card with blood type will be carried by the patient throughout the 
study (see Appendix 18.6). Baseline type and cross should be used for 
transfusions, as post-treatment blood type does not change but appears different 
due to presence of the CD38 antibody. 
 
d. 
Strongly recommend that blood pressure is controlled prior to beginning infusion 
on Day 1, Cycle 1, as per American Heart Association standards, preferable SBP 
≤ 140 and DBP ≤ 90. Blood pressure must be SBP ≤ 160 and DBP ≤ 100 on Day 
1 Cycle 1. 
 
7.2 
Pre-Medication 
 
a. 
Primary prophylactic treatment with diphenhydramine 25 to 50 mg IV (or by 
mouth), methylprednisolone 100 mg IV (or equivalent), ranitidine 50 mg IV (or 
equivalent), and acetaminophen 650 to 1000 mg orally 15 to 30 minutes (and 
never longer than 60/ minutes) should be administered to all patients prior to the 
isatuximab infusion to minimize the incidence and severity of IAR commonly 
observed with monoclonal antibodies. In the event of interruption of infusion due 
to mild or moderate hypersensitivity reaction, patients should additional pre-
medication, as indicated in Section 7.1b (above). 
 
Patients who do not experience an IAR during the first 4 isatuximab infusions may 
have the need for subsequent premedication reconsidered at the discretion of the 
treating physician (in consultation with the Study Chairs) to avoid unnecessary 
sedation.  Please contact the Study Chairs at: terri.parker@yale.edu and 
vaishali.sanchorawala@bmc.org for documentation and consultation on changes 
in subsequent pre-medication. 
 
Prophylactic treatment is commercially available and will not be supplied by the 
study. 
 
 

 
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b. 
Antiviral and proton pump inhibitor 
 
All patients should receive an antiviral (such as acyclovir 800 mg orally daily) for 
the duration of the study.  
 
A proton-pump inhibitor will be used to prevent peptic disease. Prevacid 
(lansoprazole) 15 mg orally daily or equivalent is recommended. 
 
These medications are commercially available and will not be supplied by the 
study. The treating physician will provide an outpatient prescription for these 
medications. 
 
7.3 
Treatment 
 
Agent 
Cycle(s) 1 
Day(s) 
Dose 
Route 
 
 
Isatuximab  
1 
1, 8, 15, 22 
20 mg/kg 
IV 
 
Isatuximab 3 
2 – 24 
1, 15 
20 mg/kg 
IV 
 
1 Note:  One cycle = 28 days 
2 Patient will continue on therapy until completion of 24 Cycles of therapy or until one of 
the criteria in Section 7.4 is met, whichever occurs first.  
3 For Cycles 2-24, C1D1 weight should be used for dosing, unless there is a > 10% change 
in weight. 
 
7.4 
Organ Evaluation Guidelines 
 
Please refer to Section 5.1d for eligibility requirements and Section 9.0 for additional 
timepoints. 
 
a. 
Cardiac 
 
Cardiac organ evaluation must include clinical NYHA evaluation, 2d 
echocardiogram, and serum NT pro-BNP and troponin I or T measurements.  
Echocardiogram results including LVEF, intraventricular septum wall thickness, 
and left ventricular posterior wall thickness, and if possible (though not essential) 
global longitudinal strain (GLS). It is recommended that baseline and subsequent 
echocardiograms are performed at the same location.   
 
b. 
Renal  
 
Renal evaluation must include 24-hour urine, including: Total Protein, UPEP with 
M-Spike, Urine Protein Immunofixation and Creatinine clearance; serum 
creatinine.  If a 24-hour urine specimen is being collected, the UPEP and urine IFE 
can be obtained via the 24-hour urine.  If a 24hour urine is not required, then a 
urine random/spot urine sample is adequate for the UPEP and urine IFE on day 1 
of each cycle.   
 
c. 
Autonomic Neuropathy  
 
Assessment must include clinical assessment of symptoms (nausea, diarrhea, 
early satiety) and orthostatic blood pressure and pulse rate evaluations. See 
Appendix 18.7 for instructions on obtaining orthostatic blood pressure.  Pulse 
should be recorded at the same time as each blood pressure measurement.  
 
 

 
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d. 
Peripheral Neuropathy  
 
To be assessed clinically. Neurologic Impairment Score (NIS) score is suggested 
as a tool for measurement of peripheral neuropathy but is not required. If baseline 
nerve conduction study/electromyogram (NCS/EMG) were obtained for evaluation 
of peripheral nervous system, they must be followed as part of the organ response 
assessments. See Appendix 18.2 for NIS form. 
 
e. 
Soft Tissue / Lymph Nodes:  
 
To be assessed clinically; however, if imaging was used at baseline it is suggested 
that follow-up assessments also be by imaging. 
 
f. 
Liver:  
 
Imaging (CT, US or MRI) to document size of liver, serum alkaline phosphatase 
(ALP) 
 
g. 
Gastrointestinal:  
 
Clinical assessment of GI bleeding, diarrhea; 24-hour fecal fat test 
 
h. 
Serum Chemistry: 
 
Must include: sodium, potassium, chloride, bicarbonate, blood urea nitrogen, 
creatinine/ CrCl, glucose, total protein, albumin, calcium, total bilirubin, alkaline 
phosphatase, uric acid, and SGOT/AST and SGPT/ALT.  
 
7.5 
Criteria for Removal from Protocol Treatment 
 
a. 
Hematologic progression of disease or symptomatic deterioration (as defined in 
Sections 10.2 and 10.7). Organ progression (as defined in Section 10.4) in the 
absence of hematologic progression does not necessitate removal from treatment. 
 
b. 
Unacceptable toxicity.  
 
c. 
Treatment delay >14 days, unless approved by the Study Chair, as indicated in 
Section 8.3b. Treatment must not be delayed for any reason > 42 days. For 
treatment delay of >14 days, see Section 8.3b. 
 
d. 
The patients may withdraw from the study at any time for any reason. 
 
e. 
24 cycles of treatment completed as planned. 
 
f. 
Development of overt myeloma. 
 
7.6 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.7 
Follow-Up Period 
 
All patients will be followed until 4 years after registration or until death, whichever occurs 
first. 
 

 
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8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE Version 5.0 for toxicity and serious adverse event 
reporting. A copy of the CTCAE Version 5.0 can be downloaded from the CTEP home page 
https://ctep.cancer.gov. All appropriate treatment areas should have access to a copy of 
the CTCAE Version 5.0. 
 
8.2 
Supportive Care 
 
Blood product transfusion, intravenous albumin, intravenous fluids and electrolyte 
replacement, 
antiemetics, 
antidiarrheal 
medication, 
g-csf, 
anti- 
hypersensitivity 
medications are all allowable as per institutional standards and Section 3 of the protocol. 
 
8.3 
Dose Delays 
 
a. 
No dose reduction is authorized for isatuximab. 
 
b. 
Cycle delay up to 14 days is allowed, as indicated in Table 1 below.  
 
Any additional delay (beyond 14 days) must be determined in consultation with the 
Study Chair(s), and documented via email to: terri.parker@yale.edu and 
vaishali.sanchorawala@bmc.org. The decision to continue treatment will be based 
on potential for continued clinical benefit, as determined jointly by the treating 
physician(s) and Study Chair(s). Treatment may not be delayed for any reason for 
more than 42 consecutive days. 
 
c. 
Within a cycle, an isatuximab administration can be delayed for up to +/-3 days. If 
the dose cannot be administered within +/- 3 days, the isatuximab dose will be 
omitted. If one dose of isatuximab is administered within these windows, the 
interval between the next infusions should be maintained to 1 week or 2 weeks 
respectively 
 
Only 1 omission per cycle is permitted. Further omissions must be discussed on a 
case by case basis with the Study Chair, documented by email to: 
terri.parker@yale.edu and vaishali.sanchorawala@bmc.org. 
 
d. 
If a patient experiences several AEs and there are conflicting recommendations, 
follow the most conservative dose delay. 
 
Table 1: Dose Delays for Isatuximab 
  Treatment-related 
Adverse Event 
Grade of Event 
Management for Isatuximab 
Neutropenia 
 
≤ Grade 1 
No change. 
Grade 2 
No change. 
Grade 3 
Hold isatuximab until ≤ Grade 2.  
Grade 4 
Off protocol therapy. 
¹  
G-CSF may be used per treating physician discretion 
and institutional guidelines. See Section 8.4. 
Anemia¹ 
≤ Grade 1 
No change. 
Grade 2 
Hold isatuximab until < Grade 2.  
Grade 3 
Hold isatuximab until < Grade 2.  

 
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  Treatment-related 
Adverse Event 
Grade of Event 
Management for Isatuximab 
Grade 4 
Off protocol therapy. 
¹  
Dose delay is not required for anemia, unless 
deemed necessary by the treating physician. 
Transfusions and/or erythrocyte stimulating agents 
are allowable. 
All other events 
≤ Grade 1 
No change. 
Grade 2 
Hold isatuximab until < Grade 2 OR 
patient returns to baseline (where 
patient had a predetermined 
abnormal baseline).  
Grade 3 
Hold isatuximab until < Grade 2 OR 
patient returns to baseline (where 
patient had a predetermined 
abnormal baseline).  
Grade 4 
Off protocol therapy. 
 
8.4 
White Blood Cell Growth Factors 
 
If used, white blood cell growth factors, including biosimilars, must be used per ASCO 
guidelines http://jco.ascopubs.org/content/24/19/3187.full and NCCN Guidelines® Myeloid 
Growth Factors 
http://www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf. 
 
8.5 
Guidelines for the Management of Infusion Reactions (IRs) 
 
Patients should routinely receive premedications prior to isatuximab infusion to reduce the 
risk and severity of IARs commonly observed with monoclonal antibodies. Infusion 
associated reactions are defined as AEs related to isatuximab with onset typically within 
24 hours from the start of the infusion.  
 
Patients presenting Grade 2 IAR(s) with infusion interruption may subsequently resume 
isatuximab at half of the initial infusion rate under close monitoring and supportive care as 
needed. These patients must be informed of the potential risk of recurrent infusion 
reactions upon rechallenge.  For further infusions, patients may receive additional 
premedication per the judgment of the Investigator. Additional recommended 
premedications include diphenhydramine 25 mg IV (or equivalent) and methylprednisolone 
100 mg IV. 
 
Once a Grade 2 IAR leading to interruption has improved to Grade ≤1, the infusion may be 
restarted at half the original infusion rate. If symptoms do not recur after 30 minutes, the 
infusion rate may be increased in 50 mg/hour increments every 30 minutes, to a maximum 
of 400 mg/hour. 
 
Patients presenting Grade 3 or 4 isatuximab IAR(s) must have isatuximab permanently 
discontinued and appropriate supportive therapy should be administered. The IAR(s) and 
the therapy administered must be documented in the eCRF. 
 
 

 
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Table 2 - Management of infusion associated reactions 
 
CTCAE Version 5.0 criteria definition 
Intervention recommendation 
Mild (Grade 1) 
Infusion interruption or intervention not 
indicated 
Continuation of isatuximab infusion per the 
judgment of the Investigator following close 
direct monitoring of the patient’s clinical status. 
Isatuximab infusion may be stopped at any time 
if deemed necessary. If stopped, IAR will be 
classified as Grade 2 as per CTCAE Version 
5.0.  
Moderate (Grade 2) 
Therapy or infusion interruption indicated, 
but responds promptly to symptomatic 
treatment (eg, antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 hours 
Stop isatuximab infusion. Give additional 
premedication with diphenhydramine 25 mg IV 
(or equivalent) and/or methylprednisolone 
100 mg IV (or equivalent) as needed. 
Isatuximab may be resumed only after patient 
recovery, with slower infusion rate and with 
close monitoring.  
Severe or life-threatening  
(Grade 3 or 4) 
Grade 3: prolonged (eg, not rapidly 
responsive to symptomatic medication 
and/or brief interruption of infusion); 
recurrence of symptoms following initial 
improvement; hospitalization indicated for 
clinical sequelae 
Grade 4: life-threatening consequences; 
urgent intervention indicated 
Stop isatuximab infusion. Give additional 
premedication with diphenhydramine 25 mg IV 
(or equivalent) and/ or methylprednisolone 
100 mg IV (or equivalent) and/or epinephrine 
as needed. Definitive treatment discontinuation. 
 
Note: infusion should be completed within 16 hours from the end of infusion preparation or a 
new infusion should be prepared with the remaining dose to be administered the same day. 
Abbreviations:  AE = adverse event; IAR = infusion associated reaction; IV = intravenous; 
NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; 
NSAIDs = nonsteroidal anti-inflammatory drugs. 
 
8.6 
Dose Delay Contacts 
 
For treatment or dose delay questions, please contact Dr. Terri Parker at 203/737-7059 or 
Dr. Vaishali Sanchorawala at 617/638-8265. 
 
8.7 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.0 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 

 
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9.0 
STUDY CALENDAR 
 
  
PRE-STUDY 
(w/in 28 days 
prior to 
registration, 
unless 
otherwise 
noted) 
Cycle Length = 28 days 
(+/- 3 days) 
Off TX 
Pre-
Progression 
FU 
Post 
Progression 
FU 
REQUIRED 
STUDIES 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Subsequent 
Cycles up to 24 
Cycles 
 
PHYSICAL 
  
History and Physical 
Exam O 
X 
X 
X 
X 
X 
X 
 
 
Height 
X 
  
  
  
  
  
  
  
Weight 
 
X 
X  
X  
X  
X 
X 
 
 
Performance Status 
X 
X 
X 
X 
X 
X 
  
  
Toxicity Notation 
  
X (Days 1, 8, 15, 
22) 
X (Days 
1, 15) 
X (Days 1, 15) 
X (Days 1, 
15) 
X (Days 1, 15) 
XQ 
XQ 
NYHA Assessment 
K  
X 
X 
X 
X 
X 
X 
X 
  
Vital Signs N 
X 
X  
X  
X  
X  
X  
X 
  
Clinical autonomic 
neurologic 
evaluation A, H 
X 
X (every 2 
cycles, +/- 7 
days) 
  
X (every 2 
cycles, +/- 7 
days) 
  
X (every 2 
cycles, +/- 7 
days) 
X (every 6 
months, +/- 
21 days) 
  
Clinical peripheral 
neurologic 
evaluation A, H, K 
X 
X (every 2 
cycles, +/- 7 
days) 
  
X (every 2 
cycles, +/- 7 
days) 
  
X (every 2 
cycles, +/- 7 
days) 
X (every 6 
months, +/- 
21 days) 
  
Clinical GI 
evaluation A, H, K 
X 
X (every 2 
cycles, +/- 7 
days) 
  
X (every 2 
cycles, +/- 7 
days) 
  
X (every 2 
cycles, +/- 7 
days) 
X (every 6 
months, +/- 
21 days) 
  
  
LABORATORY 
  
  
  
  
  
Type and screen 
and blood bank 
notification E 
X 
  
  
  
  
  
  
  
  
CBC w/ differential, 
Platelets C 
X 
X (Days 1, 8, 15, 
22) 
X (Days 
1, 15) 
X (Days 1, 15) 
X (Days 1, 
15) 
X (Days 1, 15) 
  
  
Serum Chemistry C, 
J, K 
X 
X (Days 1, 8, 15, 
22) 
X (Days 
1, 15) 
X (Days 1, 15) 
X (Days 1, 
15) 
X (Days 1, 15) 
  
  

 
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PRE-STUDY 
(w/in 28 days 
prior to 
registration, 
unless 
otherwise 
noted) 
Cycle Length = 28 days 
(+/- 3 days) 
Off TX 
Pre-
Progression 
FU 
Post 
Progression 
FU 
REQUIRED 
STUDIES 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Subsequent 
Cycles up to 24 
Cycles 
 
TSH, free T4, free 
T3 J 
X 
  
  
  
  
  
  
  
HIV, HBV, HCV R 
X 
  
  
  
  
  
  
  
PT/PTT/INR L, P 
X 
X 
X 
X 
X 
X 
  
  
RESPONSE ASSESSMENT 
  
  
  
  
  
  
  
Serum β2 
microglobulin, LDH, 
uric acid J 
X 
  
  
  
  
  
  
  
Serum Quantitative 
Immunoglobulins 
(IgG, IgA, and IgM)  
X 
  
  
  
  
  
  
  
SPEP with M-
protein 
quantification  
X 
X 
X 
X 
X 
X 
X 
  
Serum free kappa 
and lambda light 
chains  
X 
X 
X 
X 
X 
X 
X 
  
Serum 
Immunofixation  
X 
X 
X 
X 
X 
X 
  
  
Urine Protein 
Electrophoresis K 
X 
X 
X 
X 
X 
X 
  
  
Urine 
Immunofixation 
Electrophoresis K 
X 
X 
X 
X 
X 
X 
  
  
Troponins (T or I) A,L 
X 
X 
X 
X 
X 
X 
X 
  
NT-pro-BNP L 
X 
X 
X 
X 
X 
X 
X 
  
Urine or Serum 
Pregnancy F 
X 
X 
X 
X 
X 
X 
  
  

 
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PRE-STUDY 
(w/in 28 days 
prior to 
registration, 
unless 
otherwise 
noted) 
Cycle Length = 28 days 
(+/- 3 days) 
Off TX 
Pre-
Progression 
FU 
Post 
Progression 
FU 
REQUIRED 
STUDIES 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Subsequent 
Cycles up to 24 
Cycles 
 
24-hour urine A, H, K 
X 
X (If obtained 
w/in 28 days 
prior to C1D1, 
tests need not 
be repeated.) 
  
X 
  
X 
X 
  
Bone Marrow 
Aspirate or Biopsy, 
including FISH, 
Cytogenetics and 
Immunophenotyping  
X (w/in 35 
days) 
  
  
  
  
  
  
  
24-hour fecal fat A,G 
X  
X (If obtained 
w/in 28 days 
prior to C1D1, 
tests need not 
be repeated.) 
  
  
X (every 3 
cycles, +/- 7 
days) 
X (every 3 
cycles, +/- 7 
days) 
X (every 6 
months, +/- 
21 days) 
  
X-RAYS AND SCANS 
Ultrasound, MRI or 
CT for Disease  
Assessment of liver, 
soft tissue or lymph 
nodes A,I 
X 
X (If obtained 
w/in 28 days 
prior to C1D1, 
tests need not 
be repeated.) 
  
  
  
X (every 6 
months, +/- 21 
days) 
X (every 6 
months, +/- 
21 days) 
  
12-lead EKG  
X 
X (Days 1, 15) 
X 
  
  
  
  
  
2D ECHO G, K 
X 
X (If obtained 
w/in 28 days 
prior to C1D1, 
tests need not 
be repeated.) 
  
  
X (every 3 
cycles, +/- 
7 days) 
X (every 3 
cycles, +/- 7 
days) 
X (every 6 
months, +/- 
21 days) 
  
SPECIMEN SUBMISSION 
 
Optional Peripheral 
Whole Blood, 
Serum. Bone 
Marrow Aspirate 
X 
  
  
  
  
  
  
  

 
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PRE-STUDY 
(w/in 28 days 
prior to 
registration, 
unless 
otherwise 
noted) 
Cycle Length = 28 days 
(+/- 3 days) 
Off TX 
Pre-
Progression 
FU 
Post 
Progression 
FU 
REQUIRED 
STUDIES 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Subsequent 
Cycles up to 24 
Cycles 
 
and Biopsy Core for 
Banking B 
NOTE: 
Forms are found on the protocol abstract page on the SWOG website (www.swog.org) and on the CTSU website 
(www.ctsu.org).  
Forms submission guidelines are found in Section 14.0. Click here for footnotes. 
NOTE  
Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, 
toxicity assessment for continuous treatment, disease assessment, specimen collection and follow-up 
activities) must follow the established SWOG guidelines on the allowed protocol visits/treatment window as 
outlined in https://www.swog.org/sites/default/files/docs/2017-10/Best%20Practices%20upddate.pdf. SWOG 
Best Practices allows for a +/- 3 day window for 28 day cycles. 
 
 
 
 

 
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Footnotes for Calendar 9 (Isatuximab) 
 
A 
Tests are to be performed per Section 5.1d for suspected organ involvement. If baseline test was performed and abnormality  
 
present, the tests will be repeat until off tx prior to progression.  
B 
See Section 15.1. 
C 
Prior to treatment on each day of isatuximab, or within 3 days prior to each administration. 
E 
See Section 7.1c for type and screen requirements. See Appendix 18.6 for sample type and screen card. 
F 
For women of childbearing potential, prior to beginning treatment at each cycle (or up to 3 days prior to Day 1). 
G If required: Day 1 of Cycles 1, 4, and 7, then every 3 cycles (+/- 7 days) during treatment, then every 6 months (+/- 21 days)
hematologic progression. 
H 
If required: Day 1 of Cycles 1, 3, 5, then every 2 cycles (+/- 7 days) until completion of treatment, then every 6 months  
 
(+/- 21 days) until hematologic progression. 
I 
If required: Every 6 months during and after treatment until hematologic progression, then as clinically indicated. 
J 
TSH with reflex to free T4, and free T3 uric acid and LDH are required only when clinically indicated; however, baseline  
 
testing is encouraged to assess for thyroid involvement, if suspected. 
K 
See Section 7.4 for a detailed description of organ evaluation and 24 hour urine collection assessment criteria, including  
 
serum chemistry panel requirements. All evaluations will continue at specified intervals until one of the criteria for removal from  
 
protocol treatment has been met (see Section 7.5).   
L 
If required: Day 1 (+/- 3 days) of each cycle. 
M See treatment plan Section 7.3. 
N 
See Sections 5.1d.5 and 7.1b. 
O Must include assessment of soft tissue and lymph nodes, if present at baseline; see Section 7.4e. 
P 
May be either INR or PT and PTT.  Whichever is performed at baseline should be used throughout treatment. 
Q Assessments should continue until resolution of all acute adverse events. 
R 
Only required per Section 5.3 Eligibility. 
 
 
 
 
 

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
10.1 
Measurable disease 
 
For the purpose of measuring hematologic response, measurable disease is defined as: 
 
a. 
Positive 
monoclonal 
serum 
immunofixation 
electrophoresis 
or 
urine 
immunofixation electrophoresis, 
 
and/or 
 
b. 
Serum free light chain ratio outside of normal range (normal range: 0.25 – 1.65) 
 
10.2 
Hematologic Response and Progression  
 
Confirmation must be made by verification on two consecutive determinations. 
 
a. 
Hematologic response: (16,17) 
 
1. 
Complete Response (CR):  
CR is defined as laboratory values within the normal range free light chain 
(FLC) ratio (0.25 – 1.65) and negative serum and urine immunofixation (as 
per institutional laboratory values). 
 
2. 
Very Good Partial Response (VGPR):  
A VGPR is defined as the difference between involved and uninvolved 
FLCs [dFLC] < 4.0 mg/dL.  
 
3. 
Partial Response (PR):  
Partial Response is defined as a dFLC decrease of ≥ 50%, but remaining 
> 4.0 mg/dL 
 
b. 
Hematologic progression: 50% increase from nadir, or from baseline (if there was 
no response) in any ONE OR MORE of the following: (18) 
 
1. 
Serum M-protein: 50% increase in Serum M protein to a value greater than 
0.5 g/dL. 
 
2. 
Urine M protein: 50% increase in Urine M protein to a value greater than 
200 mg/day (a visible peak must be present) 
 
3. 
Free light chain increase of 50% to a value greater than 10 mg/dL 
 
c. 
Stable Disease:  
Patients who do not meet criteria for objective response or progression (see 
Sections 10.2a and 10.2b) will be termed to have stable disease. 
 
10.3 
Organ Response (19) 
 
Response to therapy in terms of improvement in organ dysfunction will be defined based 
on functional improvement in one or more involved organ systems. Only 1 parameter is 
required to satisfy the organ response criteria. In order to be classified as a confirmed 
organ response, confirmation must be made by verification on a second consecutive 
assessment at least 4 weeks after the first observation of response. 
 
 

 
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a. 
Liver response requires either: 
 
1. 
A 50% decrease in (or normalization of, <1.5 IULN) alkaline phosphatase 
level, or  
 
2. 
A reduction in the span of the liver by at least 2 cm by radiographic 
determination.   
 
b. 
Renal response is defined as either: (20) 
 
1. 
A 30% decrease in urine total albumin; or  
 
2. 
A decrease to less than 500 mg/24 hours urine total protein without renal 
progression (where renal progression is defined in Section 10.4a.1). 
 
c. 
Gastrointestinal response is defined as either:  
 
1. 
Reduction in 24-hour fecal fat excretion by ≥ 50% in patients with 
steatorrhea; or  
 
2. 
≥ 50% reduction in number of loose stools per day in patients with 
diarrhea. 
  
d. 
Cardiac response is defined as either: (21) 
 
1. 
NT-proBNP response (>30% decrease and at least 300 pg/mL decrease 
is needed from the baseline result if NT- proBNP > 650 pg/mL at baseline) 
or 
 
2. 
NYHA class decrease from 1 to 0; 2 to 1 or 0 or from 3 to 1 (2 class 
decrease if baseline NYHA III). (That is, If NYHA is 1 or 2, a 1-class level 
drop is required. If NYHA is a 3, a 2-class level drop is required.) 
 
e. 
A neurologic response is defined as: 
 
1. 
Clear improvement in neuropathy (peripheral or autonomic) in the opinion 
of the treating investigator. For peripheral neuropathy, the Neuropathy 
Impairment Tool – Lower Limbs (NIS-LL) must be used to assess 
response.   
 
The NIS (LL is a scoring system graduated from 0 points (the normal 
finding) to a maximum of 88 points (the absence of all motor, sensory, and 
reflex activity in the lower extremities). The scale is additive of all deficits 
(64 potential points for muscle strength, 8 points for reflexes, and 16 points 
for sensory function) in the lower extremities. A NIS-LL score 
demonstrating a decrease from baseline of ≥ 2 points is indicative of organ 
response. (22) 
 
See Section 18.2. 
 
2. 
For autonomic neuropathy, a clear improvement in the opinion of the 
investigator including improvement in orthostatic blood pressure (systolic 
blood pressure (SBP)) readings and symptoms of dizziness and nausea 
on 2 separate occasions. 
 

 
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a. 
Orthostatic hypotension is defined as a decrease in systolic blood 
pressure of 20 mm Hg or a decrease in diastolic blood pressure 
of 10 mm Hg within three minutes of standing when compared with 
blood pressure from the sitting or supine position. Orthostatic 
symptoms include dizziness, lightheadedness, nausea 
 
f. 
Soft tissue/lymph nodes: There is no reliable method for assessing soft tissue 
responses.  Determination of soft tissue response will be performed by the site 
investigator in conjunction with the PI/Medical Monitor. Examples of soft tissue 
responses would include decreased size and thickness of tongue, or improved 
tongue mobility, on physical examination (for macroglossia); objective decrease in 
size of soft tissue deposits on examination or imaging. 
  
10.4 
Criteria for Organ Progression 
 
Progression will be defined based on objective evidence of worsening of organ 
dysfunction due to AL amyloid.  
 
a. 
Any ONE of the following criteria must be met to be termed as organ progression 
for the purpose of this study:  
 
1. 
Renal:  A 50% increase (at least 1 g/day) of 24-hour urine protein to > 1 
g/day OR 25% worsening of serum creatinine or creatinine clearance 
(Cockcroft-Gault method). 
 
2. 
Hepatic progression is defined by either:  
 
a. 
A 50% increase of alkaline phosphatase level above lowest level, 
or  
 
b. 
An increase in liver span by at least 2 cm (radiographic 
determination). 
 
3. 
Gastrointestinal: Worsening of diarrhea with an increase 50% of previous 
movements per day (not attributable to the study drug or an alternative 
explanation in the opinion of the treating physician) or 24-hour fecal fat 
increase by 50%. 
 
4. 
Cardiac: An increase in cardiac wall thickness by 2 mm or an increase in 
NYHA class by one grade with a decreasing ejection fraction of 10%, or 
an increase in NT-proBNP by > 30% and >300 pg/mL or an increase in 
troponin T or I by > 33%. 
 
5. 
Neurologic: Clearly progressive neuropathy (peripheral or autonomic) that 
in the opinion of the treating investigator is unrelated to study drug.  
 
a. 
For peripheral neuropathy, the Neuropathy Impairment Tool – 
Lower Limbs (NIS-LL) must be used to assess progression.  
 
The NIS (LL is a scoring system graduated from 0 points (the 
normal finding) to a maximum of 88 points (the absence of all 
motor, sensory, and reflex activity in the lower extremities). The 
scale is additive of all deficits (64 potential points for muscle 
strength, 8 points for reflexes, and 16 points for sensory function) 
in the lower extremities. A NIS-LL score demonstrating an 

 
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increase from baseline of ≥ 2 points is indicative of organ 
progression. (23) 
 
See Section 18.2. 
 
b. 
Clear worsening of orthostatic vital signs (SBP) and symptoms of 
dizziness or nausea on 2 separate occasions. 
  
6. 
Soft 
tissue/lymph 
nodes: 
Clearly 
progressive 
macroglossia 
or 
symptomatic soft tissue deposits. 
 
10.5 
Time to Hematologic Response 
 
From date of registration to date of first documentation of hematologic PR, VGPR, or CR 
as defined in Section 10.2. 
 
10.6 
Overall Survival 
 
From date of registration to date of death due to any cause. Patients last known to be alive 
are censored at date of last contact. 
 
10.7 
Progression-Free Survival 
 
From date of registration to date of first documentation of progression, symptomatic 
deterioration (as defined below), or death due to any cause. Patients last known to be alive 
and progression-free are censored at date of last contact. 
 
Symptomatic Deterioration: The global deterioration of health status requiring discontinuation 
of treatment without objective evidence of progression. 
 
10.8 
Performance Status 
Patients will be graded according to the Zubrod performance status scale. 
 
POINT  
DESCRIPTION 
 
0  
Fully active, able to carry on all pre-disease performance without restriction. 
 
1  
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work. 
 
2  
Ambulatory and capable of self-care but unable to carry out any work activities; 
up and about more than 50% of waking hours.  
 
3. 
Capable of limited self-care, confined to bed or chair more than 50% of waking 
hours. 
 
4  
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Two-Stage Design 
 
The primary goal of this study is to test the hypothesis that the rate of confirmed overall 
hematologic response (CR+VGPR+PR) to treatment is at most 10% versus the alternative 
that the true hematologic response rate is 30% or greater.  

 
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A two-stage design will be used for patient accrual, with a total of 35 eligible patients who 
are evaluable for hematologic response per the definition in Section 11.2b below. (24)  
Patients who received at least one dose of study drug will be considered evaluable.  
Initially, 20 eligible, evaluable patients will be accrued. If one or fewer hematologic partial 
or better responses are observed in the first 20 patients, this treatment will be considered 
insufficiently active in this population and further accrual will be terminated. If two or more 
confirmed, partial or better responses are observed, then an additional 15 eligible, 
evaluable patients will be accrued.  If at least 8 out of the total 35 patients have a confirmed 
response, the treatment may be recommended for further testing in subsequent studies. 
An estimated 39 patients will be enrolled to this study (including 35 eligible and evaluable 
patients, with 20 enrolled to Stage 1 and 15 enrolled to Stage 2, and with an additional 4 
patients enrolled overall to account for ineligible and unevaluable patients).  
 
With an estimated accrual rate of 1-2 patients per month, it is anticipated that the study will 
reach full accrual in 20 to 40 months. 
 
11.2 
Sample size and Power Justification 
 
a. 
Assuming the number of hematologic responses is binomially distributed this 
design has a significance level of 2% and a power of 87% for detecting a true 
overall hematologic response rate of at least 30% versus the null hypothesis 
response rate of 10% of less. 
 
b. 
All eligible patients who receive any study treatment will be considered to be 
evaluable for response and toxicity, and will be included in the analysis.   
 
c. 
Patients who go off study or die prior to the first response assessment will be 
considered as non-responders. 
 
11.3 
Analysis of Primary Endpoint 
 
The primary endpoint of this study is overall confirmed hematologic response rate (ORR), 
which includes partial response (PR), very good partial response (VGPR) and complete 
response (CR) as defined in Section 10.2. 
 
 
Hematologic response will be reported with a binomial confidence interval.  All eligible 
patients who received at least one day of treatment, including those that go off study or die 
prior to the first response evaluation, will be included in the calculation of response rates.  
The null hypothesis of a response rate of 10% or lower will be evaluated as described 
above, with potential adjustments to the critical values once the exact number of patients 
is determined. 
 
11.4 
Analysis of Secondary and Other Endpoints 
 
Toxicity will be evaluated using the CTCAE Version 5.0 items.  All eligible patients that 
have initiated treatment will be considered evaluable for toxicity analyses. The maximum 
Grade for each toxicity will be recorded for each patient, and frequency tables will be 
reviewed to determine toxicity patterns.  Assuming 35 eligible, evaluable patients, any 
toxicity event seen with at least 5% probability is likely to be observed at least once (83% 
chance). With 35 eligible patients, response rates and rates of individual toxicities can be 
estimated to within +/- 17% (95% confidence interval). 
 
Organ response will be evaluated in the subset of patients with evaluable organ 
involvement using current criteria Organ involvement will be considered evaluable if it 
qualifies based on the criteria defined in Section 10.3.  There may be eligible patients 
whose organ involvement is based upon a feature (such as amyloid deposition or certain 
types of soft tissue involvement) that does not have an associated response/progression 

 
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definition. These patients will not be evaluated for organ response. The proportion of 
patients with organ response will be estimated as the number of patients with documented 
organ response out of the number of patients with documented evaluable organ 
involvement at baseline.   
 
OS and PFS will be estimated using the Kaplan-Meier method.  
 
11.5 
Safety Analysis  
 
There is no formal Data and Safety Monitoring Committee for this study.  Accrual reports 
are generated weekly and study-specific accrual is monitored by the Study Chair, Study 
Statistician and the Disease Committee Chair.   
 
There will be a run-in to ensure safety of this treatment combination.  Ten patients will 
initially be treated.  The following adverse events of special interest are specified as a 
potential safety concern, if a patient experiences one of them in the 1st cycle of treatment.  
If two or fewer patients experience any of the toxicities listed below during the first cycle of 
treatment, then accrual will continue as planned.  If three or more patients experience at 
least one of these toxicities during the first cycle of treatment, the trial will be temporarily 
closed to accrual pending a decision as to whether to continue accrual.  If accrual is re-
opened, a protocol revision will include justification for continued accrual and for any 
treatment regimen modifications.  If accrual is proceeding quickly, enrollment will be 
paused until all ten patients in the initial safety cohort have completed one cycle of 
treatment or experienced one of the events listed below. 
 
 
Events to be monitored during safety run-in: 
 
• 
Grade 3 and 4 infusion-associated reaction (IARs) defined as anaphylactic 
reaction, hypertension, or dyspnea. 
• 
Grade 4 cardiac event (including CHF and arrhythmias) (or > 2 NYHA 
grades higher than patient baseline)  
• 
Grade 4 neutropenia or thrombocytopenia that does not resolve to < Grade 
3 within 10 days 
• 
Grade 4 infection. 
• 
Grade 4 gastrointestinal ileus, or obstruction.   
• 
Grade 4 LFT abnormalities (AST, ALT, Bilirubin)  
 
Reports summarizing adverse events, serious adverse events (SAEs) and treatment 
administration are provided monthly to the Study Chair and Study Statistician for 
monitoring.  In addition, all SAEs, which by definition require expeditious reporting, are 
reviewed and processed by the Adverse Event Coordinator at the SWOG Operations Office 
and a physician reviewer based on data provided via the NCI CTEP-AERS system.  
Cumulative study-specific SAE reports are provided to the Study Chair and Study 
Statistician upon occurrence of an event. Formal reports summarizing the study are 
prepared for all SWOG members every 6 months.   
 
 
12.0 
DISCIPLINE REVIEW 
 
This study will not utilize discipline review. 
 
 
 

 
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13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than 5 working days 
prior to planned start of treatment). 
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a Cooperative Group. Each investigator must have an NCI investigator number and must 
maintain an “active” investigator registration status through the annual submission of a 
complete investigator registration packet to CTEP. 
 
a. 
CTEP Investigator Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute 
(NCI) policy require all individuals contributing to NCI-sponsored trials to register 
and to renew their registration annually.  To register, all individuals must obtain a 
Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) account (https://ctepcore.nci.nih.gov/iam).  In addition, persons with a 
registration type of Investigator (IVR), Non-Physician Investigator (NPIVR), or 
Associate Plus (AP) (i.e., clinical site staff requiring write access to OPEN, RAVE, 
or TRIAD or acting as a primary site contact) must complete their annual 
registration using CTEP’s web-based Registration and Credential Repository 
(RCR) <https://ctepcore.nci.nih.gov/rcr >.  Documentation requirements per 
registration type are outlined in the table below 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and 
certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if 
applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and CTSU (Cancer Trials Support Unit) websites and 
applications.  In addition, IVRs and NPIVRs must list all clinical practice sites and 

 
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IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) 
tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks 
Log (DTL).  
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
< 
https://ctep.cancer.gov/investigatorResources/default.htm 
>.  
For 
questions, 
please contact the RCR Help Desk by email at < RCRHelpDesk@nih.gov >. 
 
b. 
CTEP Associate Registration Procedures 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) application is a web-based application intended for use by both 
Investigators (i.e., all physicians involved in the conduct of NCI-sponsored clinical 
trials) and Associates (i.e., all staff involved in the conduct of NCI-sponsored 
clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration 
and annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only. (See 
CTEP Investigator Registration Procedures above for information on registering 
with CTEP as an Investigator, which must be completed before a CTEP-IAM 
account can be requested.) 
 
An active CTEP-IAM user account will be needed to access all CTEP and CTSU 
(Cancer Trials Support Unit) websites and applications, including the CTSU 
members’ website. 
 
Additional 
information 
can 
be 
found 
on 
the 
CTEP 
website 
at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm. For ques-tions, 
please contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov. 
 
c. 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
1. 
IRB Approval:   
 
Each investigator or group of investigators at a clinical site must obtain 
IRB approval for this protocol and submit IRB approval and supporting 
documentation to the CTSU Regulatory Office before they can be 
approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a 
determination of whether a site has fulfilled all regulatory criteria including 
but not limited to: an active Federal Wide Assurance (FWA) number, an 
active roster affiliation with the Lead Network or a participating 
organization, a valid IRB approval, and compliance with all protocol 
specific requirements. 
 

 
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Sites participating on the NCI CIRB initiative that are approved by the 
CIRB for this study are not required to submit IRB approval documentation 
to the CTSU Regulatory Office. For sites using the CIRB, IRB approval 
information is received from the CIRB and applied to the RSS in an 
automated process. Signatory Institutions must submit a Study Specific 
Worksheet for Local Context (SSW) to the CIRB via IRBManager to 
indicate their intent to open the study locally.  The CIRB’s approval of the 
SSW is then communicated to the CTSU Regulatory Office.  In order for 
the SSW approval to be processed, the Signatory Institution must inform 
the CTSU which CIRB-approved institutions aligned with the Signatory 
Institution are participating in the study. 
 
2. 
Downloading Site Registration Documents:   
 
Site registration forms may be downloaded from the S1702 protocol page 
located on the CTSU members’ website.   
 
Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
 
Click on the Protocols tab in the upper left of your screen 
 
Either enter the protocol # in the search field at the top of the protocol 
tree, or 
 
Click on the By Lead Organization folder to expand 
 
Click on the SWOG link to expand, then select trial protocol S1702 
Click on LPO Documents, select the Site Registration documents link, 
and download and complete the forms provided.    
 
3. 
Requirements For S1702 Site Registration: 
 
• 
CTSU Transmittal Sheet (optional)  
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol 
of 
Human 
Subjects 
Assurance 
Identification/IRB 
Certification/Declaration of Exemption Form, or combination is 
accepted) 
 
4. 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office, via 
the Regulatory Submission Portal, where they will be entered and tracked 
in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org (members’ area)  
Regulatory Tab  Regulatory Submission 
 
When applicable original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 1100 
Philadelphia, PA 19103 
Institutions with patients waiting that are unable to use the Portal should 
alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order 
to receive further instruction and support. 
 
 

 
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5. 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the 
CTSU website.   
 
• Go to https://www.ctsu.org and log in to the members’ area using your 
CTEP-IAM username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation 
and institutional compliance with protocol-specific requirements as 
outlined by the Lead Network. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available on a 24/7 basis.  To access 
OPEN, the site user must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and a 'Registrar' role on either the LPO or participating 
organization roster. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 

 
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l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated with 
the CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient in the Rave database.  OPEN can be accessed at 
https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench. 
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes 
and the affirmation of eligibility on the Registration Worksheet has been 
signed 
by 
the 
registering 
investigator 
or 
another 
investigator 
designate. Site staff should refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
c. 
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.  Please print this confirmation for your records. 
 
d. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org. 
For any additional questions contact the CTSU Help Desk at 888/823-5923 or 
ctsucontact@westat.com. 
 
 

 
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13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
www.swog.org and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details. 
 
14.3 
Data Submission Procedures 
 
a. 
Data collection for this study will be done exclusively through the Medidata Rave® 
clinical data management system. Access to the trial in Rave is granted through 
the iMedidata application to all persons with the appropriate roles assigned in 
Regulatory Support System (RSS). To access Rave via iMedidata, you must have 
an active CTEP-IAM account (check at  
https://eapps-ctep.nci.nih.gov/iam/index.jsp) and the appropriate Rave role (Rave 
CRA, Read-Only, Site Investigator) on either the LPO or participating organization 
roster at the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata. To accept the invitation, site users must log into the Select Login 
https://login.imedidata.com/selectlogin using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page. Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed. Trainings will be in 
the form of electronic learnings (eLearnings), and can be accessed by clicking on 
the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial registration approval for the study in RSS will also receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website, Rave tab under the Rave resource materials 
(Medidata Account Activation and Study Invitation Acceptance). Additional 
information on iMedidata/Rave is available on the CTSU members’ website under 
the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU help Desk at 
888/823-5923 or by e-mail at ctsucontact@westat.com . 
 

 
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b. 
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site http://swog.org and logon to the Members Area using your SWOG Roster 
ID Number and password. After you have logged on, click on Workbenches, then 
CRA Workbench to access the home page for the CRA Workbench and follow the 
link to Rave® provided in the left-hand navigation panel. 
 
To access the CRA Workbench the following must be done (in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, 
3. 
Your Web User Administrator has added you as a web user and has given 
you the appropriate system permissions to view data for that institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  For 
point 3, contact your local Web User Administrator (refer to the "Who is my Web 
User Administrator?" function on the swog.org Members logon page). 
 
14.4 
Data Submission Overview and Timepoints  
 
a. 
WITHIN 7 DAYS OF REGISTRATION: 
 
Submit the following: 
 
Onstudy Form 
 
AL Baseline Tumor Assessment Form 
 
Pathology report, confirming AL amyloidosis (as defined in Section 5.1)  
 
If organ involvement was assessed by biopsy, submit the pathology report 
documenting the involvement (see Section 5.1d). 
 
If patient has involvement of the liver or lymph nodes, submit radiology reports 
(ultrasound, CT, or MRI) to assess liver and lymph node size at baseline. 
 
See Section 15.0 for specimen submission requirements. 
 
b. 
WITHIN 35 DAYS AFTER REGISTRATION: 
 
Submit the following: 
 
S1702 Cytogenetics and FISH Analysis Form. 
 
Institutional Flow Cytometry Report for Immunophenotyping and S1702 
Immunophenotyping Form 
 
Institutional Cytogenetics Report, FISH Analysis Report, and Bone Marrow 
Aspirate and Biopsy Report 
 
c. 
WITHIN 14 DAYS AFTER EACH CYCLE OF TREATMENT: 
 
Submit the following: 
 
S1702 Treatment Form 
 

 
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S1702 Adverse Event Form 
 
AL Follow Up Tumor Assessment Form 
 
d. 
WITHIN 30 DAYS OF DISCONTINUATION OF TREATMENT: 
 
Submit the following: 
 
Off Treatment Notice 
 
S1702 Treatment Form 
 
S1702 Adverse Event Form 
 
AL Follow Up Tumor Assessment Form 
 
e. 
WITHIN 14 DAYS OF PROGRESSION/RELAPSE: 
 
Submit the S1702 Treatment Form and S1702 Adverse Event Form (if the patient 
was still on protocol treatment),  
 
Submit the AL Follow Up Tumor Assessment Form 
 
f. 
EVERY 6 MONTHS FOR 4 YEARS AFTER REGISTRATION: 
 
Submit the following: 
 
Follow Up Form 
 
Late Effects Form (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the patient experiences any severe 
[Grade ≥ 3] long term toxicity that has not been previously reported). 
 
g. 
WITHIN 14 DAYS OF SECOND MALIGNANCY: 
 
Submit the following: 
 
Follow Up Form 
 
h. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
Submit the Notice of Death and a final S1702 Treatment Form and S1702 Adverse 
Event (if the patient was still on protocol treatment) or Follow-Up Form (if the 
patient was off protocol treatment) documenting death information. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Translational Medicine and Banking (OPTIONAL) 
 
Specimens for translational medicine and banking (submitted to the SWOG Biospecimen 
Bank– Solid Tissue, Myeloma and Lymphoma Division-Lab #201) (optional for patient): 
 
a. 
With patient’s consent, specimens (peripheral whole blood, serum, bone 
marrow aspirate and bone marrow biopsy core) must be collected prior to 
initiation of protocol therapy. Collection instructions are outlined in Section 15.1b 
and shipping instructions are outlined in  Section 15.1c. (See also Section 9.0): 

 
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1. 
Tissue (frozen bone marrow biopsy core): Pretreatment (within 35 days 
prior to registration).  
 
2. 
Blood (whole blood and serum) must be fresh drawn prior to treatment on 
Cycle 1, Day 1. 
 
b. 
Specimen Collection Instructions: 
 
1. 
Peripheral Whole Blood: 
 
a. 
Fill one 4 mL lavender plastic EDTA tube completely with 4mL 
peripheral blood.  
 
b. 
Do NOT centrifuge. Immediately after collection, mix by gently 
inverting the tube at least 8 to 10 times.  
 
c. 
Clearly and appropriately label the sample tube (per instructions 
in the STS). 
 
d. 
Within 30 minutes of collection (after gently mixing), freeze 
the blood in an upright position at -80ºC for storage until shipment. 
If freezer is not immediately available, samples must be stored on 
dry ice until shipment.  
 
2. 
Bone Marrow Aspirate:  
 
a. 
Collect 3 – 4 mL of bone marrow aspirate into a sodium heparin 
(NaHep, green top) tube.  
 
b. 
Mix gently by inverting the tube 8 to 10 times. Do not centrifuge 
and do not freeze. 
 
*  Note that marrow specimens should be submitted within 24 hours of 
draw for viability. 
 
3. 
Bone Marrow Biopsy Core: 
 
a. 
Biopsy core specimen should be 1 – 2 cm in length.  
 
b. 
Snap-freeze immediately after resection.  
 
*  Note that marrow specimens should be submitted within 24 hours of 
draw for viability. 
 
4. 
Serum:  
 
a. 
Collect 5 – 7 mL of blood into a red top tube. 
 
b. 
Allow blood to clot (30 – 60 minutes) before processing.  Refer to 
processing 
instructions 
on 
the 
SWOG 
website 
(https://www.swog.org/clinical-trials/biospecimen-
resources/biospecimen-processing-and-submission-procedures.     
 

 
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5. 
Additional specimen collection, labelling, and shipment instructions for the 
serum, bone marrow aspirate and bone marrow biopsy core specimens 
can be accessed on the SWOG Specimen Submission webpage: 
www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures. 
 
6. 
Specimen collection kits are not being provided for this submission; sites 
will use institutional supplies. 
  
c. 
Specimen Labeling 
 
1.   
Blood, serum, and bone marrow labels should include: 
• 
SWOG patient number 
• 
Patient initials 
• 
Collection date (date the specimen was collected from the patient) 
• 
Laterality (bone marrow only – e.g. left, right) 
 
2.    
Tissue specimen labels should include: 
• 
SWOG patient number* 
• 
Patient initials 
• 
Collection date (date the specimen was collected from the patient) 
• 
Collection site (e.g., lymph node) 
• 
Specify if the tissue is from Primary (P) or Metastatic (M) 
• 
Surgical Pathology ID (SPID) and Block number (e.g., A2, 3E, 2-1, 
etc.)  
 
* To obtain a SWOG Patient ID prior to patient registration, go to the 
SWOG 
specimen 
tracking 
system 
(https://crawb.crab.org/TXWB/ctsulogon.aspx) and select “Specimen 
Tracking.”  Use the “Log a Specimen” link from the Specimen Tracking 
Home page. Use the “No Patient ID yet?” link and enter demographic 
information for the patient on the next page. This will assign a SWOG 
patient ID number and will remain the patient’s ID number. If the patient 
does register to the study, it is important to remember to use this 
patient ID number on the OPEN system so the specimens will 
match with the correct patient. Specimens will be destroyed if the 
patient is not subsequently registered to the study. 
 
d. 
SHIPPING SAMPLES 
 
1. 
SWOG Specimen Tracking System (STS) 
 
All specimen submissions for this study must be entered and tracked using 
the SWOG online Specimen Tracking system. SWOG members may log 
on the online system via the CRA Workbench. To access the CRA 
Workbench, go to the SWOG Web site http://swog.org and logon to the 
Members Area. After you have logged on using your SWOG roster ID 
number and password, click on the CRA Workbench link to access the 
home page for CRA Workbench website. Non- SWOG users may log into 
SpecTrack using their CTSU UserID and password on the SpecTrack login 
page located at https://spectrack.crab.org (select the option “SWOG – 
SWOG – CTSU”).  SpecTrack start-up instructions (both written and 
demo) are available after signing in to SpecTrack.  
 
A copy of the Shipment Packing List produced by the online Specimen 
Tracking system should be printed and placed in the pocket of the 

 
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specimen bag if it has one, or in a separate resealable bag. The Specimen 
Submission Form is NOT required when the online system is used. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database 
errors 
or 
connectivity 
issues, 
please 
send 
an 
email 
to 
technicalquestion@crab.org. For procedural help with logging and 
shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page (https://spectrack.crab.org/Instructions); or 
contact the Data Operations Center at 206/652-2267 to be routed to the 
Data Coordinator for further assistance. 
 
In the online specimen tracking system, the appropriate SWOG laboratory 
for submission of peripheral whole blood, serum, bone marrow 
aspirate and bone marrow biopsy core samples for SWOG 
Biospecimen Bank for Translational Medicine and banking is identified as 
follows: 
 
Lab #201:          SWOG Biospecimen Bank 
Solid Tissue, Myeloma and Lymphoma Division   
Phone:    614-722-2865 
Contact:  SWOG Bank Coordinator  
Email:     bpcbank@nationwidechildrens.org  
 
2. 
Federal guidelines for the shipment of blood products: 
 
a. 
The tube must be wrapped in an absorbent material. 
 
b. 
The tube must then be placed in an AIRTIGHT container (like a 
resealable bag). 
 
c. 
Pack the resealable bag and tube in a Styrofoam shipping 
container. 
 
d. 
Pack the Styrofoam shipping container in a cardboard box. 
 
e. 
Mark the box "Biohazard". 
 
e. 
Obtaining SWOG Patient ID Prior to Patient Registration 
 
To obtain a SWOG patient ID for purposes of specimen submission prior to 
registration, use the SWOG specimen tracking system  
(https://crawb.crab.org/TXWB/ctsulogon.aspx).  Select “Specimen Tracking,” then 
click the “Log a Specimen” link from the Specimen Tracking Home page, and then 
the “No Patient ID yet?” link.  Enter demographic information for the patient on the 
next page. This will assign a SWOG patient ID number and will remain the patient’s 
ID number. If the patient does register to the study, it is important to remember to 
use this patient ID number on the OPEN system, so the specimens will match with 
the correct patient. Specimens will be destroyed if the patient is not subsequently 
registered to the study.  Note that patients must sign consent prior to specimen 
submission. 
 
 
 

 
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16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
Drug Accountability 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
protocol- and patient-specific CDUS data will be submitted electronically to CTEP on a quarterly 
basis by FTP burst of data.  Reports are due January 31, April 30, July 31, and October 31.  
Instructions for submitting data using the CDUS can be found on the CTEP Web site  
(http://ctep.cancer.gov/reporting/cdus.html). 
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events (both 
routine and expedited) that have occurred on the study and meet the mandatory CDUS reporting 
guidelines must be reported via the monitoring method identified above.  If your study has been 
assigned to CDUS-Abbreviated reporting, no adverse event reporting (routine or expedited) is 
required to be reported via CDUS, but expedited adverse events are still required to be submitted 
via CTEP-AERS. 
 
Confidentiality 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements 
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse 
events are reported in a routine manner at scheduled times during a trial. 
(Directions for routine reporting are provided in Section 14.0.) Additionally, 
certain adverse events must be reported in an expedited manner to allow for 
more timely monitoring of patient safety and care. The following guidelines 
prescribe expedited adverse event reporting for this protocol.  

 
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b. 
Reporting method 
 
This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program Adverse Event Reporting System (CTEP-AERS).  
CTEP's guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. A 
CTEP-AERS report must be submitted to the SWOG Operations Office 
electronically via the CTEP-AERS Web-based application located at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_
events.htm.  
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via 
CTEP-AERS. When Internet connectivity is disrupted, a 24-hour notification is 
to be made to SWOG by telephone at 210-614-8808, or by email at 
adr@swog.org.  Once Internet connectivity is restored, a 24-hour notification 
that was made by phone or using adr@swog.org must be entered electronically 
into CTEP-AERS by the original submitter at the site. 
 
When the adverse event requires expedited reporting, submit the report within 
the number of calendar days of learning of the event specified in Table 16.1.  
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local 
policy and procedures. 
 
e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of 
the investigational agent(s) as part of the trial. Reporting requirements are 
provided in Table 16.1. The investigational agent used in this study isatuximab 
(SAR650984). If there is any question about the reportability of an adverse 
event or if on-line CTEP-AERS cannot be used, please telephone or email the 
SAE Specialist at the Operations Office, 210/614-8808 or adr@swog.org, 
before preparing the report. 
 

 
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Table 16.1: 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse events 
that Occur on Studies under an Non-CTEP IND within 30 Days of the Last Administration of 
the Investigational Agent/Intervention1   Isatuximab (SAR650984). 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 
CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the 
NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in 
the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
or Section 16.1f. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar 
days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 
10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or definite 
require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
 
May 5, 2011 

 
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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Phase 1 and Early Phase 2 Studies Utilizing an Agent 
under a non-CTEP-IND: 
 
1. 
Group-specific instructions. 
 
Supporting Documentation Submission - Within 5 calendar days 
submit the following to the SWOG Operations Office by fax to 210-614-
0006 or mail to the address below: 
• 
Printed copy of the first page of the CTEP-AERS report 
• 
Copies of clinical source documentation of the event 
• 
If applicable, and they have not yet been submitted to the 
SWOG Data Operations Center, copies of Off Treatment 
Notice and/or Notice of Death. 
 
2. 
The adverse events listed below also require expedited monitoring for this 
trial: 
 
• 
≥ Grade 3 infusion-associated reactions (IARs);  
• 
Acute IARs Grade 3 or 4. An IAR is an AE related to isatuximab 
typically with onset within 24 hours from the start of isatuximab 
infusion 
• 
Symptomatic overdose (serious or nonserious) with study treatment  
• 
An overdose (accidental or intentional) with the study treatment is an 
event suspected by the Investigator or spontaneously notified by the 
patient (not based on systematic pills count) and defined as: 
• 
Increase of at least 30% of the dose to be administered in the 
specified duration or if the dose is administered in less than half the 
recommended duration of administration. 
• 
Of note, asymptomatic overdose has to be reported as a standard 
AE. 
 
3. 
For study arm(s) [applicable study arm(s)], the adverse events listed below 
do not require expedited reporting via CTEP-AERS: None. 
 
g. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy). A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
 
SWOG requires all secondary malignancies that occur following 
treatment with an agent under a Non-NCI IND to be reported via CTEP-
AERS.  Three options are available to describe the event. 
 
• 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
 
• 
Myelodysplastic syndrome (MDS) 
 
• 
Treatment-related secondary malignancy 
 
 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 

 
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Second Malignancy: A second malignancy is one unrelated to the 
treatment of a prior malignancy (and is NOT a metastasis from the 
initial malignancy).  Second malignancies require ONLY routine 
reporting via CDUS unless otherwise specified. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d
ocs/aeguidelines.pdf.  
 
2. 
Any supporting documentation should be submitted to CTEP per NCI 
guidelines for AE reporting located at:   
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d
ocs/aeguidelines.pdf. 
 
A copy of the report and the following supporting documentation must 
also be submitted to SWOG Operations Office within 30 days by fax to 
210-614-0006 or mail to the address below: 
 
• 
a copy of the pathology report confirming the AML/ALL 
/MDS diagnosis 
• 
(if available) a copy of the cytogenetics report   
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 
h. 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – Other 
(pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Pregnancy Loss Pregnancy loss defined in CTCAE as “Death in utero”. 
Pregnancy loss should be reported expeditiously as Grade 4 
“pregnancy loss” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
A pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-
AERS recognizes this event as a patient death. 
 
 

 
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3. 
Death Neonatal Death neonatal is defined in CTCAE as “Newborn death 
occurring during the first 28 days after birth.   
 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the 
General disorders and administration SOC. 
 
Neonatal death should NOT be reported as a Grade 5 event under the General 
disorders and administration SOC as currently CTEP-AERs recognized this event 
as a patient death.  
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 301-230-0159.  The potential risk 
of exposure of the fetus to the investigational agent(s) or chemotherapy agent(s) 
should be documented in the “Description of Event” section of the CTEP-AERS 
report. 
 
The Pregnancy Information Form is available at:  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm. 
 
i. 
Sanofi-Direct Additional SAE Reporting Requirements 
 
1.   
Pregnancy reporting: 
 
In the event that the partner of a study participant becomes pregnant while 
the participant is on study treatment, additional reporting of pregnancy 
information to Sanofi is requested.   
  
In the event of such a pregnancy, the site must make reasonable efforts 
to obtain consent from the study participant’s partner for pregnancy 
reporting.  The additional consent is the responsibility of the site and must 
take place according to local Institutional Review Board requirements.  A 
sample consent template is included as Appendix 18.4. 
 
If consent is obtained, information about the pregnancy and the outcome 
of the pregnancy must be reported via the Sanofi Exposure During 
Pregnancy (EDP) Form.  The form must be submitted directly to Sanofi 
according to the instructions on the form included in Appendix 18.5. 
 
Institutional support for this additional data collection and submission may 
be obtained by submitting the Pregnancy Reporting Reimbursement 
Form, which is located on the protocol abstract page of the SWOG website 
(www.swog.org) or the CTSU website (www.ctsu.org).  Note that this 
additional support is available ONLY to institutions submitting the Sanofi 
Exposure During Pregnancy Form in the event that a female partner of a 
study participant becomes pregnant.  Pregnancy and outcome information 
submitted via CTEP-AERS performed in accordance with NCI guidelines 
as part of regular adverse event reporting requirements is not reimbursed. 
 
2.      
Additional information 
 
Reporting information provided in the protocol takes precedence over 
information provided in the supplemental reporting requirements.   
 

 
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17.0 
BIBLIOGRAPHY 
1  
Gertz MA. Immunoglobulin light chain amyloidosis: 2011 update on diagnosis, risk-stratification, 
and management. Am J Hematol 86(2): 180-6, 2011. PMID: 21264900. 
 
2  
Cibeira MT, Sanchorawala V, Seldin DC, et al. Outcome of AL amyloidosis after high-dose 
melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. 
Blood 118(16):4346-52, 2011. PMID:  21828140. 
 
3  
Palladini G, Perfetti V, Perlini S, et al. The combination of thalidomide and intermediate-dose 
dexamethasone is an effective but toxic treatment for patients with primary amyloidosis (AL). Blood 
105:2949-5, 2005. PMID:  15572585. 
 
4  
Sanchorawala V, Skinner M, Quillen K, et al. Long-term outcome of patients with AL amyloidosis 
treated with high-dose melphalan and stem-cell transplantation. Blood 110(10):3561-3, 2007. 
PMID: 17673601. 
 
5  
Dispenzieri A, Buadi F, Laumann K, et al. Activity of pomalidomide in patients with immunoglobulin 
light-chain amyloidosis. Blood, 119(23), 5397-5404, 2012. PMID: 22493299. 
 
6  
Kastritis E, Anagnostopoulos A, Roussou M, et al. Treatment of light chain (AL) amyloidosis with 
the combination of bortezomib and dexamethasone. Haematologica. 92(10):1351-8, 2007. PMID: 
18024372. 
 
7  
Reece DE, Sanchorawala V, Hegenbart U, et al. Weekly and twice-weekly bortezomib in patients 
with systemic AL amyloidosis: results of a phase 1 dose-escalation study. Blood 114:1489–97, 
2009. PMID: 19498019. 
 
8  
Mikhael JR, Schuster SR, Jimenez-Zepeda VH, et al. Cyclophosphamide-bortezomib-
dexamethasone (CyBorD) produces rapid and complete hematologic response in patients with AL 
amyloidosis. Blood. 10;119(19):4391-4, 2012. PMID: 22331188. 
 
9  
Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-
refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 
9;387(10027):1551-60. Epub 2016 Jan 7. PMID: 26778538. 
 
10  
Sher T; Fenton B, Gertz, M, et al. First report of safety and efficacy of daratumumab in two cases 
of advanced immunoglobulin light chain amyloidosis. Blood. http://dx.doi.org/10.1182/blood-2016-
06-722496. 2016. 
 
11  
Stanford U. (Kaufman GP, et al: Daratumumab yields rapid and deep hematologic responses in 
patients with heavily pretreated AL amyloidosis. Blood, 2017). 
 
12  
Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in 
immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International 
Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol.  
Aug;79(4):319-28, 2005. PMID: 16044444. 
 
13  
Bortezomib with or without dexamethasone in primary systemic (light chain) amyloidosis.. J Clin 
Oncol. Feb 20;28(6):1031-7. doi: 10.1200/JCO.2009.23.8220. Epub 2010 Jan 19, 2010. PMID: 
20085941. 
 
 

 
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14  
Palladini G, Hegenbart U, Milani P, et. al.  A staging system for renal outcome and early markers 
of renal response to chemotherapy in AL amyloidosis. Blood. Oct 9;124(15):2325-32. doi: 
10.1182/blood-2014-04-570010. Epub 2014 Aug 12, 2014. PMID: 25115890. 
 
15  
Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment 
of multiple myeloma. Leukemia. Jan;23(1):3-9. doi: 10.1038/leu.2008.291. Epub 2008 Oct 30, 
2009. PMID: 18971951. 
16  
Comenzo RL, Reece D, Palladini G, et al. Consensus guidelines for the conduct and reporting of 
clinical 
trials 
in 
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light-chain 
amyloidosis. 
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17  
Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in 
immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International 
Symposium on Amyloid and Amyloidosis, Tours, France, April 18-22, 2004. Am J Hematol. 
Aug;79(4):319-328. 2005. PMID:  16044444. 
 
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Comenzo RL1, Reece D, Palladini G, et al. Consensus guidelines for the conduct and reporting of 
clinical trials in systemic light-chain amyloidosis, 2012.100. leu. Epub Apr 5, 2012. PMID:    
22475872. 
 
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Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in 
immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International 
Symposium on Amyloid and Amyloidosis, Tours, France, April 18-22, 2004. Am J Hematol. 
Aug;79(4):319-328. 2005. PMID:    16044444. 
 
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Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers of 
renal response to chemotherapy in AL amyloidosis. Blood. Oct 9;124(15):2325-32. 2014. PMID: 
25115890. 
21  
Palladini G, Dispenzieri, A, Gertz MA. New Criteria for Response to Treatment in Immunoglobulin 
Light Chain Amyloidosis Based on Free Light Chain Measurement and Cardiac Biomarkers: Impact 
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Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid 
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Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid 
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18.0 
APPENDIX 
 
18.1  
New York Heart Association Classifications 
 
18.2 
Neuropathy Impairment Scale – Lower Limbs 
 
18.3 
SWOG Biospecimen Bank Appendix 
 
18.4 
Sanofi-Direct Pregnancy Reporting Consent 
 
18.5 
Sanofi Exposure During Pregnancy (EDP) Form 
 
18.6 
Isatuximab Type and Screen Card  
 
18.7 
Measuring Orthostatic Blood Pressure 
 
 
 
 

 
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18.1 
New York Heart Association Classifications 
 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
 
 
 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
 
** At accustomed occupation or usual tasks. 
 
 

 
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18.2 
Neuropathy Impairment Scale – Lower Limbs  
 
The NIS (LL is a scoring system graduated from 0 points (the normal finding) to a 
maximum of 88 points (the absence of all motor, sensory, and reflex activity in the 
lower extremities). The scale is additive of all deficits (64 potential points for muscle 
strength, 8 points for reflexes, and 16 points for sensory function) 
in the lower 
extremities. 
 
Instructions: Complete each assessment outlined below and assign a score for the 
right side and for the left side. 
 
S1702 Patient ID: 
___ ___ ___  __ ___ ___ 
Date of Visit:                                     _____________________ 
□ Registration 
□ Cycle ___, Day 1 
□ Post-Treatment (Pre-Hematolgic Progression) 
□ Post-Adverse Event Follow-up 
□ Unscheduled Visit 
Assessment 
Right 
Left 
Sum 
Muscle Weakness Score each assessment as: 
0: normal, 1: 25% weakened, 2: 50% weakened, 3: 75% weakened, 4: paralysis 
Hip Flexion (iliopsoas) 
Hip Extension (gluteus max.) 
Knee Flexion (biceps femoris) 
Knee Extension (quadriceps) 
Ankle Dorsiflexors (tibialis ant. +) 
Ankle Plantar Flexors (gastroc. soleus) 
Toe Extensors 
Toe Flexors 
Reflexes Score each, assessment as:  0: normal, 1: reduced, 2: absent 
Quadriceps femoris 
Triceps surae/gastroc. soleus 
Sensation: Great Toe (terminal phalanx) Score each assessment as:  
0: normal, 1: reduced, 2: absent 
Touch pressure 
Pinprick 
Vibration 
Joint position 
Total Score:_________________ 
Source: Dyck PJ, Litchy WJ, Lehman KA, et al. Variables influencing neuropathic endpoints: the Rochester 
Diabetic Neuropathy Study of Healthy Subjects. Neurology. 1995e45(6):1115(21. 
 
Performed by (Print Name):   _________________________    ___________________ 
 
  
 
Date: 
/ 
/  
 
Signature 
 
 
 
 
 
    dd 
       mm 
yyyy 

 
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18.3 
SWOG Biospecimen Bank Appendix 
 
Specimen Receipt, Processing, and Storage 
 
The SWOG Biospecimen Bank will receive frozen serum, frozen blood, snap-frozen bone 
marrow biopsy, and fresh bone marrow aspirate.  
 
The Bank will accession and barcode frozen specimens for long-term storage; serum and 
frozen blood will be stored in a -80°C freezer for long-term storage, and the bone marrow 
biopsy will be stored in a liquid nitrogen vapor phase freezer.  
 
The fresh bone marrow aspirate will be processed using a ficoll-hypaque gradient, and the 
resulting cells wil be sorted (CD138 +/-), aliquoted into 1 x 107 cells per vial, and stored in 
a liquid nitrogen vapor phase freezer until distribution.  
 
Distribution of Specimens from the SWOG Biospecimen Bank to TM Investigators: 
At the end of the study, the Bank will receive a list of specimens for distribution.  
 
Frozen Whole Blood will be shipped to the SWOG Biospecimen Bank for extraction, and 
then forwarded to Sanofi for genotyping analysis.  
 
 
 

 
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18.4 
Sanofi-Direct Pregnancy Reporting Consent 
 
*  
NOTES FOR LOCAL INSTITUTION INFORMED CONSENT AUTHORS: 
 
• 
This template Sanofi-direct pregnancy reporting consent is provided as a tool to be used 
in the event that the female partner of a male study participant becomes pregnant while 
the study participant is on study treatment. This consent is not mandatory for female 
partners of all male patients, only those who will submit additional pregnancy information 
to Sanofi. Sites may use local pregnancy reporting consent forms providing that they 
include adequate information as provided in this document, and pregnancy reporting 
consent is obtained in some written and IRB approved form prior to reporting pregnancy 
information to Sanofi. Note that patients consent to pregnancy prevention as part of the 
clinical trial consent, so pregnancy events are not expected during the trial. 
 
• 
This template has been reviewed by the DCTD/NCI and is the official consent document 
for this study. Local IRB changes to this document are allowed. It is suggested that sections 
of this document that are in bold type be used in their entirety. 
 
*  
These notes for investigators are instructional and should not be included in the informed 
consent form given to the prospective participant. 
 
 
Sanofi-Direct Pregnancy Reporting Consent for Female Partners of  
Male Study Participants 
 
What is the purpose of this consent form? 
 
You are the partner of a male study participant that took the drug isatuximab as part of 
the study S1702, and you have become pregnant. Sanofi, the drug’s manufacturer, is 
trying to learn more about how the drug affects the developing baby and the pregnancy. 
They would like to collect information about you, your pregnancy, the baby’s 
development during the pregnancy, and the outcome of the pregnancy. This will help 
them to better inform future patients and the partners of future patients who receive the 
drug about what their pregnancy risks might be. The purpose of this consent form is to 
ask your permission for the study doctor/nurse to collect this information and provide it 
to Sanofi.  If you accept, your medical information regarding the pregnancy may be 
shared with people or groups associated with the study. 
 
Procedures 
 
Study participants should not father a child during the study treatment, or for up to 12 
weeks after the study is over. The participant’s consent form for the treatment study 
discussed this in more detail.  Information on your sex life habits might be collected. 
 
If a participant fathers a child during the study treatment or for up to 12 weeks after the 
study is over, they are asked to notify the study doctor within 24 hours of finding out that 
their partner is or might be pregnant. The pregnant female partner will be asked to 
provide information about the pregnancy and the baby for at least one year after the birth. 

 
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The information Sanofi will ask for is as follows: 
 
• What are the first date of your last menstrual period and estimated date of 
conception? 
• When during your pregnancy was the first exposure to the drug? 
• Do you have any other risk factors that would affect the pregnancy (high blood 
pressure, diabetes, history of abnormal pregnancy, etc.)? 
• Did you smoke, drink alcohol, or use any illegal drugs during the pregnancy? 
• How many previous pregnancies and children have you had, and were there any 
problems? 
• Outcome of the pregnancy (birth, stillbirth, miscarriage, etc.)? 
• Was the baby born with any abnormalities? 
• Is the baby male or female, and what is his/her length, weight and head 
measurement? 
 
Your personal identifying information will not be provided to Sanofi. Your partner’s 
SWOG patient ID will be the only identifying information sent. Sanofi will not have 
access to the secure study database for S1702 that links SWOG patient IDs to patient 
identifying information. 
 
If you consent, the study doctor/nurse will gather this information on a form and send it 
to Sanofi. The information will be sent over a secure system. The doctor/nurse may need 
to ask you questions to get the necessary information. Sanofi will put your information 
into a database with the information from others who have provided pregnancy 
information, and analyze it to see if and how the drug has affected the reported 
pregnancies. They will need to collect this information throughout your pregnancy and 
for a year after your baby is born – at the time you initially learn of the pregnancy, at the 
time of any event during the pregnancy, at the end of the pregnancy, and a year after the 
baby is born.  
 
You will be told about any new information that might change your decision to be in this 
follow-up. 
 
You may be asked to sign a revised consent form if this occurs. 
 
If you do not sign this consent, it will not affect your or your partner’s treatment on the 
S1702 study. 
 
By signing this consent form, you are agreeing to allow the information about you, 
your pregnancy, and your baby’s development during the pregnancy and up to a 
year after your baby is born to be sent to Sanofi. 
 
 
 

 
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What possible risks are there? 
 
Since this follow-up is observational only, no physical risk is expected. 
 
If you provide this information, you may be asked sensitive or private questions 
about you and your pregnancy and sexual activity which you normally do not 
discuss. You may have some emotional discomfort from answering these questions. 
 
There is also a possible risk that your personal or medical information or your 
child’s personal or medical information might be compromised. Secure programs 
and procedures are in place to protect your personal information, your personal 
information is not provided to Sanofi, and we will do our best to make sure that 
personal information is kept private. However, we cannot guarantee total privacy. 
There is a chance that some of this personal or medical information may be given 
out as required by law. If any information that is sent to Sanofi is published or 
presented at scientific meetings, your name and personal identifying information 
will not be used. 
 
What possible benefits can I expect? 
 
This is not a treatment study.  You are not expected to receive any direct medical benefits 
from this follow-up. 
 
The information from this follow-up may lead to a better knowledge and treatment in the 
future for pregnant women and fetuses who could be exposed to isatuximab. 
 
You will not be paid for your participation in this follow-up. 
 
What are the costs? 
 
You will not have any costs for being in this follow-up.   
 
This follow-up will not cover any costs related to your pregnancy, delivery or care of 
your child.  You and/or your medical/hospital insurance carrier will still be billed for 
your regular medical care expenses as they normally would. 
 
Can I stop providing information? 
 
Your participation in this follow-up is voluntary.  You can decide to stop providing 
information to Sanofi at any time. However, information that has already been sent 
cannot be taken back. If you decide to stop, no further information about you, your 
pregnancy, or the pregnancy outcome will be sent to Sanofi. 
 

 
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Your decision will not result in any penalty or loss of benefits to which you or your child 
are entitled. 
 
Your participation in this follow-up may be stopped at any time by your doctor or the 
sponsor without your consent for any reason.  
 
Who can answer my questions about this? 
 
You can talk to the study doctor about any questions or concerns you have about this 
study or to report side effects or injuries. Contact the study doctor __________________ 
(insert name of study doctor[s]) at __________________ (insert telephone number). 
 
Signature 
 
I have read this consent form or had it read to me. I have discussed it with the study 
doctor and my questions have been answered. I will be given a signed copy of this form. I 
agree to take part in this follow-up. 
 
 
Partner’s signature________________________________ 
 
Date of signature_ 
 
 
 
 
 
 
 
 

 
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18.5 
Sanofi Exposure During Pregnancy (EDP) Form 
 
Complete whenever an embryo or fetus has been exposed to isatuximab.  
 
Submit via e-mail as soon as pregnancy of female partner of male patient has been 
diagnosed. 
 
E-mail:  corina.oprea@sanofi.com and derya.cetiner-ext@sanofi.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
 
First Date of Late Menstrual Period (DD-MM-YYYY): ________________ 
 
 
 
Estimated Date of Conception (DD-MM-YYYY):          ________________ 
Relevant History 
Risk factors for adverse pregnancy outcomes including environmental or occupational 
exposures, e.g. hypertension, diabetes, etc. Family history of congenital 
abnormality/genetic diseases, consanguinity (or any family relation or lineage) between 
parents (specify degree): 
 
 
 
 
1) Did mother smoke during pregnancy? 
☐ No   ☐ Yes: Number per day? _____________ 
 
2) Did the mother drink alcohol during the pregnancy? 
☐ No   ☐ Yes: Frequency? _____________ 
 
3) Did the mother use illicit drugs during the pregnancy? 
☐ No   ☐ Yes: Frequency? _____________ 

 
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Exposure to Products: Maternal 
Were any drugs (e.g., OTC, medical prescription) taken by the mother during the 
pregnancy?  
 
☐No  
 
☐Yes, please specify (for each drug):                                                                       
 
Drug Name: 
Indication: 
Start Date: 
Stop Date:  
Reason for Stopping: 
Dose: 
Formulation: 
Frequency: 
 
Drug Name: 
Indication: 
Start Date: 
Stop Date:  
Reason for Stopping: 
Dose: 
Formulation: 
Frequency: 
 
Drug Name: 
Indication: 
Start Date: 
Stop Date:  
Reason for Stopping: 
Dose: 
Formulation: 
Frequency: 
 
Drug Name: 
Indication: 
Start Date: 
Stop Date:  
Reason for Stopping: 
Dose: 
Formulation: 
Frequency: 
 
(Include Product Indication; Start Date \ Stop Date; Reason for stopping; Dose; 
Formulation and Frequency for each drug taken) 
Obstetrical History 
Number of previous pregnancies/children. Outcome of previous pregnancies (live birth, 
miscarriage, elective termination, late fetal death, ectopic pregnancy, molar pregnancy). 
Previous maternal pregnancy complications. Previous fetal/neonatal abnormalities and 
type. History of sub-fertility.: 
 
 
 
 

 
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Outcome of Pregnancy            Date of outcome (DD-MM-YYYY): ___________ 
Check one  
☐Full term live birth  
☐Preterm live birth  
☐Stillbirth 
☐Spontaneous abortion/miscarriage 
☐Induced abortion  
☐Unknown 
 
Gestational age at birth in weeks, (if known): _____________ 
Infant 
Check one  
☐Normal  
☐Congenital Malformation/Anomaly**  
 
☐Other neonatal problem** ☐Unknown 
☐Other neonatal problem/abnormality (include dysmaturity, neonatal illness, 
hospitalization, drug therapies) Specify: 
 
_____________ 
 
 
Apgar Score:  1min  
_____________ 
5min  
_____________ 
 
☐Male  
☐ Female  
 
Birthweight  
_____________grams  
Or, if birthweight in grams unknown: Birthweight ☐ lb  ☐oz 
 
Length at birth: in cm Head Circumference at birth:  
_____________☐ in  ☐cm 
 
**Complete also the Serious Adverse Event section of the report, specifying the 
diagnosis as the Serious Adverse Event

 
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18.6 
Isatuximab Type and Screen Card 
 
Patient 
Last 
Name: 
_________________________First 
Name:  
______________________________ 
Subject/Patient Date of Birth:  I_ ._ I_ ._ I_ ._ ._ ._  I 
I am being treated with ISATUXIMAB, which may interfere with type and screen test results. 
Since:  I_  ._  I_  ._  I_  ._  ._  ._   I (MM/DD/YYYY)   Until :  I_  ._  I_  ._  I_  ._  ._  ._   I (MM/DD/YYYY)  
 
 
The blood bank should be aware that you are receiving an anti-CD38 treatment (isatuximab) 
before any red blood cells transfusion: 
 
Before starting isatuximab my blood test results collected on    
/   /   
   were (MM/DD/YYYY)  
 
        Blood type: _______________________________________________________________ 
        Indirect Coombs test (antibody screen): _______________________________________ 
 
Contact details of institution where the blood tests were performed: ___________________________ 
________________________________________________________________________________ 
________________________________________________________________________________ 
________________________________________________________________________________ 
 
Note to Transfusion Services: Treatment with anti-CD38 antibodies can result in interference with  
blood bank serologic tests. Please review the bulletin from the American Association of Blood  
Banks for more information on this potential interference  
(http://www.aabb.org/programs/publications/bulletins/Documents/ab16-
02.pdf#search=anti%3DCD38). 
 
 
 
 

 
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18.7 
Measuring Orthostatic Blood Pressure 
 
Instructions: 
 
1. 
Have the patient lie down for 5 minutes.  
 
2. 
Measure and record blood pressure and pulse rate.  
 
3. 
Have the patient sit for 1-2 minutes.  
 
4. 
Measure and record blood pressure and pulse rate.  
 
5. 
Have the patient stand for 1-2 minutes (stand by patient for safety).  
 
6. 
Measure and record blood pressure and pulse rate.  
 
A drop in blood pressure of > 20 mm Hg, or in diastolic blood pressure of >10 mm 
Hg, or experiencing lightheadedness or dizziness is considered abnormal.  
 
Note:  The remainder of this form is provided as a tool and may be used and maintained in 
the patient chart; however, sites are not required to use or maintain this form. 
 
Recording Measurements 
 
Patient ID:  
 
Date:   
 
Time: 
 
You do not need an 
order for measuring 
Orthostatic Blood 
Pressure. Position  
 
Time  
Blood Pressure and 
Heart Rate  
Associated 
Symptoms  
 
Lying down 
  
 
 
 
 
5 minutes  
BP______/_____  
HR____________  
BP ______/______  
  
 
Sitting  
 
 
 
 
 
 
1-2 minutes  
HR___________  
BP______/______  
HR_____________ 
 
 
Standing  
 
 
 
 
 
1-2 minutes  
HR___________  
BP______/______  
HR_____________ 
 
 
Symptoms of Orthostatic Hypotension 
Patients Most at Risk 
Dizziness, feeling faint 
Older patients (approx. 20% of people > 65) 
Light headedness 
HI Bleed/Anemic 
Blurred vision 
Dehydration 
Disorientation and confusion 
Surgical patients 
Weakness/fatigue/falling 
Diabetics 
Chest pain 
Heart disease 
Expectation:  Perform Orthostatic BP on all high-risk patients at least once per shift. 
 
Adapted from Tip Sheet available at  
http://www.hret-hiin.org/Resources/falls/16/measuring_orthostatic_blood_pressure_tip_sheet_3.7.16.pdf.