Clinical trial NCT01248455
Conditions: Multiple Myeloma Myeloma Smoldering Multiple Myeloma
Keywords: Monoclonal Antibody NK Cell Mediated Killing Response Rate Pharmacokinetics Biological Activity Smoldering Multiple Myeloma SMM
Sponsor: National Cancer Institute (NCI)
Start date: 2010-11-01; Completion date: 2015-04-01
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* Recent studies have shown that smoldering multiple myeloma has a high risk of progressing to multiple myeloma, an aggressive type of bone marrow cancer, within 5 years of diagnosis. People with smoldering multiple myeloma have abnormal blood test results that show a high level of monoclonal protein (M-protein) in the blood and of plasma cells in the bone marrow. There are currently no known effective treatments to prevent smoldering multiple myeloma from developing into multiple myeloma, and there are no known tests for determining whether an individual with smoldering multiple myeloma will develop multiple myeloma.
* Certain cells in the immune system, known as natural killer (NK) cells, are active against multiple myeloma. The experimental drug anti-killer cell immunoglobulin-like receptor (anti-KIR) has been shown to help NK cells kill multiple myeloma cells. Researchers are interested in determining whether anti-KIR can be given to individuals with smoldering multiple myeloma to improve their abnormal blood test results.

Objectives:

\- To evaluate the safety and effectiveness of anti-KIR as a treatment for abnormal blood test results related to smoldering multiple myeloma.

Eligibility:

\- Individuals at least 18 years of age who have been diagnosed with smoldering multiple myeloma.

Design:

* Participants will be screened with a physical examination and medical history, and will provide baseline blood, urine, and bone marrow samples before beginning the study drug.
* Participants will receive anti-KIR intravenously for 1 hour, and will be closely monitored for 24 hours after receiving the first dose. If there are no serious side effects, participants will receive five additional anti-KIR doses, one every other month, for a total of six treatment cycles.
* Participants will have monthly visits to provide additional blood and urine samples, and may have additional bone marrow biopsies as directed by the study researchers.
* Participants will have followup visits every 3 to 6 months for up to 5 years after receiving anti-KIR treatment.

Detailed description:
Background:

* Multiple myeloma (MM) is an incurable plasma cell neoplasm with a median survival of 3-4 years.
* Smoldering multiple myeloma (SMM) is a premalignant plasma cell disorder characterized by monoclonal protein greater than or equal to 3 g/dL or bone marrow plasma cells greater than or equal to 10 percent in the absence of myeloma-related tissue impairment with 51 percent progression to MM at 5 years.
* Current recommendations do not endorse treatment of SMM with chemotherapy.
* Transplanted Natural Killer (NK) Cells have anti-myeloma activity.
* Anti-KIR (IPH2101) is a monoclonal antibody that facilitates NK cell mediated killing of myeloma cells by blocking inhibitory receptors (KIR) on NK cells.

Objectives:

* To assess the response rate of anti-KIR(IPH2101) in patients with SMM
* To evaluate the toxicity of anti-KIR(IPH2101) in patients with SMM
* To evaluate the pharmacokinetic parameters and biological activity of anti-KIR (IPH2101)

Eligibility:

* A confirmed diagnosis of SMM
* Age greater than or equal to 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status in the range of 0-1.
* Without serious co-morbidity that would interfere with receipt of anti-KIR(IPH2101)

Design:

* Single-arm Phase II trial of anti-KIR(IPH2101) for patients with SMM.
* All patients will have initial evaluation and confirmation of diagnosis.
* Patients will receive anti-KIR(IPH2101) (1mg/kg) every other month for 6 cycles.
* Patients will have routine blood work with serum protein electrophoresis (SPEP) and immunofixation monthly.
* Pre- and post-treatment bone marrow biopsies will be obtained for confirmation of diagnosis and correlative studies.
* Patients may donate cellular products or tissues as appropriate for research purposes.
* Optimal two-stage phase II design will be employed, initially enrolling 9 patients. If 3 or more have a positive outcome, then a total of 21 patients will be enrolled in this study.

Arms: arm 1: Patients will receive anti-KIR(IPH2101) (1mg/kg) every other month for 6 cycles
Interventions: intervention 1: (Anti-KIR)
Intervention descriptions: intervention 1: Patients will receive anti-KIR(IPH2101) (1mg/kg) every other month for 6 cycles

Protocol documents:
ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
11-C-0024 
PRINCIPAL INVESTIGATOR: 
Mark Roschewski, M.D.. 
STUDY TITLE:  
A Phase II Trial of IPH2101 (anti-KIR) in Smoldering Multiple Myeloma (SMM) 
Continuing Review Approved by the IRB on 06/11/12 
Amendment Approved by the IRB on 03/10/13 (E) 
Date posted to web: 3/14/13 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
Recent studies have shown that a condition called smoldering multiple myeloma (SMM) is 
thought to have a high risk of progressing to multiple myeloma (MM), a type of cancer involving 
the bone marrow.  People with SMM have a high level of M-protein in the blood and of plasma 
cells in the bone marrow.  Fifty-one percent of people with SMM develop multiple myeloma 
within 5 years of their diagnosis.  The mechanism by which this change takes place is not 
currently known.  Additionally, studies have shown that certain cells in the immune system, 
known as NK cells or natural killer cells, have activity against MM.  The experimental agent in 
this study, anti-KIR (also known as IPH2101) is a monoclonal antibody (or mAb) that helps NK 
cells kill MM cells.  There are currently no known effective treatments to prevent SMM from 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0024 
CONTINUATION: page 2 of 9 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
developing into MM; and there are no known tests for determining who will SMM will develop 
MM. 
In this study we will test whether giving individuals with a diagnosis of SMM this anti-KIR 
experimental agent will help improve the abnormal blood test results seen in SMM.  In addition, 
this study will evaluate the side effects of the experimental agent, the effects of anti-KIR on the 
body (pharmacokinetics), the biological activity (research tests) and its ability to prevent MM. 
Why are you being asked to take part in this study? 
You are being asked to take part in this study because your blood tests show that you have a 
diagnosis of smoldering multiple myeloma.   
How many people will take part in this study?  
From 9 to 21 people with SMM will participate in this study. 
Description of Research Study 
What will happen if you take part in this research study?   
Before you begin the study 
Eligibility criteria have been established to ensure that you are a medically appropriate candidate 
for this trial.  These criteria will also help ensure that the results of this study can be useful for 
making decisions regarding other patients.  No exceptions will be made to these criteria for study 
participation unless agreed upon by the Sponsor and your physician. 
To determine if you are eligible you will have a history taken and a physical examination done 
by one of the study doctors.  Standard laboratory blood tests will be done to make sure it is safe 
for you to participate.  You may not participate if you have received any other investigational 
agent within the past 3 months, if you have amyloidosis or known heart problems.  You may not 
have any active infections or autoimmune disease.  If you have previously had a bone marrow or 
organ transplant or if you are pregnant of breastfeeding a baby, you will not be able to participate 
for your safety and the safety of your child. 
During the study 
Once it is determined that you are eligible and you decide to participate, baseline tests will be 
done.  Before starting the anti-KIR experimental agent, approximately 8 tablespoons of blood 
will be taken from your vein for research blood tests.  We will ask you to provide a urine sample, 
and a bone marrow aspiration will be done for specific research testing.  
You will be given the anti-KIR agent through an intravenous line (IV – small plastic tube or 
catheter put into a vein in your arm).  You will receive the anti-KIR over 1 hour, once every 
other month; therefore in 1 year you will receive 6 doses of anti-KIR. It is possible that you 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0024 
CONTINUATION: page 3 of 9 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
might be offered an additional year of therapy (up to 6 additional doses of anti-KIR). In this case, 
the same schedule of treatment and follow up will be used.  
In order to watch you closely, you will be admitted to the Clinical Center hospital for the first 
dose of anti-KIR.  If you do not have side effects during the first infusion, all subsequent doses 
can be given to you in the Clinical Center Day Hospital. 
The nurses and doctors will watch you closely during and after the anti-KIR, taking your blood 
pressure, heart rate, and temperature frequently during the infusion and for up to 6 hours after the 
anti-KIR infusion.  A heart tracing (EKG) will be done 2 hours after the end of each infusion.  If 
you have any side effects, your next dose may be delayed. But if it is delayed more than one 
month, you will not receive any further doses of anti-KIR. 
Every month we will ask you to come to the Clinical Center for a physical examination, routine 
blood tests, and research samples (up to 8 tablespoons of blood and a urine sample).   
You are not allowed to receive any other treatment for your SMM while on this study.  Certain 
medicines are also prohibited such as corticosteroids (for treatment of SMM) or cytokines.  
Please check with your study doctor or nurses before taking any new medications, including 
medicines that may be prescribed by other doctors. 
After you have completed treatment 
Two months after your last dose of anti-KIR, you will return to the Clinical Center for a physical 
examination, routine blood tests, and research samples (up to 8 tablespoons of blood and a urine 
sample).  A second bone marrow aspiration and biopsy will be done during that visit to test the 
effects on your bone marrow cells.  
After your first follow-up visit, you will return to the Clinical Center every 3 to 6 months for two 
years after the completion of therapy. After the two year visit, you will come annually for a total 
of five years or until the study has completed. At these follow up visits, you will undergo a 
physical examination and laboratory testing but not a bone marrow biopsy unless your study 
doctor thinks it is necessary. 
What does this study involve? 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for four months after you finish study treatment.  If you think that you or 
your partner is pregnant, you should tell your study doctor or nurse at once.   
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0024 
CONTINUATION: page 4 of 9 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Effective forms of birth control include:  
• Abstinence  
• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 
• tubal ligation 
• vasectomy 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
 
Instead of being in this study, you have these options: 
• Because there are no known effective treatments for SMM, you may be observed by your 
doctor for this condition without being in a study 
• Take part in another study 
Please talk to your doctor about these and other options. 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
Likely: the most frequently reported side effects that have been reported in other studies 
using Anti-KIR were: 
• Fever 
• Fatigue 
• Headache 
• Chills 
• Rash 
• Itching 
• Slow heart rate 
Less Likely:  other side effects that occurred in participants of other studies using Anti-
KIR included: 
• Changes in blood tests showing anemia, lowered platelet count, increase lipase (fat), 
increased creatinine (test of kidney function), lowered neutrophil count (may increase 
risk of infection), high level of potassium, high level of uric acid. 
• Swelling of the breasts in men 
• Lowered blood pressure 
• Difficulty breathing 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0024 
CONTINUATION: page 5 of 9 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
• Nausea 
• Pain in the stomach 
• Flushing 
Rare but Serious 
• One patient in a study of Anti-KIR had sudden onset kidney failure after one dose.     
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if this experimental agent will decrease abnormal blood values 
seen in people with SMM and decrease the risk of developing MM.  This study is also testing the 
side effects of this experimental agent.  We hope that you will get personal medical benefit from 
taking part in this study, but we cannot be certain.  Because there is not much information about 
the drug’s effect on SMM, we do not know if you will benefit from taking part in this study, 
although the knowledge gained from this study may help others in the future who have cancer.   
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
• 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs even if they are not covered by your insurance 
company. 
• 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Stopping Participation in this Study 
Your doctor may decide to stop your participation for the following reasons: 
• if he/she believes that it is in your best interest 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0024 
CONTINUATION: page 6 of 9 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
• if you develop MM during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
• if the study is completed 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time.  However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Innate Pharma or 
designated representatives. If you withdraw your consent and leave the trial, any samples of 
yours that have been obtained for the study and stored at the NCI can be destroyed upon request. 
However, any samples and data generated from the samples that have already been distributed to 
other researchers or placed in the research databases cannot be recalled and destroyed. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of 
interest. 
 
The 
following 
link 
contains 
details 
on 
this 
process 
http://ethics.od.nih.gov/procedures/COI-Protocol-Review-Guide.pdf. You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
Optional Studies 
We would like to keep some of the specimens and data that are collected for future research.  
These specimens and data will be identified by a number and not your name.  The use of your 
specimens and data will be for research purposes only and will not benefit you.  It is also 
possible that the stored specimens and data may never be used.  Results of research done on your 
specimens and data will not be available to you or your doctor.  It might help people who have 
cancer and other diseases in the future.   
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0024 
CONTINUATION: page 7 of 9 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
If you decide now that your specimens and data can be kept for research, you can change your 
mind at any time. Just contact us and let us know that you do not want us to use specimens 
and/or data.  Then any specimens that remain will be destroyed and your data will not be used 
for future research.  
 
Please read each sentence below and think about your choice. After reading each sentence, circle 
and initial the answer that is right for you.  No matter what you decide to do, it will not affect 
your care. 
 
1. My specimens and data may be kept for use in research to learn about, prevent, or treat cancer. 
 
Yes              No               Initials_________ 
 
2. My specimens and data may be kept for use in research to learn about, prevent or treat other 
health problems (for example: diabetes, Alzheimer's disease, or heart disease).  
 
Yes              No               Initials_________ 
 
3. Someone may contact me in the future to ask permission to use my specimens and/or data in 
new research not included in this consent.  
 
Yes 
        No 
    Initials_________


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  11-C-0024 
CONTINUATION: page 8 of 9 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Mark Roschewski M.D. Building 10, Room 3B40, Telephone:  301-451-
9021. You may also call the Clinical Center Patient Representative at (301) 496-2626. If you 
have any questions about the use of your specimens or data for future research studies, you may 
also contact the Office of the Clinical Director, Telephone: 301-496-4251. 
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  11-C-0024 
CONTINUATION: page 9 of 9 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JUNE 11, 2012 THROUGH JUNE 10, 2013.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name 
 

Prot_SAP_002.pdf: 
Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
1 
 
 Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
 
CC Protocol # : 11C0024 I 
 
Version Date:  12/26/2018 
 
NCT Number: NCT01248455 
 
 
A Phase II Trial of IPH2101 (Anti-KIR) in Smoldering Multiple Myeloma (SMM) 
 
 
NCI Principal Investigator: Dickran Kazandjian, M.D.  
Joint Appointment: 
 Lymphoid Malignancies Branch (LYMB) 
Center for Cancer Research (CCR) 
National Cancer Institute (NCI) 
 Office of Hematology and Oncology Products, FDA  
Building 10, Room 4N115 
National Institutes of Health (NIH) 
9000 Rockville Pike 
Bethesda, MD 20892 
Phone:  (240) 383-6311 
Email:  kazandjiand@mail.nih.gov  
 
  
 
 
Investigational Agents: 
Drug Name: 
IPH2101, anti-KIR 
IND Number: 
109654—IND withdrawn 01-03-2014 
Sponsor: 
Ola Landgren, MD 
 
Commercial Agents:  None 
 
 
 
 
 
 
 
 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
2 
PRÉCIS 
Background:  
x Multiple myeloma (MM) is an incurable plasma cell neoplasm with a median survival of 
3-4 years. 
x Smoldering multiple myeloma (SMM) is a premalignant plasma cell disorder 
FKDUDFWHUL]HGE\PRQRFORQDOSURWHLQJG/RUERQHPDUURZSODVPDFHOOV0% in the 
absence of myeloma-related tissue impairment with 51% progression to MM at 5 years. 
x Current recommendations do not endorse treatment of SMM with chemotherapy. 
x Transplanted Natural Killer (NK) Cells have anti-myeloma activity. 
x Anti-KIR (IPH2101) is a monoclonal antibody that facilitates NK cell mediated killing of 
myeloma cells by blocking inhibitory receptors (KIR) on NK cells. 
 
Objectives: 
x To assess the response rate of anti-KIR(IPH2101) in patients with SMM 
x To evaluate the toxicity of anti-KIR(IPH2101) in patients with SMM 
x To evaluate the pharmacokinetic parameters and biological activity of anti-KIR 
(IPH2101) 
Eligibility: 
x A confirmed diagnosis of SMM 
x Age greater than or equal to 18 years 
x ECOG performance status in the range of 0-1. 
x Without serious co-morbidity that would interfere with receipt of anti-KIR(IPH2101) 
Design: 
x Single-arm Phase II trial of anti-KIR(IPH2101) for patients with SMM. 
x All patients will have initial evaluation and confirmation of diagnosis. 
x Patients will receive anti-KIR(IPH2101) (1mg/kg) every other month for 6 cycles. 
x Patients will have routine blood work with SPEP and immunofixation monthly. 
x Pre- and post-treatment bone marrow biopsies will be obtained for confirmation of 
diagnosis and correlative studies. 
x Patients may donate cellular products or tissues as appropriate for research purposes. 
x Optimal two-stage phase II design will be employed, initially enrolling 9 patients.  If 3 or 
more have a positive outcome, then a total of 21 patients will be enrolled in this study. 
 
 
 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
3 
TABLE OF CONTENTS 
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
1 
INTRODUCTION .................................................................................................................. 5 
1.1 
Study Objectives ........................................................................................................... 5 
1.2 
Background and Rationale ............................................................................................ 5 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ......................................................... 7 
2.1 
Eligibility Criteria ......................................................................................................... 7 
2.2 
Screening Evaluation .................................................................................................... 8 
2.3 
Registration Procedures .............................................................................................. 10 
3 
STUDY IMPLEMENTATION ............................................................................................ 10 
3.1 
Study Design............................................................................................................... 10 
3.2 
Clinical Studies ........................................................................................................... 11 
3.3 
Drug Administration ................................................................................................... 12 
3.4 
Dose Modifications..................................................................................................... 13 
3.5 
Study Calendar ........................................................................................................... 14 
3.6 
Post-Treatment Evaluation ......................................................................................... 15 
3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria ........................ 15 
4 
CONCOMITANT MEDICATIONS/MEASURES .............................................................. 16 
4.1 
Supportive Care .......................................................................................................... 16 
4.2 
Concurrent Therapies ................................................................................................. 16 
4.3 
Radiation Therapy Guidelines .................................................................................... 16 
5 
DATA COLLECTION AND EVALUATION ..................................................................... 16 
5.1 
Data Collection ........................................................................................................... 16 
5.2 
Response Criteria ........................................................................................................ 17 
5.3 
Toxicity Criteria ......................................................................................................... 17 
6 
BIOSPECIMEN COLLECTION .......................................................................................... 18 
6.1 
Correlative Studies for Research/Pharmacokinetic Studies ....................................... 18 
6.2 
Sample Storage, Tracking, and Disposition ............................................................... 21 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
 
24 
7.1 
Definitions .................................................................................................................. 24 
7.2 
NIH Intramural IRB and  Clinical Director Reporting ............................................... 26 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
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4 
7.3 
FDA Reporting Criteria .............................................................................................. 26 
7.4 
DATA SAFETY AND MONITORING PLAN ......................................................... 28 
8 
STATISTICAL CONSIDERATIONS.................................................................................. 28 
8.1 
Sample Size Determination ........................................................................................ 28 
8.2 
Accrual Rate ............................................................................................................... 29 
8.3 
Analysis of Secondary Endpoints ............................................................................... 29 
9 
COLLABORATIVE AGREEMENT ................................................................................... 29 
9.1 
Clinical Trial Agreement (CTA) ................................................................................ 29 
10 HUMAN SUBJECTS PROTECTIONS ............................................................................... 29 
10.1 
Rationale for Subject Selection .................................................................................. 29 
10.2 
Participation of Children ............................................................................................ 30 
10.3 
Evaluation of Benefits and Risks/Discomforts ........................................................... 30 
10.4 
Risks/Benefits Analysis .............................................................................................. 31 
10.5 
Consent and Assent Process and Documentation ....................................................... 31 
11 PHARMACEUTICAL INFORMATION ............................................................................. 31 
11.1 
IPH2101 (Anti-KIR) ................................................................................................... 31 
12 REFERENCES ..................................................................................................................... 35 
13 APPENDICES ...................................................................................................................... 37 
APPENDIX A:  Bone Marrow Sample Processing .................................................................. 37 
APPENDIX B:  Performance Status Criteria............................................................................ 40 
 
 
 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
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5 
 
1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
x The primary objective of the study is to assess the response rate 1 of anti-
KIR(IPH2101) in patients with SMM. 
1.1.2 Secondary Objectives 
x To evaluate the toxicity of anti-KIR(IPH2101) in patients with SMM 
x To estimate time to progression (refer to Section 3.7.2.1 for definition of 
progression), time to development of MM, and duration of response to anti-
KIR(IPH2101) 
x To evaluate pharmacokinetic parameters of the alternate month dosing schedule of 
anti-KRI(IPH2101) 
x To evaluate the biological activity of anti-KIR(IPH2101) on KIR occupancy, NK cell 
function, and NK cell phenotype. 
1.2 
BACKGROUND AND RATIONALE 
Multiple myeloma (MM) is a neoplasm characterized by the proliferation and accumulation of 
malignant plasma cells in the bone marrow that lead to the overproduction of monoclonal 
proteins in the serum or urine, affecting nearly 20,000 people annually.2  End-organ damage 
resulting from this disorder includes hypercalcemia, renal insufficiency, anemia, and lytic bone 
lesions.3  Myeloma remains incurable, with a median survival of 3-4 years in the United States, 
although newer therapies appear to be improving survival.4-6  Importantly, two recent studies 
have proven that all cases of MM are preceded by a premalignant state, monoclonal gammopathy 
of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), although at this 
time the biological mechanism of this progression is not understood.7,8  Currently, clinicians do 
not have access to any established markers that reliably predict progression to myeloma in 
patients with MGUS or SMM.  
MGUS is a premalignant plasma cell proliferative disorder that is characterized by elevated 
monoclonal immunoglobulin (M-protein) < 3 g/dL and bone marrow plasma cells < 10% in the 
absence of any other plasma cell disorder.3  Epidemiological studies have estimated the 
prevalence of MGUS as 3.2% in patients older than 50 years; these patients have a 1% annual 
risk of progression to MM.9,10  However, risk factors of M-SURWHLQJG/QRQ-IgG M-
protein, and abnormal serum free-light chain ratio are known to confer a higher rate of 
progression (58% at 20 years).11 Similar to MGUS, SMM is a precursor condition to MM 
defined by the clinical parameters of M-SURWHLQJG/RUERQHPDUURZSODVPDFHOOV
Its risk of progression is higher than that of MGUS; 51% of patients progress to MM within 5 
years of diagnosis.12   
The current standard of care for SMM is close follow-up without treatment until symptomatic 
MM develops.13 Using standard chemotherapy in SMM, early treatment has not been found to 
delay of progression to active disease and overall survival14. The first randomized phase III study 
using novel drugs (lenalidomide/dexamethasone vs. surveillance) in SMM was presented by the 
Spanish study group at ASH 200915. After a median of about 1.5 years of follow-up, their interim 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
6 
analyses show the following: in the surveillance arm, the progression rate was similar to 
historical controls, while in the treatment arm, only 2 patients had progressed to MM.  
Interestingly, there is emerging evidence to suggest that the innate immune system (natural killer 
(NK) cells) have anti-MM activity 16 17 18. In vitro studies demonstrated that allogeneic (allo) and 
auto-NK cells have the ability to kill CD138-purified primary MM cells19. Also in a previous 
study focusing on allogeneic stem cell transplantation in patients with high-risk hematologic 
malignancy, KIR-ligand mismatch between donor KIR and patient HLA class I resulted in 
markedly reduced relapse rates, indicating that KIR may exert a significant control over clinical 
NK cell–mediated responses20.  A more recent study using infused, haplo-identical, T-cell 
depleted, KIR-ligand mismatched NK cells in conditioned patients with relapsed or refractory 
MM found evidence of either complete response (absence of M-protein by SPEP and IFE with 
<5% bone marrow plasma cells) or very good partial response (absence of M-protein by SPEP) 
in 5 out of 10 patients treated, indicating a promising role for KIR-mediated NK cell activity in 
clinical responses for patients with myeloma.21 In Phase I and II trials, IPH2101 has so far shown 
to be tolerable and manageable in subjects with AML or MM. Based on the Investigator’s 
Brochure, 4th Edition (February 25, 2010), adverse events evaluated as related to the trial product 
and reported for more than one subject were: fever/pyrexia, asthenia/fatigue, headache, chills, 
rash and pruritus. There are no evident signs of IPH2101 inducing AEs related to auto-reactivity 
(such as skin rash and gastrointestinal symptoms), infusion (such as rash, pruritus, erythema, 
fatigue, headache, pyrexia) or cytokine release (such as pyrexia, fatigue, malaise, headache) to a 
degree that has raised any safety concerns. As stated in the Investigator’s Brochure, 62 of the 
298AEs reported (20.8%) were evaluated as possibly, probably or definitely related to the trial 
product. No increase in frequency of AEs after multiple dosing (trials 102 and 103) when 
compared to that after single dosing (trial 101) is evident. One subject in the 103 trial received 1 
dose of 0.075 mg/kg trial product and presented with the SAE acute renal failure nine days later, 
which led to withdrawal from the trial. As this was judged to be a dose-limiting toxicity, three 
additional subjects were added at the 0.075 mg/kg dose level, in accordance with the protocol. 
The acute renal failure and the SAEs related to this event (hyperkalemia, hyperuricaemia and 
increased blood creatinine at two occasions) were initially evaluated as “definitely” related to the 
trial product, but later re-evaluated as “probably” related as the subject seemed to be in disease 
progression. The disease progression could potentially have caused the kidney failure, as this is a 
common co-morbidity in patients with MM. No further signs of any dose-limiting toxicity have 
been observed, and higher dose levels are currently being explored in the ongoing trials. 
Based on these facts, we are planning a SMM treatment study based on anti-KIR(IPH2101), a 
fully human IgG4 monoclonal antibody (mAb) that facilitates natural killer (NK) cell–mediated 
killing of  myeloma cells by blocking the interaction of inhibitory killer cell immunoglobin (Ig)-
like receptors (KIR) on NK cells with their human leukocyte antigen-C (HLA-C) ligands on 
target cells. Anti-KIR(IPH2101) binds specifically, and with high affinity, to specific members 
of the KIR family of NK cell receptors, namely KIR2DL1, -2 and -3 and 2DS1 and -2. The mAb 
prevents interactions between KIR and HLA-C and, in a dose-dependent fashion, augments NK 
cell–mediated killing of human tumor cells that express HLA-C. Knowing that effective 
activation of NK cells is the net result not only of the blockade of inhibitory signals but also of 
the binding of activating receptors by their ligands which are over-expressed by some MM tumor 
cells - but not, or less, by healthy cells - IPH2101 has the potential to enhance an elective 
cytotoxicity of NK cells against MM tumor cells without affecting healthy tissue. In vivo 
efficacy was demonstrated in a non-obese diabetic–severe combined immunodeficiency (NOD-


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
7 
SCID) mouse model of NK cell–mediated tumor rejection.22 Similarly, tumor killing was 
observed in normal mice treated with the murine Anti-Ly49(5E6F(ab’)2) mAb, which is 
functionally homologous to Anti-KIR and was also used for the mechanism-related GLP-
toxicology study. No killing of healthy cells was observed with either antibody. 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 Diagnosis of SMM will be made in accordance with the clinical diagnostic criteria set 
forth by the International Myeloma Working Group.3  These criteria include: 
x Serum M-SURWHLQJGODQGRUERQHPDUURZSODVPDFHOOV 
x Absence of anemia: +HPRJORELQJGO 
x Absence of renal failure: calculated creatinine clearaQFHDFFRUGLQJWR0'5'
ml/min (or alternatively based on standard creatinine level criteria of  2 mg/dl) 
x $EVHQFHRIK\SHUFDOFHPLD&DOFLXPPJGO 
x Absence of lytic bone lesion (skeletal survey) 
x The diagnoses will be confirmed by serum/urine protein electrophoresis, 
immunofixation and light-chain assays; as well as immunohistochemical analyses 
of the bone marrow biopsy. 
2.1.1.2 Age greater than or equal to 18 years. 
2.1.1.3 ECOG performance status of 0-1. 
2.1.1.4 Male or female patient who accepts and is able to use recognized effective 
contraception (oral contraceptives, IUCD, barrier method of contraception in 
conjunction with spermicidal jelly) through the study and for four months following the 
final dose of study drug when relevant. 
2.1.1.5 The patient must be competent to sign an informed consent form. 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients with a diagnosis of MM or a clinical suspicion of an ongoing progression into 
full-blown MM 
2.1.2.2 Patients without measurable disease defined as serum M-protein <1 g/dL. 
2.1.2.3 Previous treatment having a proven or potential impact on myeloma cell proliferation or 
survival (including conventional chemotherapies, immunomodulatory drugs (IMiDs), or 
proteasome inhibitors). 
2.1.2.4 Use of any investigational agent within the last 3 months. 
2.1.2.5 Clinical laboratory values at screening 
x 
Platelet levels <75 x 109 /L 
x 
ANC levels < 1 x 109 /L 
x 
Bilirubin levels >1.5 ULN ; ALT and AST >3.0 ULN (grade 1 NCI) 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
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8 
2.1.2.6 Primary or associated amyloidosis 
2.1.2.7 Known abnormal cardiac status with any of the following: 
x NYHA stage III or IV congestive heart failure 
x Myocardial infarction within the previous 6 months 
x Symptomatic and/or treatment-refractory cardiac arrhythmia.  Patients with 
controlled or asymptomatic arrhythmia are not excluded from this study. 
2.1.2.8 Current active infectious disease or positive serology for: 
x Human Immunodeficiency Virus (HIV) 
x Hepatitis C Virus (HCV) 
x Hepatitis B Surface Antigen 
2.1.2.9 Severe type of autoimmune disease defined as:  
x One which currently requires or previously required long-term systemic 
immunosuppressive or immunomodulatory therapy (including corticosteroids, 
administered by systemic route)  
x And/or it has a substantial probability to cause an irreversible injury to any tissue 
(e.g. Hashimoto thyroiditis). 
x And/or it is recent or unstable, or has a substantial risk to progress and cause severe 
complications (e.g., Graves disease) 
x Enrollment of other non-severe types of auto-immunes disease requiring topical 
therapy, or NSAIDS can be considered on a case by case basis by the Principal 
Investigator. 
2.1.2.10 History of a lymphoproliferative malignancy.3 
2.1.2.11 History of other malignancy (apart from basal cell carcinoma of the skin or in situ 
cervical carcinoma) except if the patient has been free of symptoms and without active 
therapy during at least the previous 5 years. 
2.1.2.12 Serious concurrent uncontrolled medical disorder. 
2.1.2.13 History of allograft or solid organ transplantation. 
2.1.2.14 Any psychological or familial condition potentially interfering with compliance with the 
study protocol and follow-up schedule. 
2.1.2.15 Pregnant or lactating women. 
2.2 
SCREENING EVALUATION 
2.2.1 Clinical Evaluation 
2.2.1.1 A complete history and physical examination with documentation of measurable disease 
(if any) and assessment of performance status using the ECOG scale must be performed 
prior to study entry. 
2.2.1.2 The following laboratory tests will be completed prior to study entry: 
x CBC with differential and reticulocyte count 
o If Hgb <10 g/dL, will follow with serum folate, vitamin B12, and iron studies. 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
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9 
x Chem 14 (metabolic panel that includes Calcium and Creatinine) 
x Lactate Dehydrogenase level 
x Uric Acid 
x Quantitative immunoglobulin levels 
x C-Reactive Peptide levels 
x Viral serologies 
o HIV enzyme-linked immuno-assay (ELISA) 
 If positive, will follow with Western Blot 
o Hepatitis B surface antigen 
o Anti-Hepatitis C (HCV) antibody 
 If positive, will follow with HCV RNA PCR 
x Review of bone marrow core biopsy and aspirate by NCI Department of Pathology 
x Urine pregnancy test in women of child-bearing potential. 
2.2.1.3 A skeletal survey of the axial and appendicular skeleton will be performed.  Exception 
may be made if skeletal survey has been performed within the past 6 months and was 
found to be negative.  In this case, films will be forwarded to the Clinical Center for an 
additional reading by the Department of Radiology. 
2.2.2 Laboratory Tests 
2.2.2.1 The following laboratory tests will be performed prior to start on study: 
x Serum protein electrophoresis (SPEP) and immunofixation to assess for presence 
and quantity of monoclonal protein (M-protein) 
x Urine protein electrophoresis (UPEP) and immunofixation to assess for monoclonal 
protein in the urine (Bence-Jones proteinuria) 
x Serum free light-chain studies, determined using the FreeliteTM assay system 
x Prior to treatment, patients will undergo high resolution HLA typing including the 
HLA Cw loci to define their KIR-L expression (i.e. to define the presence or 
absence of group I (binds KIR2DL2/3) and group II (binds KIR2DL1) KIR ligands). 
2.2.2.2 The following laboratory tests will be performed within one month of study entry: 
x Immunophenotyping of aberrant plasma cells by flow cytometry currently involves, 
but is not limited to, the use of the following reagents: CD138, CD19, CD45, CD38, 
and CD56.  Characteristic changes in immunophenotypically abnormal plasma cells 
(CD138 positive) include but are not limited to absent CD19 and CD45, decreased 
CD38, and increased CD56.23,24  These studies will be performed under the direction 
of Maryalice Stetler-Stevenson of the flow cytometry unit in the NCI Laboratory of 
Pathology. 
x Interphase FISH cytogenetics will be performed on patients enrolled in this protocol 
under the direction of Ana Roschke of the Molecular Cytogenetics Cor Laboratory 
of the NCI Genetics Branch. 
x Samples for gene expression profiling (GEP) and array comparative genomic 
hybridization (aCGH) of CH138 positive plasma cells will be collected, batched, 
and entered into a biobank. 
x Blood samples will be collected at baseline and after IPH2101 treatment for flow 
cytometric based functional assays to calculate the percentage change in NK cell 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
10 
cytotxic granule release and NK cell intracellular cytokine secretion against KIR-
Ligand matched myeloma cells.  See section 6.1.4. 
x Bone marrow aspirates will be analyzed by multiparameter flow cytometry pre- and 
anti-KIR (IPH2101) for the impact on cells of the bone marrow microenvironment 
including but not limited to dendritic cell subsets, macrophages and stromal 
cells.  Expression of NK cell markers will also be analyzed pre- and post-therapy. 
2.2.3 Novel Imaging Studies 
2.2.3.1 There are no planned novel imaging studies for this protocol. 
2.2.3.2 Imaging studies such as PET-CT or MRI will be used as clinically indicated. 
2.3 
REGISTRATION PROCEDURES 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent. A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and faxed to 301-
480-0757. After confirmation of eligibility at Central Registration Office, CRO staff will call 
pharmacy to advise them of the acceptance of the patient on the protocol prior to the release of 
any investigational agents. Verification of Registration will be forwarded electronically via e-
mail to the research team. A recorder is available during non-working hours.  
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
Patients with SMM will enroll in the study for the purpose of determining if the use of the 
monoclonal anti-KIR (IPH2101) will result in a sufficiently large fraction of patients with SMM 
who will experience a decline of 50% or more in their monoclonal immunoglobulin levels as 
measured at up to 12 months after their initial baseline M-protein level determination. 
This study will be conducted as a single-arm phase II trial.  Patients will receive one infusion of 
anti-KIR (IPH2101) 1mg/kg by intravenous route over 1 hour every other month for 6 cycles.  
For the purposes of evaluation, a cycle will be defined as 2 months.  Patients will have monthly 
evaluation of M-protein by SPEP and immunofixation.  Additionally, bone marrow biopsy will 
be performed prior to treatment and after treatment is completed.  Figure 1 shows the study 
design schematically. 
If a patient has more than 25% reduction in M-spike (minimal response criteria for multiple 
myeloma) in combination with concomitant decreased disease burden in bone marrow biopsy 
after 6 cycles, the patient may receive a second year of treatment at the discretion of the 
investigator. The same dosing schedule would be implemented (6 cycles of anti-KIR (IPH2101) 
(1mg/kg) every other month) with the same monitoring including a bone marrow biopsy after 
treatment is completed. 
 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
11
Figure 1: 
 
Remark: If a patient has more than 25% reduction in M-spike (minimal response criteria for 
multiple myeloma) in combination with concomitant decreased disease burden in bone marrow 
biopsy after 6 cycles, the patient may receive a second year of treatment with the same dosing 
schedule at the discretion of the investigator (See Section 3.1 above). 
3.2
CLINICAL STUDIES 
3.2.1
Routine Evaluations
3.2.1.1
Studies that will be performed at each visit, which will occur at monthly intervals 
following enrollment or as clinically indicated.  These include: 
x History and Physical Examination 
x Evaluation of Performance Status using the ECOG scale 
x Routine laboratory studies including: 
x CBC with differential of WBCs and platelet count 
x Reticulocyte count 
x Chem 14 Metabolic Panel (Na, K, Cl, CO2, Cr, glucose, BUN, albumin, Ca, Alk 
Phos, ALT/AST, total and direct bilirubin, total protein) 
x Lactate Dehydrogenase level  
x Uric Acid 
x SPEP with immunofixation 
x Urine protein electrophoresis (UPEP) 
x Serum free light-chains with quantitative serum immunoglobulins 
x Research samples, as described below in section 3.2.2. 
Review of available medical records will take place at the pre-study visit. 
3.2.2 Research Evaluations 
Research samples may be obtained for correlative research studies and will be obtained in strict 
compliance with clinical center guidelines.  Samples may be obtained at the time of diagnostic 
Pre-treatment work-up 
(incl bone marrow) 
Post-treatment work-up 
(incl bone marrow) 
= anti-KIR (IPH2101) treatment 
= blood work (incl 
monitoring of M-protein 
concentrations) 
2 months 
treatment 
2 months 
treatment 
2 months 
treatment 
2 months 
treatment 
2 months 
treatment 
2 months 
treatment 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
12 
procedures.  Procedures may also be performed for research studies only, as long as they 
constitute minimal risk to the patient. 
3.2.2.1 Venipuncture:  
Up to 100cc of peripheral blood will be collected into heparinized tubes.  The amount of blood 
collected will be dictated by the number of experiments to be performed, and by the patient’s 
peripheral blood count. 
3.2.2.2 Urine Sample Collection:  
Approximately 45 mL of urine will be collected into a standard urine collection cup for further 
analysis.  The amount of urine collected will be dictated by the number of experiments to be 
performed. 
3.2.2.3 Bone Marrow Aspiration and Biopsy:  
For the purpose of analyzing CD138 positive and CD138 negative cells from the bone marrow, 
two bone marrow aspirates and core biopsies will be collected, one prior to treatment and one 
subsequent to treatment.  3 to 5cc of marrow per aspirate will be collected into sterile, 
heparinized tubes.  Core biopsies will be collected into a core cylinder.  Core biopsies and one 
fraction of the aspirate samples will be fixed and paraffin-embedded for 
histological/immunohistochemical analysis and long-term storage.  One fraction of marrow 
aspirates will be stored as air-dried aspirate smears and the rest will be frozen.  CD138 positive 
plasma cells will be isolated from a subset of these samples (see APPENDIX A). 
3.3 
DRUG ADMINISTRATION 
3.3.1 Anti-KIR (IPH2101): One infusion of IPH2101 (Innate Pharma) 1mg/kg by intravenous 
route over 1 hour every other month for 6 cycles. The chosen dose of 1 mg/ kg is slightly 
above the dose saturating the receptors for a period of at least 1 month.  For the purposes 
of evaluation, a cycle will be defined as 2 months. For patients with more than 25% 
reduction in M-spike (minimal response criteria for multiple myeloma) in combination 
with concomitant decreased disease burden in bone marrow biopsy after 6 cycles, the 
patient may receive a second year of treatment with the same dosing schedule at the 
discretion of the investigator (6 cycles of anti-KIR (IPH2101) (1 mg/kg) every other 
month). 
3.3.2 Patients will be treated at the Clinical Center as inpatient for the first dose (monitoring 
and PK blood draws).  Subsequent doses may be administered in the Outpatient Day 
Hospital if the first dose is tolerated without toxicity.  Toxicity monitoring for the first 
dose is as follows: Vital signs: heart rate, blood pressure (diastolic and systolic) and body 
temperature prior to infusion and every hour until stable, then at 3 and 6 hours post 
infusion, or more frequently as clinically indicated.  Toxicity monitoring for subsequent 
doses is as follows: Vital signs: heart rate, blood pressure (diastolic and systolic) and 
body temperature prior to infusion and every hour until stable, then at 3 and 4 hours post 
infusion, or more frequently as clinically indicated.   
3.3.3 An ECG should be performed within 2 hours after the end of infusion. 
3.3.4 Concomitant Treatment Permitted: 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
13 
Patients should receive all necessary supportive care in the form of treatment or 
prophylaxis as clinically indicated (e.g. transfusion of blood products, antibiotics, anti-
histaminic drugs, or analgesics). 
Any blood product and/or concomitant medication administered should be recorded in 
the medical record and clinical research database (C3D), including dose, start, and stop 
dates. 
Prophylactic oral bisphosphonates for non-myeloma indications (such as osteoporosis) 
are allowed if they were already administered before enrollment and if their dosage is not 
increased during the study. 
3.3.5 Concomitant Treatment NOT Permitted (minimal time interval for stopping concomitant 
treatments prior to start of treatment on this study is 6 months) 
The following concomitant treatments are not permitted during this study and must be 
stopped before the start of treatment accordingly with their pharmacological effects: 
x Any chemotherapy 
x Corticosteroids IV or PO administered with the intent of treating plasma cell 
myeloma, with the exception of substitutive doses of hydrocortisone 
x Any other investigational drug(s) 
x Any other anti-myeloma treatment including thalidomide, lenalidomide or other 
immunomodulatory drugs; proteasome inhibitors; IV bisphosphonates 
x Cytokines 
3.4 
DOSE MODIFICATIONS 
No individual dose reduction is planned for IPH2101.  
Dose reduction of IPH2101 has not yet been explored in previous or still ongoing clinical 
studies.  Lower doses (< 1 mg/kg) may still fully occupy and block the mAb target receptors, 
KIRs, although more transiently (e.g. slightly less than 1 week at 0.015 mg/kg). Such a dose 
reduction could likely not prevent, if any, acute toxicity observed within the first 24 hours (or 
even 48 hours) after IPH2101 administration. 
Very low doses, leading to incomplete KIR occupancy, would likely be ineffective, a complete 
blockade of KIR being required to achieve enhancement of NK cytotoxicity, the expected 
biological effect of IPH2101. 
Treatment delay is to be made according to the body system showing the greatest degree of 
toxicity.  Toxicities will be graded according to the CTCAE version 4.0. 
,QFDVHRI&7&$(JUDGHWR[LFLW\WKHILUVWGD\RIDF\FOHDGPLQLVWUDWLRQZLOOEHGHOD\HGE\
RQHZHHNDQGXSWRWZRZHHNVXQWLOWKHWR[LFLW\KDVUHVROYHGWR&7&$(JUDGH$ny patient 
who requires a delay of more than 1 month whatever the reason, will be taken off study. 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
14 
3.5 
STUDY CALENDAR 
 
Studya 
Pre-
Study 
Visit 
Wk 1 
Day 1 
Wk 1 
Day 2 Wk 2, 3,4 
Wk 5,13, 
21, 29, 37, 
45 
Wk 9, 17, 
25, 33, 41 
Wk 49 
Day 1 
Wks 53, 
61, 69, 77, 
85, 93 
Wks 57, 
65, 73, 81, 
89 
Follow 
Up  
Visitsc 
History and Physical 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Review of Medical Record 
X 
 
 
 
 
 
X 
 
 
 
Informed Consent 
X 
 
 
 
 
 
X 
 
 
 
Routine Labs (Chem14 metabolic panel, 
LDH, Uric Acid, CBC/diff)b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Protein Analysis (SPEP, 
Immunofixation, Free-Light Chains, 
Quantitative Immunoglobulins) 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
C-Reactive Protein 
X 
 
 
 
 
 
X 
 
 
 
Urine Pregnancy Test 
X 
 
 
 
 
 
X 
 
 
 
Viral Serology (HIV ELISA, anti-HCV, 
HBV surface antigen) 
X 
 
 
 
 
 
 
 
 
 
Urine Protein Analysis (UPEP) 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Research Blood Collection 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research Urine Collection 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone Marrow Biopsy and Aspirate (with 
Flow Cytometry) 
 
Xb 
 
 
 
 
 
 
 
X 
Skeletal Survey 
X 
 
 
 
 
 
 
 
 
 
Administer Anti-KIR (IPH2101) 
 
X 
 
 
 
X 
X 
 
X 
 
 
a. Any of the above studies, excluding administration of anti-KIR (IPH2101) may be performed if clinically indicated. 
b. May be performed after pre-study visit but before treatment week 1. 
c. All follow-up visits will be completed by May 1, 2014.  
 
 
 


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15 
3.6 
POST-TREATMENT EVALUATION 
Patients who complete treatment will proceed to follow up. The first follow-up visit will be held 
2 months after the last dose of anti-KIR and will consist of a physical examination, routine blood 
tests, collection of research samples and a second bone marrow aspiration and biopsy.  
After the first follow-up visit, patients will be followed every 3 to 6 months for two years after 
the completion of therapy. Thereafter, patients will be followed annually for a total of five years 
after completion of treatment, or until May 1, 2014, whichever occurs first. At these follow up 
visits, patients will undergo a physical examination and laboratory testing but will not undergo a 
bone marrow biopsy unless this is clinically indicated. Adverse events that occur during the 
follow-up period that are unrelated to study treatment will not be reported.  
3.7 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
3.7.1 Criteria for removal from protocol therapy 
3.7.1.1 Patients with grade 3 or 4 adverse events related to anti-KIR (IPH2101) may be taken 
off therapy at the discretion of the principal investigator or lead associate investigator, 
but will be followed until treatment related AE resolves or returns to baseline. 
3.7.1.2 Patient completes protocol therapy as outlined in Section 3.3.  
3.7.1.3 Worsening of smoldering myeloma as defined by an increase in M-protein of 25% from 
baseline measurement. The absolute increase in M protein concentration must be 0.75 
gm/dl AND the measurement must be repeated at 2 time points a minimum of 4 weeks 
apart to document the increase. 
3.7.2 Criteria for removal from Study 
3.7.2.1 Progression of disease to MM or a related lymphoproliferative malignancy requiring 
treatment.  Treatment is indicated when myeloma related end-organ or tissue 
impairment is clinically evident.  Indicators of myeloma related end-organ or tissue 
impairment are listed in published guidelines3 and comprise: 
x Hypercalcemia defined as serum calcium at least 1 mg/dL above the upper limit of 
normal with no alternate etiology 
x Renal failure defined calculated creatinine clearance (according to MDRD) <40  
ml/min (or alternatively based on standard creatinine level of >1.95 mg/dl) in the 
absence of another cause of acute kidney injury or chronic kidney disease 
x Anemia, defined as hemoglobin <10 g/dL with iron studies within normal limits and 
decreased reticulocyte count. 
x Bone lesions defined as lytic lesions noted on skeletal survey. 
3.7.2.2 Patient non-compliance. 
3.7.2.3 Patient voluntary withdrawal. 
3.7.2.4 The principal investigator may take any patient off study if it is determined that this 
would be in the best interest of the patient. 
3.7.2.5 Treatment delay: any patient who requires a delay of more than one month, whatever 
the reason, will be taken off study. 
3.7.2.6 All patients will be removed from the study as of May 1, 2014.  


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3.7.3 Off Protocol Therapy and Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off-
study. An off-study form from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and 
faxed to 301-480-0757. 
4 
CONCOMITANT MEDICATIONS/MEASURES 
4.1 
SUPPORTIVE CARE  
Patients enrolled on this protocol with ECOG performance status 0-1 are not expected to require 
substantial supportive care.  Supportive care will be offered as clinically indicated. 
4.2 
CONCURRENT THERAPIES 
Patients on this protocol are not to receive any concurrent therapies for their diagnosis of 
Smoldering Myeloma. 
4.3 
RADIATION THERAPY GUIDELINES 
Patients on this protocol are not to receive radiation therapy while on study. 
5 
DATA COLLECTION AND EVALUATION 
5.1 
DATA COLLECTION 
5.1.1 Data Collection 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts. All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
Data will be prospectively collected and entered into the NCI C3D clinical trials database.  
Adverse events related to either anti-KIR (IPH2101) or research procedures will be collected into 
the NCI C3D database. 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed until satisfactory resolution. AEs should be reported up to 30 days 
following the last dose of study drug.   
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following: 
x 
Results in discontinuation from the study 
x 
Is associated with clinical signs or symptoms  
x 
Requires treatment or any other therapeutic intervention 
x 
Is associated with death or another serious adverse event, including hospitalization.  
x 
Is judged by the Investigator to be of significant clinical impact 


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17 
x 
If any abnormal laboratory result is considered clinically significant, the investigator 
will provide details about the action taken with respect to the test drug and about the 
patient’s outcome. 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
5.1.2 Record Keeping 
Complete records must be maintained on each patient; these records will consist of the hospital 
chart as well as any other outside information obtained from outside laboratories, radiology 
reports, or physician’s records.  These records will serve as the primary source material that 
forms the basis for the research record.  All relevant data will also be entered on a computer 
database from which formal analyses are done.  The primary source documentation will include 
patient eligibility data, patient history, flow sheets (including specialty forms for pathology, 
radiology, or surgery), an off-study summary sheet, and a final assessment by the treating 
physician. 
5.1.3 Forwarding of Patient Data from Other Institutions 
Either due to extenuating medical circumstances or for convenience, some patients may elect to 
have certain routine laboratory studies or protein marker analyses performed at an outside 
institution between scheduled interval visits to the CRC for this protocol.  These results will be 
forwarded to the research nurse on the Myeloma Team who will enter the data into the study 
database.  Additional blood or tissue samples drawn on patients enrolled in this protocol between 
scheduled visits may be forwarded and entered into the database as well.   
5.2 
RESPONSE CRITERIA 
Response criteria for MM have been defined by the International Myeloma Working Group.25  
As data is limited and current recommendations are to not treat SMM outside of clinical trials, 
there are no formal guidelines to define response to therapy in SMM.  Similar to the ongoing 
Spanish Multicenter SMM treatment study 15, we define response criteria based on change in 
monoclonal antibody levels: 
x Stringent Complete Response: absence of M-protein by SPEP and immunofixation as 
well as <5% bone marrow plasma cells and serum free light-chain ratio within normal 
limits 
x Complete Response: absence of M-protein by SPEP and immunofixation 
x Very Good Partial Response: absence of M-protein by SPEP but presence by 
immunofixation 
x Partial Response: 50% reduction in M-protein 
x Minor Response: 25% reduction in M-protein. 
Progression of smoldering myeloma is defined in Section 3.7.1.3. 
5.3 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study. Adverse events occurring during the study will be graded according to 


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the NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) 
http://ctep.info.nih.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_v40. 
6 
BIOSPECIMEN COLLECTION 
6.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
6.1.1 Biomarker Studies 
Peripheral blood and/or urine samples from patients will be analyzed for potential serum or urine 
biomarkers for disease progression and correlated to clinical outcomes.  Such biomarkers may 
include but are not limited to: monoclonal protein, free immunoglobulin light-chains, circulating 
proteosomes, and total immunoglobulin levels.  Biomarkers will be chosen, in part, in accord 
with their utility as markers of progression in other, ongoing studies. 
6.1.2 Immunophenotyping by Flow Cytometry 
Erythrocyte lysed bone marrow aspirate samples from patients will be analyzed by 
multiparameter flow cytometry to determine the percentage of aberrant (myelomatous) plasma 
cells.  Previously reported aberrant phenotypes are shown in Table 1 DNA index will also be 
assessed by flow cytometry of these same samples using a double-staining procedure using 
propidium iodide (to stain nuclear DNA) and anti-CD38 plus anti-CD138 antibodies. 
Table 1: FLOW CYTOMETRY BASED IMMUNOPHENOTYPES OF ABERRANT 
PLASMA CELLS IN MGUS AND SMM.24 
CD45 
CD19 
CD56 
% 
- 
- 
++ 
50 
- 
- 
- 
24 
-Ļ 
- 
+ 
11 
- 
+ 
++ 
8 
Ļ 
- 
- 
5 
- 
+ 
- 
1 
+ 
Ļ 
++ 
1 
Perez-Persona et. al. Blood 2007.24 
Instructions for collecting bone marrow specimens for immunophenotyping by flow cytometry 
are described below in section 6.1.3 and can be found at: 
http://home.ccr.cancer.gov/lop/Clinical/specimencollections.asp#Bone%20Marrow 
6.1.3 Collection of Bone Marrow 
Bone marrow samples will be collected as bone marrow core biopsies and aspirates for analyses.  
Bone marrow core biopsies and one fraction of marrow aspirates will be fixed and paraffin-
embedded for histological/immunohistochemical analysis and long-term storage.  One fraction of 
marrow aspirates will be stored as air-dried aspirate smears and the rest will be frozen.  CD138 
positive plasma cells will be isolated from a subset of these samples.  The procedure for sample 
acquisition is as follows: 
x Notify the CCR Hematology lab that flow immunophenotyping is being performed (301-
496-4473). The hematology BM collection tech will bring a BM transport media tube to 


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19 
the specimen collection site and prepare an extra smear for the Flow Cytometry 
Laboratory.  
x Get sterile heparin suitable for injection from the nurse’s station.  
x Rinse syringe and needle with sterile heparin, leaving no more than 0.2-0.5 mL in 
syringe.  
x After aspirate for morphology, reposition needle and, for cellular specimens, slowly 
aspirate 2-3 mL of bone marrow for flow cytometry. Aspiration of greater than 3mL 
results in significant dilution of the specimen in peripheral blood. For specimens with low 
cellularity, reposition and aspirate 3-5mL of bone marrow a second time. Note this on the 
requisition or the specimen will be rejected.  
x Immediately discharge syringe into transport media tube, cap tube tightly and mix by 
gentle inversion 5-6 times. Label tube with patient name, unique identifier number and 
date.  
x Deliver immediately to the Flow Cytometry Laboratory B1B58 (specimens containing 
hematopoietic neoplasms have a tendency to clot and must be processed immediately). 
Call for STAT Escort pickup and delivery if you cannot deliver the specimen yourself 
(301-496-9295).  
x The Active CRIS order should include the fellow’s name and pager number, the patient 
history and clinical question. This information is vital as to the set-up strategy used. If 
rapid diagnosis and notification of result is required to begin treatment, indicate STAT 
nature, explain reason and leave name as well as pager number of fellow on evening call. 
6.1.4 Functional Assays for Natural Killer Cells 
Blood samples will be collected to calculate the percentage change in NK cell cytotoxic granule 
release and NK cell intracellular cytokine secretion against KIR-L matched myeloma cells.  Prior 
to treatment, patients will undergo high resolution HLA typing including the HLA Cw loci to 
define their KIR-L expression (i.e. to define the presence or absence of group I (binds 
KIR2DL2/3) and group II (binds KIR2DL1) KIR ligands). Blood will be collected into ACD 
tubes at baseline, 24 hours following IPH2101 treatment, then weekly for the first 4 weeks 
following IPH2101 treatment. Thereafter blood will be collected monthly until the completion of 
treatment or until the time of withdrawal from protocol study. PBMCs will be isolated from these 
blood samples by ficolling then will be frozen viably for subsequent NK cell cytotoxicity, NK 
cell intracellular cytokine-based flow studies, and FACS analysis. To assess for changes in NK 
cell cytotoxicity, PBMC will be thawed and NK cell cytotoxic granule release following an 8 
hour co-culture with a KIR-ligand matched myeloma tumor cell line will be assessed by flow 
cytometry, gating on CD3-/ CD56+ and/or CD16+ NK cells that become CD107a positive vs NK 
cell controls that are not cultured with myeloma cells. To assess for changes in NK cell cytokine 
release associated with IPH2101 treatment, PBMC will also be thawed and co-cultured for 6 
hours with a KIR-ligand matched myeloma tumor cell line. Flow cytometry will be performed 6 
hours later, gating on CD3-/ CD56+ and/or CD16+ NK cells to quantitate the percentage of NK 
cells that become intracellular cytokine positive for either IFN-g, IL-2, or TNF-alpha vs NK cell 
controls that are not cultured with myeloma cells. The myeloma tumor targets used in these 
experiments will have group I and/or group II KIR-ligands that are matched to the patient (i.e. if 
the patient is homozygous for group I KIR-ligands, the myeloma line used in the cytotoxicity 
assays will also be homozygous for group I KIR-ligands, if the patient is heterozygous for both 
group I and group II KIR-ligands, the myeloma line used in the cytotoxicity assays will also be 


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20
heterozygous for group I and group II KIR-ligands). Using this technique, the percentage change 
in NK cell cytotoxic granule release and NK cell intracellular cytokine secretion following 
treatment with IPH2101 at multiple time-points compared to baseline prior to antibody treatment 
will be determined. 
6.1.5 Analysis of Microenvironmental Interactions 
The extrinsic interactions of bone marrow stromal cells, angiogenesis, and immunologic factors 
with CD138 positive plasma cells have been implicated in both the pathogenesis of MM and the 
mechanism of action of anti-KIR(IPH2101).  CD138 negative bone marrow aspirate cells are 
components of the bone marrow microenvironment.  Analysis of the microenvironmental 
changes in the marrow by methods such as determination of cytokine profiles and 
immunohistochemistry of matrix proteins, osteoblasts, reticular cells, osteoclasts, and endothelial 
cells will be performed.  The plasma from aspirate and peripheral blood plasma will also be used 
to determine matrix components of the myeloma microenvironment. 
6.1.6
Pharmacodynamic Studies  
KIR occupancy will be analyzed on peripheral blood samples by the Trepel Lab at baseline, 
before each dose and 2 months after the last dose.  Testing will be performed using the KIR 
occupancy flow cytometric assay protocol measuring the binding of a labeled 
immunofluorescent anti-KIR relative to standard fluorescent beads, developed and provided by 
Innate Pharma.  
Figure 2: Schematic for handling of patient samples for diagnostic and research studies. 
 
 


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21 
6.2 
SAMPLE STORAGE, TRACKING, AND DISPOSITION  
6.2.1 General 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  
Samples will not be sent outside NIH without IRB notification and an executed MTA. 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below.  
The study will remain open so long as sample or data analysis continues.  Samples from 
consenting patients will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed.  The PI will 
report any loss or destruction of samples to the IRB as soon as he is made aware of such loss. 
If the patient withdraws consent his/her data will be excluded from future distributions, but data 
that have already been distributed for approved research use will not be able to be retrieved. 
The PI will report destroyed samples to the IRB if samples become unsalvageable because of 
environmental factors (e.g., broken freezer or lack of dry ice in a shipping container) or if a 
patient withdraws consent.  Samples will also be reported as lost if they are lost in transit 
between facilities or misplaced by a researcher.  Freezer problems, lost samples or other 
problems associated with samples will also be reported to the IRB, the NCI Clinical Director, 
and the office of the CCR, NCI. 
6.2.2 Transplantation Immunotherapy Laboratory (Childs Lab) 
All BMPC (unclotted) blood samples obtained for this protocol will be stored in the Section of 
Transplantation Immunotherapy in the Hematology Branch of the NHLBI.  PBMCs obtained 
from peripheral blood samples will be ficolled, then cryopreserved viably in 1 mL aliquots in 
freezing media containing 10% DMSO by technicians working in the Section of Transplantation 
Immunotherapy Laboratory headed by Richard Childs, M.D.  Laboratory personnel are assessed 
for competency prior to being permitted to work with patient samples.  Efforts to ensure 
protection of patient information include: 
x The laboratory is located in a controlled access building and laboratory doors are kept 
locked at all times. Visitors to the laboratory are required to be accompanied by 
laboratory staff at all times.   
x Hard copy records or electronic copies of documents containing patient information are 
kept in the locked laboratory or other controlled access locations.   
x An electronic database is used to store information related to patient samples processed 
by the laboratory.   
o The database resides on a dedicated program server that is kept in a central, locked 
computer facility.   
o The facility is supported by IT specialists who maintain up to date security features 
including virus and firewall protection.   
o Program access is limited to specified computers as designated by the laboratory 
director.  Each of these computers has a password restricted login screen.   
o The database sample entry program itself is accessed through a password protected 
entry screen.   


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o The database program has different levels of access approval to limit unauthorized 
changes to specimen records and the program maintains a sample history.   
x Upon specimen receipt each sample is assigned a unique laboratory accession ID 
number.  All products generated by the laboratory will be stored in the laboratory liquid 
nitrogen freezers and are identified by this accession ID. 
x Inventory information will be stored at the vial level and each vial will be labeled with 
both a sample ID and a vial sequence number.   
x Vial labels do not contain any personal identifier information.    
x Samples are stored inventoried in locked laboratory freezers.     
x Access to stored clinical samples is restricted.  Investigators establish sample collections 
under “Source Codes” and the investigator responsible for the collections, typically the 
protocol Principal Investigator or Lead Associate Investigator, specifies who has access 
to the collection.  Specific permissions will be required to view, input or withdraw 
samples from a collection.  Prior to that date sample input was not restricted and 
restrictions were limited to specimen withdrawal.   
x Sample withdrawal requests submitted to approved laboratory staff by anyone other than 
the repository source code owner are submitted to the source code owner for approval.  
The repository facility will also notify the Source Code holder of any submitted requests 
for sample withdrawal.   
x It is the responsibility of the Source Code holder (generally the NCI Principal 
Investigator) to ensure that samples requested and approved for withdrawal are being 
used in a manner consistent with IRB approval.   
x When requests are submitted by the NCI investigator for shipment of samples outside of 
the NIH it is the policy of the laboratory to request documentation that a Material 
Transfer Agreement is in place that covers the specimen transfer.  The laboratory does 
not provide patient identifier information as part of the transfer process but may, at the 
discretion of the NCI investigator, group samples from individual patients when that is 
critical to the testing process.    
x The NCI investigator responsible for the sample collection is responsible for ensuring 
appropriate IRB approvals are in place and that a Material Transfer Agreement has been 
executed prior to requesting the laboratory to ship samples outside of the NIH. 
6.2.3 Clinical Pharmacology Program (Figg Lab) 
Aliquots of clotted blood samples and all urine samples obtained for this protocol will be stored 
in the Clinical Pharmacology Program (CPP), which will process and cryopreserve samples in 
support of this study under the direction of William D Figg, PharmD.   
For sample pickup, page 102-11964.  For immediate help, call 240-760-6180 (main blood 
processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab 
number).  For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. 
6.2.3.1 Sample Data Collection 
All samples sent to the Blood Processing Core (BPC) of the Clinical Pharmacology Program 
under the direction of Dr. Figg will be barcoded, with data entered and stored in the LABrador 
(aka LabSamples) utilized by the BPC. This is a secure program, with access to LABrador 
limited to defined Figg lab personnel, who are issued individual user accounts. Installation of 
LABrador is limited to computers specified by Dr. Figg. These computers all have a password 


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23 
restricted login screen. All Figg lab personnel with access to patient information annually 
complete the NIH online Protection of Human Subjects course.  
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without LABrador access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
6.2.3.2 Sample Storage and Destruction 
Barcoded samples are stored in barcoded boxes in locked freezers at appropriate temperatures 
(e.g., -20ºC to -80ºC) according to stability requirements.  These freezers are located onsite in the 
BPC and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the 
laboratory are required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables. 
6.2.4 Procedures for Collecting, Processing, and Storage of Bone Marrow Biopsies 
x Orders for bone marrow biopsies should be placed in the Clinical Research Information 
System (Clinical Research Center, NIH, Bethesda, MD). 
x Bone marrow biopsies will be submitted in native condition to the NCI Department of 
Pathology and handled according to routine procedures for diagnosis.  Bone marrow core 
biopsies will be fixed and paraffin-embedded for histological and immunohistochemical 
analysis and long-term storage.  Bone marrow aspirates will be prepared according to 
routine procedures.  Five to ten air-dried aspirate smears will be stored long-term.   
x Materials for research studies will be documented on form NIH 2803-1. 
x Initial processing of bone marrow aspirates for research will depend on the size of the 
aspirate.  CD138 positive plasma cells will be isolated from a subset of these samples. 
x For the purposes of storage, all research bone marrow samples will be assigned a unique 
number and cataloged.  Viably frozen cells will be stored in a temperature controlled, 
alarm secured nitrogen tank in the NCI Department of Hematopathology.  Frozen bone 
marrow biopsies and processed biologic material (such as RNA and protein) will be 
stored at -80°C in a temperature controlled, alarm secured freezer.   
x For research purposes, one aliquot of aspirate will be sent to the laboratory of Jane Trepel 
of the Developmental Therapeutics Branch, phone number (301) 496-1547, prior to 
sorting.  Biospecimens in the Trepel lab will be processed using validated SOPs that will 


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24 
ensure both specimen quality and patient confidentiality. Using a computerized inventory 
system and a backup hardcopy process, all specimen collection and processing steps will 
be documented and the specific location of each specimen will be tracked. Each new 
specimen collected will be assigned a unique barcode identifier that can be linked to the 
original specimen collected and other relevant information within the inventory system.  
Specimen labels will indicate: protocol number, order in which the patient enrolled on the 
trial, type of sample, collection time, and total volume collected, as appropriate.  The 
inventory process contains other security provisions sufficient to safeguard patient 
privacy and confidentiality. Access to the inventory system and associated documents 
will be restricted to appropriate individuals. Requests to use specimens stored in the 
repository must be approved. SOPs ensure that any changes in informed consent made by 
a patient and relayed to the PI will be reflected in the inventory system to ensure that 
specimens are destroyed as appropriate. All laboratory personnel will be trained to adhere 
to SOPs and will be monitored for high-quality performance. 
x All other research samples except stored serum will be stored in the laboratory of the 
Lymphoid Malignancies Branch. For information regarding these samples, please contact 
Mark Roschewski, MD at 301-451-9021.  
x Processed biologic material (such as DNA, RNA, and protein) from the bone marrow 
aspirates will be stored at -80°C in a temperature controlled, alarm secured freezer.  All 
processed bone marrow aspirates will be stored in the laboratory of the Lymphoid 
Malignancies Branch. For information regarding these samples, please contact Mark 
Roschewski, MD at 301-451-9021.   
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
DEFINITIONS 
7.1.1 Adverse Event 
Any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in research, whether or not considered related to the 
subject’s participation in the research. 
7.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected adverse reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or is not listed at the specificity or severity that has been observed; or, 
if an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. 
"Unexpected”, also refers to adverse events or suspected adverse reactions that are mentioned in 


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25 
the investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
7.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
x 
Death, 
x 
A life-threatening adverse drug experience 
x 
Inpatient hospitalization or prolongation of existing hospitalization 
x 
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
x 
A congenital anomaly/birth defect. 
x 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate 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. 
7.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH definition) 
Any change, divergence, or departure from the IRB approved research protocol. 
7.1.9 Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) 
policies, IRB requirements, or regulatory requirements for the protection of human research 
subjects. 
7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
x Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents, and 


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(b) the characteristics of the subject population being studied; AND 
x Is related or possibly related to participation in the research; AND 
x Suggests that research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
7.2 
NIH INTRAMURAL IRB AND  CLINICAL DIRECTOR REPORTING 
7.2.1 NIH Intramural IRB and NCI CD Expedited Reporting of Unanticipated Problems and 
Deaths 
The Protocol PI will report in the NIH Problem Form to the to the NIH Intramural IRB and NCI 
CD: 
x All deaths, except deaths due to progressive disease  
x All Protocol Deviations 
x All Unanticipated Problems 
x All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.2.2 NIH Intramural IRB Requirements for PI Reporting at Continuing Review 
The protocol PI will report to the NIH Intramural IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
x All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
x All Grade 3 and 4 events that are possibly, probably or definitely related to the 
research;  
x All Grade 5 events regardless of attribution;  
x All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.2.3 NIH Intramural IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NIH Intramural IRB. 
7.3 
FDA REPORTING CRITERIA 
NOTE:  This section retained for historical purposes; however, note that the IND for this study 
was withdrawn in 2014.   
7.3.1 IND Safety Reports to the FDA (Refer to 21 CFR 312.32) 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
27 
7.3.1.1 Expedited reporting to the FDA 
The Sponsor will notify the FDA of any unexpected fatal or life-threatening suspected adverse 
reactions as soon as possible but no later than 7 calendar days of initial receipt of the information 
using the MedWatch Form 3500a.  
The study Sponsor will also report expeditiously as above: 
x suspected adverse reaction that is both serious and unexpected 
x any findings from clinical, epidemiological, or pooled analysis of multiple studies or any 
findings from animal or in vitro testing that suggest a significant risk in humans exposed 
to the drug 
x clinical important increase in the rate of a serious suspected adverse reaction over that 
listed in the protocol or investigator brochure  
to the FDA and to all investigators no later than 15 calendar days after determining that the 
information qualifies for reporting using the MedWatch Form 3500a. If FDA requests any 
additional data or information, the sponsor must submit it to the FDA as soon as possible, but no 
later than 15 calendars days after receiving the request.  
7.3.1.2 Exclusions to expedited reporting to the FDA 
The following events will not be reported in an expedited manner but will be included in the 
annual report:  
x pain due to disease; 
x thrombus due to vascular access devices;  
x events associated with indwelling stents placed for disease management and not part of 
the protocol; 
x events associated with anesthesia that resolve as anticipated. 
7.3.2 FDA Annual Reports (Refer to 21 CFR 312.33) 
The study Sponsor will submit a brief report annually of the progress of the trial within 60 days 
of the anniversary date that the IND went into effect as indicated in 21CFR 312.33, and any 
associated FDA correspondences regarding the IND annual report.  
7.3.3 Expedited Adverse Event Reporting Criteria to the IND Manufacturer 
During the duration of this trial, the Principal Investigator will assume responsibility for 
reporting any serious and unexpected adverse events that occur in subjects prior to their off-study 
date, to Innate Pharmaceuticals Inc. by fax within 24 hours of receipt of the SAE notification to 
the following contact: 
Primary contact:  
Christine D’ARNOUX 
Fax: +33.4.30.30.30.10  
Email : Christine.D-Arnoux@innate-pharma.fr 
Phone: +33.4.30.30.30.89  
Secondary contact:    
Renaud BUFFET  
Fax: +33.4.30.30.30.10  
Email : renaudbuffet@wanadoo.fr  
Phone: +33. 6.20.76.74.74 
 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
28 
7.4 
DATA SAFETY AND MONITORING PLAN 
7.4.1  Principal Investigator/Research Team  
The clinical research team will meet weekly when patients are being actively treated on the trial 
to discuss each patient. Decisions about dose level enrollment and dose escalation if applicable 
will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS (if applicable) and to the 
IND manufacturer.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
7.4.2 Sponsor Monitoring Plan 
This trial will be monitored by personnel employed by a CCR Contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
At least 25% of enrolled patients’ will be randomly selected and monitored at least biannually or 
as needed, based on accrual rate. The patients selected will have 100% source document 
verification done. Additional monitoring activities will include: adherence to protocol specified 
study eligibility, treatment plans, data collection for safety and efficacy, reporting and time 
frames of adverse events to the IRB and FDA, and informed consent requirements. Written 
reports will be generated in response to the monitoring activities and submitted to the Principal 
investigator and Clinical Director or Deputy Clinical Director, CCR, NCI. 
8 
STATISTICAL CONSIDERATIONS 
8.1 
SAMPLE SIZE DETERMINATION 
The primary objective of this study is to determine if the use of a monoclonal antibody will result 
in a sufficiently large fraction of patients with smoldering multiple myeloma who will 
experience a decline of 50% or more in their antibody levels as measured at up to 12 months 
after their initial baseline antibody level determination.  
The study will be conducted as an optimal two-stage phase II trial 26, in order to rule out an 
unacceptably low 25% of patients who experience at least a 50% decline in their antibody levels 
from baseline to up to 12 months (p0=0.25) in favor of a modestly high 50% fraction who have 
this magnitude of decline (p1=0.50). Declines of 50% at either time point will be considered a 
‘positive outcome’. With alpha=0.15 (probability of accepting a poor treatment=0.15) and beta = 
0.15 (probability of rejecting a good treatment=0.15), the study will initially enroll 9 evaluable 
patients and if 0-2 of the 9 have a positive outcome, then no further patients will be accrued. If 3 
or more of the first 9 have a positive outcome, then accrual would continue until a total of 19 
patients have enrolled. As it may take up to maximum 12 months to determine if a patient has 
experienced a positive outcome as defined, a temporary pause in the accrual to the trial may be 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
29 
necessary to ensure that enrollment to the second stage is warranted. If there are 3-6 patients with 
a positive outcome in 19 patients, this would be an uninterestingly low response rate, while if 
there were 7 or more patients with a positive outcome in 19 patients, then this would be 
sufficiently interesting to warrant further study in later trials. Under the null hypothesis (25% 
positive outcome rate), the probability of early termination is 60%. 
Secondary endpoints include evaluation of toxicity of anti-KIR(IPH2101), estimated time to 
progression, duration of response, pharmacokinetic analysis and evaluation of biological activity; 
and are intended to be exploratory in this initial trial.  Data collected on these endpoints will be 
analyzed and reported descriptively. 
8.2 
ACCRUAL RATE 
It is anticipated that up to 2 patients per month may be enrolled onto this protocol.  To allow for 
the possibility of a small number of inevaluable patients (10% drop out rate), the accrual ceiling 
for the trial will be set at 21.  Thus, approximately one year may be required to enroll 19 
evaluable patients. In order to allow for the possibility of a small number of non-evaluable 
patients, the accrual ceiling will be set at 21. 
8.3 
ANALYSIS OF SECONDARY ENDPOINTS 
The time to event secondary endpoints are defined as follows: time to progression (time from 
registration to progression, censored at date last known progression-free for those who have not 
progressed), and duration of response (time from response to disease progression or death, or 
date last known progression-free and alive for those who have not progressed or died). Time to 
progression to symptomatic MM to be documented in study, and in a post study follow up (See 
Section 3.5 Study Calendar).  Time to progression and the duration of response will be estimated 
using the Kaplan-Meier and log-rank methods. 
Toxicity, quality/duration of response, and patterns of treatment failure observed in this study, as 
well as scientific discoveries or changes in standard care will be taken into account in any 
decision to terminate the study. 
9 
COLLABORATIVE AGREEMENT 
9.1 
CLINICAL TRIAL AGREEMENT (CTA)  
Anti-KIR (IPH2101) is provided to the investigator by Innate Pharmaceuticals, Inc. under a CTA 
(00843-10). 
10 HUMAN SUBJECTS PROTECTIONS 
10.1 
RATIONALE FOR SUBJECT SELECTION 
MM is an almost always incurable plasma cell neoplasm that comprises approximately 10% of 
all hematologic malignancies.2  It has recently been shown that, prior to diagnosis of MM, a 
precursor state (MGUS or SMM) can be detected in all patients who ultimately progress to 
MM.7,8  MGUS, SMM, and MM increase in incidence with age.10,27  MGUS affects 
approximately 3.2% of Caucasians over the age of 50 and 5.9% of African-Americans.12,28,29  
SMM affects all races and genders.12  As such, we expect that the majority of patients enrolled in 
this trial will be older adults of either gender or race.  SMM patients enrolled on this study will 
consist of patients referred to and screened at the NIH Clinical Center.  There will be no subject 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
30 
selection bias with regard to gender, ethnicity, or race.  This protocol will be reviewed by the 
IRB. This protocol excludes lactating and pregnant women from receiving this investigational 
drug to avoid any possible risks to the fetus or newborn.  A potential toxicity of IPH2101 for 
embryo-foetogenesis is not expected but has not been explored.  Additionally, the median age of 
diagnosis for SMM is in the range of 50 to 60 years, thus few patients with SMM are expected to 
be pregnant or lactating. 
10.2 
PARTICIPATION OF CHILDREN 
Pediatric patients with SMM are extremely rare.  Patients under the age of 18 are excluded from 
this study because inclusion of a rare younger patient will not provide adequate generalizable 
information to justify their inclusion in this study.  Also, there is currently no Phase I data on this 
use of anti-KIR(IPH2101) in the pediatric population. 
10.3 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
NK cells are large granular lymphocytes that comprise approximately 10-15% of peripherally 
circulating lymphocytes and play a crucial role in cellular innate immunity.  NK cells lyse tumor 
cell targets through the balance of activating and inhibitory signals received through receptor 
families such as KIR for inhibitory signals. 
IPH2101 (anti-KIR) has features that should allow prolonged pharmacological blockade of KIR 
in patients that prevent the inhibitory signals induced by all HLA-C allotypes of NK cells. NK 
cells have therefore the potential to kill tumor or infected cells without affecting healthy tissues. 
Three phase I studies have been conducted with IPH2101. 
A single-dose escalation phase 1 trial (IPH2101-101) has been performed in patients with AML 
in complete remission followed by an extension protocol (IPH2101-102) allowing patients 
treated in the IPH2101-101 study to receive repeated administrations once the dose level they 
had been assigned to was considered safe by the safety committee. 
A phase 1 dose-escalation repeated dosing trial in patients with relapsed or refractory MM 
(IPH2101-103) has been performed in the US. 
For both trials IPH2101-101 and IPH2101-103 the escalation phase, i.e. 7 dose levels ranging 
from 0.0003mg/kg to 3mg/kg has been successfully completed, with good tolerance and safety 
up to the maximum dose tested. 
A first phase II study (IPH2101-201) is ongoing in France, evaluating the product in 
monotherapy, in patients with MM in stable plateau phase (maintenance setting) after first-line of 
treatment. 
Overall, tolerance was good for all dose levels tested, without serious unexpected serious adverse 
reactions (SUSAR) reported except for the following two: 
x One SUSAR was reported in a patient in trial IPH2101-103 after he received one dose of 
0.075 mg/kg and considered as “probably related” to IPH2101.  This was a grade 3 acute 
renal failure in a patient with progressing MM.  It was decided to hydrate the subjects 
with 250 mg/hr one hour before and after dosing to prevent acute renal failure due to 
dehydration. 
x Another SUSAR occurred in a patient in trial IPH2101-101 after he received one dose of 
3 mg/kg IPH2101; this was a grade 2 bradycardia possibly related to IPH2101 treatment.  


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31 
A cardiologist believed it to probably be of vagal origin in a setting of grade 2 fever, 
chills, and hypotension. 
x No other clinically relevant events were reported in the other patients recently treated at 
the same 3 mg/kg dose. 
x The most frequently reported adverse events were: 
x Fever 
x Fatigue 
x Headache 
x Chills 
x Rash 
x Itching (pruritis) 
x Bradycardia 
There are no evident signs of IPH2101 inducing AEs related to auto-reactivity, infusion, or 
cytokine release to a degree that has raised any safety concerns. 
IPH2101 has so far shown to be tolerable and manageable in subjects with AML or MM.  It has 
to be emphasized that the maximal tolerated dose (MTD) has not been reached at the maximal 
tested dose of 3 mg/kg in any of the phase I trials. 
10.4 
RISKS/BENEFITS ANALYSIS 
The safety profile of IPH2101 appears to be very satisfactory as documented in phase I and II 
studies up to 3 mg/kg at single and repeated dosing.  Regarding the pharmacodynamic effect, the 
preliminary data show that all patient displayed KIR occupancy; the degree and duration is dose 
dependant.  A dose of 1mg/kg allows a full saturation (90%) of KIR receptors over 4 weeks.  
Therefore, this dose every two months should lead to the maintenance of a complete saturation 
between doses. 
Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell proliferative disorder with 
a high risks of progression (cumulative risk 73% at 15 years) to symptomatic multiple myeloma 
(MM).  MM is an incurable malignancy and any possible way to decrease or delay this risk of 
progression will bring a clear benefit to these patients with SMM.  No therapy for SMM is 
currently available so investigational approaches should be considered and should be safe in 
asymptomatic patients. 
10.5 
CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
Informed consent will be obtained from all patients on this trial.  There will be no minors 
enrolled < 18 years of age; therefore, assent is unnecessary.  The informed consent contains all 
elements required for consent.  In addition, the Principal Investigator or an associate investigator 
or member of the research team will discuss the protocol in detail with the patient and will be 
available to answer all patient questions to allow the patient to give informed consent. 
11 PHARMACEUTICAL INFORMATION 
11.1 
IPH2101 (ANTI-KIR) 
11.1.1 Source 
Anti-KIR (IPH2101) is provided to the investigator by Innate Pharmaceuticals, Inc. under a 
Clinical Trials Agreement (CTA). 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
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32 
11.1.2 Toxicity  
Table 2: ALL ADVERSE EVENTS POTENTIALLY RELATED TO ANTI-KIR(IPH2101) in 
Trials 101 and 102 
Adverse Event (CTCAE 4.0 Term) 
IPH2101-101 
IPH2101-102 
 
N (%) E 
N (%) E 
Related Adverse Events 
15 (65) 27 
6 (67) 15 
Subjects Exposed 
23 
9 
BLOOD AND LYPHATIC SYSTEM DISORDERS 
Anemia 
1 (4) 1 
 
Thrombocytopenia 
1 (4) 1 
 
CARDIAC DISORDERS 
Bradycardia 
1 (4) 1 
 
Sinus Bradycardia 
1 (4) 1 
 
EAR AND LABYRINTH DISORDERS 
Vertigo 
1 (4) 1 
 
EYE DISORDERS 
GASTROINTESTINAL DISORDERS 
Diarrhea 
1 (4) 2 
 
Dry Mouth  
1 (11) 1 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fever 
3 (13) 3 
1 (11) 1 
Chills 
1 (4) 1 
1 (11) 1 
Weakness 
1 (4) 1 
 
Fatigue  
1 (11) 1 
General physical health deterioration  
1 (11) 1 
Malaise  
1 (11) 1 
INVESTIGATIONS 
Lipase Increased 
1 (4) 1 
 
METABOLISM AND NUTRITION DISORDERS 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
NERVOUS SYSTEM DISORDERS 
Dizziness 
1 (4) 1 
 
Headache 
1 (4) 1 
1 (11) 1 
Parosmia  
1 (11) 1 
Tremor  
1 (11) 1 
PSYCHIATRIC DISORDERS 
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS 
Dyspnea  
1 (11) 1 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
Gynecomastia 
1 (4) 1 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Rash 
4 (17) 4 
1 (11) 1 
Papular Rash  
1 (11) 1 
Pruritis 
4 (17) 5 
1 (11) 3 
Erythema 
1 (4) 1 
 
VASCULAR DISORDERS 


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33 
Adverse Event (CTCAE 4.0 Term) 
IPH2101-101 
IPH2101-102 
Hypotension 
1 (4) 1 
 
N = number of subjects having the given event; E = the number of adverse events reported; % 
= the percentage of exposed subjects experiencing the event. 
 
Table 3: ALL ADVERSE EVENTS RELATED TO IPH2101 IN TRIAL 103 
Adverse Event (CTCAE 4.0 Term) 
IPH2101-103 
 
N (%) E 
Related Adverse Events 
7 (28) 20 
Subjects Exposed 
25 
BLOOD AND LYPHATIC SYSTEM DISORDERS 
CARDIAC DISORDERS 
Tachycardia 
1 (4) 1 
GASTROINTESTINAL DISORDERS 
Abdominal Pain 
1 (4) 1 
Nausea 
1 (4) 2 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fever 
3 (12) 3 
Chills 
3 (12) 3 
Fatigue 
1 (4) 1 
INVESTIGATIONS 
Serum creatinine increased 
1 (4) 2 
Neutrophil count decreased 
1 (4) 1 
METABOLISM AND NUTRITION DISORDERS 
Hyperkalemia 
1 (4) 1 
Hyperuricemia 
1 (4) 1 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
NERVOUS SYSTEM DISORDERS 
Headache 
2 (8) 2 
RENAL AND URINARY DISORDERS 
Acute Renal Failure 
1 (4) 1 
RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
VASCULAR DISORDERS 
Flushing 
1 (4) 1 
N = number of subjects having the given event; E = the number of adverse events reported; % 
= the percentage of exposed subjects experiencing the event. 
11.1.3 Formulation and Preparation 
IPH2101 is a fully human IgG4 monoclonal antibody.  It will be provided as 5 mL fill 
in a 6 mL vial of a liquid for infusion with a formulation strength of 10 mg/mL 
11.1.4 Stability and Storage 
11.1.4.1 The storage and shipping conditions for IPH2101 are: 
x Temperature: +2°C to +8°C (35.6 to 46.4°F) 


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34 
11.1.4.2 Stability studies of IPH2101 (anti-KIR) are ongoing. 
11.1.5 Packaging and labeling 
IPH2101 will be provided in boxes of 4 vials.  Labeling will be in accordance with local law and 
trial requirements 
11.1.6 Administration Procedures 
For all dose administration, the individual dose will be a single dose per kg of body weight.  The 
dose calculation will be based on the body weight of the subject.  IPH2101 will be administered 
undiluted over a one hour IV infusion by the use of a pro-programmed syringe driver. See 
Section 3.3. Saline can be used to flush the line. 
11.1.6.1 Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of all agents received from Innate Pharmaceuticals Inc. 
using the NCI Drug Accountability Record Form (DARF). 
11.1.7 Incompatibilities 
No incompatibility has been identified at this stage of development. 
 
 


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35 
 
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A b brevi ate d Title :  A nti- KI R (I P H 2 1 0 1) i n S M M 
Versi o n D ate :  1 2/ 2 6/ 2 0 1 8 
3 7 
1 3  A P P E N DI C E S 
A P P E N DI X A:   B O N E M
A R R O W S A M P L E P R O C E S SI N G  
1 3. 1. 1  Pr oce d ure f or se p arati n g s peci me n sa m ples 
Bef ore perf or mi n g t he b o ne marr o w as pirate pr oce d ur e ma ke s ure t hat t he s yri n ge, us e d t o dra w 
t he s peci me n, c o ntai ns 1 ml of 7 % E DT A s ol uti o n t o pre ve nt c oa g ul ati o n. 
1.   Har vest 1 0 ml b o ne marr o w as pirate i n o n e or t w o t u bes c o ntai ni n g at least 1 ml of 7 % 
E D T A s ol uti o n per t u be. 
2.   Place i m me diatel y o n i ce.  
3.   Dil ute sa m ple t o 3 2 ml wit h of P B S + 2 m M E D T A. 
4.   Se parate m o n o n ucl ear cells fr o m re d cells b y Fic oll gra die nt. 
a. Place 6 ml Fic oll i nt o eac h of f o ur 1 5 ml c o nical t u bes. 
b.  Caref ull y la yer 8 ml of dil ute d b o ne marr o w as pirate sa m ple o ver t he fic oll i n 
eac h t u be, creati n g a s har p sa m ple-fic oll i nter p has e. 
c. Ce ntrif u ge (at R T) at 1 2 0 0 x g f or 3 0 mi n wit h o ut bra ke. 
d.  Re m o ve 1 ml of u p per la yer fr o m eac h t u be a n d place i n 4 se parate 1. 5 ml cr y o 
t u bes. Freeze o n dr y ice a n d st ore at - 8 0 C u ntil s hi p me nt. 
e. Re m o ve a n d discar d t h e t o p la yer of clear  s u p er nat a nt t o wit hi n 1 ml a b o ve t he 
m o n o n uclear cells la yer, lea vi n g it u n dist ur be d at t he i nter p hase. 
f. F or all f o ur t u bes, c ollect t he re mai n de r of t he t o p la yer, t he m o n o n uclear cell 
la yer, a n d a b o ut half of t he fic oll bel o w it; tra nsfer it t o a 5 0 ml t u be. 
g.  Fill t he 5 0 ml c o nical t u be wit h P B S/ E D T A, mi x ge ntl y, a n d ce ntrif u ge f or 1 0 
mi n utes at R T at ~ 3 0 0 g ( 1 2 0 0 r p m). 
h.  Caref ull y re m o v e t he s u p er nata nt c o m plet el y. 
i. Was h t he cells a gai n wit h P B S/ E D T A c o ntai ni n g 0. 5 % B S A p H 7. 2 
j. Res us pe n d cells i n 4 0 ml b uffer 
k.  Pass cell t hr o u g h a t hr o u g h a 3 5 
m N yl o n cell strai ner ca p ( B D # 3 5- 2 2 3 5) i n a 
5 0 ml t u be, n o b u b bles. 
l. Ce ntrif u ge f or 5 mi n utes at 1 2 0 0 R P M. As pirate s u per nata nt. 
m.  Res us pe n d cells i n 1. 6 ml of b uffer us e d  f or m a g n etic se parati o n ( bel o w). 
n.  Re m o ve 1 0 ul ali q u ot f or ce ll c o u nt, w hic h ca n be d o ne later wit h ot her c o u nts; 
s h o ul d be a t otal of a b o ut 0. 5- 1. 5 X 1 0 E 8 m o n o n ucl ear cells. 
o.  Pr ocee d t o ma g netic p ositi ve selecti o n of C D 1 3 8- p ositi ve cells. 
1 3. 1. 2  C D- 1 3 8 Ma g netic Bea d Is olati o n f or fres h B o ne Marr o w Sa m ples 
( Pr ot oc ol per Milte n yi- Bi otec h)  
1.  C D- 1 3 8 Is ol ati o n pr oce d ure: Use c ol d ( b ut  n ot ice c ol d) de gasse d fres h se p arati o n 
b uffer o nl y. ( P B S/ E D T A/ 0. 5 % B S A p H 7. 2). W or k fast t o kee p cells c ol d. 
2.  A d d 4 0 0 ul bea ds t o 1. 6 ml of m o n o n uclear cells.  Mi x b y ge ntl y pi petti n g.  
3.  In c u bate i n t he refri gerat or f or 1 5 mi n utes. 
4.  Pre pare t hr ee M S c ol u m ns f or e ver y sa m ple. W hile i nc u bati n g s a m ples, place 
c ol u m ns o n ma g nets a n d was h wit h 0. 5 ml b uffer. A v oi d i ntr o d uci n g b u b bl es w hile 
pi petti n g.  
5.  After i nc u b ati o n, was h cells i n  2 0 ml of se parati o n b uffer.  
6.  S pi n at 1 2 0 0 r p m f or 1 0 mi n. Re m o ve s u per nata nt c o m pletel y. Re s us pe n d pellet i n 
0. 5 ml se parati o n b uff er.  


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
38 
7. Place a clean 15ml tube under the first column to collect the negative fraction. Apply 
cell suspension to column, no bubbles. Allow unlabeled cells to pass through.  
8. Wash columns 3x with 0.5 ml buffer. 
9. Apply entire flow through of 2 ml to a second column, and repeat washes. 
10. Collect total effluent of 3.5 ml in 15 ml centrifuge tube, and mix gently. Spin at 1200 
rpm for 10 min, remove supernatant, and resuspend in 1 ml. This is the unlabeled cell 
fraction (negative fraction).  Remove 10 microliters for a cell count, which can be 
done later. 
11. Set aside this negative fraction for further processing (below) 
12. Remove the two columns from magnet and place in a suitable tube, pipette 1ml 
separation buffer on top of each column and elute retained cells using the plunger 
supplied with the column. 
13. Spin down eluted cells and resuspend pellet in 0.5 ml of buffer. 
14.  Apply eluted fraction to a new column. 
15. Discard effluent and washes. 
16. Same as 12 except with one column. 
17. Spin down eluted cells and resuspend in 1 ml of buffer. This is the positively selected 
fraction. Remove 10 microliter aliquot for cell count 
 
13.1.3 After CD 138 enrichment 
NOTE: 10% of the cells will be used to harvest protein for Tissue Lysate Arrays; the remaining 
cells will be used to generate RNA for gene expression profiling and cDNA for RAS sequencing.  
Please separate the cells into duplicate samples for each, as described. 
1. Remove 2 aliquots of 100ul each from the 1ml of CD138+ cells and the 1ml of flow-
through CD138-negative cells into separate microcentrifuge tubes.  These will be used 
for the Tissue Lysate Arrays. 
2. Separate the remaining 800ul of each fraction into two separate tubes containing 400ul 
each. 
3. Centrifuge all aliquots (ie, the positive and negative fractions) at 1000xg for 5 min. 
4. Remove all supernatant. 
5. Freeze pellets on dry ice and store at -80 deg until shipment. 
13.1.4 Summary of samples from each bone marrow aspirate: 
Supernatant from Ficoll = 4 cryotubes containing 1 ml each 
Cell pellets =  8 tubes for each aspirate:  
 
10% of the CD138+ fraction (for protein) in each of two tubes,  
 
40% of the CD139+ fraction (for nucleic acids) in each of two tubes,  
 
10% of the CD138 negative fraction (for protein) in each of two tubes,  
 
40% of the CD138 negative fraction (for nucleic acids) in each of two tubes. 
 
13.1.5 Reagents: 
Miltenyi Biotec - 12740 Earhart Ave - Aubutn, CA 95602 - (530) 888-8925 
Columns: Miltenyi  MS MACS columns (cat # 130-042-201)  
Magnets:  MiniMACS high-energy permanent magnet, and MACS Multistand  
Beads:     Miltenyi CD 138 microbeads (cat# 130-051-301)  


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
39 
 
Separation Buffer   PBS + 2mM EDTA + 0.5% BSA, pH 7.2  
(make fresh, use within 2 weeks) 
 
For 50 ml: 
 
5 ml  10x PBS 
 
 
  
0.2 ml  0.5 M EDTA 
 
 
  
0.25 g BSA 
 
 
 
qs to 50 ml with ultra H2O, pH to 7.2, and sterile filter. Store 4oC. 
 
0.5 M EDTA 18.61 g/ 100 ml H2O, pH 8.0 
 
 
 
Sterile filter. Store at room temp. 
 
 
 


Abbreviated Title:  Anti-KIR (IPH2101) in SMM 
Version Date:  12/26/2018 
40 
APPENDIX B:  PERFORMANCE STATUS CRITERIA 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory.  
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). 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and 
about more than 50% of waking 
hours. 
60 
Requires occasional assistance, 
but is able to care for most of 
his/her needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Disabled, requires special care 
and assistance. 
30 
Severely disabled, 
hospitalization indicated.  Death 
not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead.