Clinical trial NCT03333746
Conditions: Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma
Sponsor: Yvonne Efebera
Start date: 2018-03-21; Completion date: 2018-11-16
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well lenalidomide and nivolumab work in treating patients with multiple myeloma that has come back or does not respond to treatment. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Monoclonal antibodies, such as nivolumab, may interfere with the ability of cancer cells to grow and spread. Giving lenalidomide and nivolumab may work better in treating patients with multiple myeloma.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the efficacy of nivolumab in combination with lenalidomide (Revlimid) in terms of overall response rate in patients with relapse/refractory multiple myeloma (MM).

OUTLINE:

Patients receive lenalidomide orally (PO) on days 1-21 and nivolumab intravenously (IV) over 1 hour on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Arms: arm 1: Patients receive lenalidomide PO on days 1-21 and nivolumab IV over 1 hour on days 1 and 14. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Lenalidomide intervention 3: Nivolumab intervention 4: Pharmacological Study
Intervention descriptions: intervention 1: Correlative studies intervention 2: Given PO intervention 3: Given IV intervention 4: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
OSU-17160 Protocol Amd 3 – 19 Dec 2017 
1 / 65 
 
OSU Study #:  
OSU-17160  
IRB Protocol #:  
2017C0132 
Version:  
 
Amendment 3: 12/19/2017 
IRB Approved:  
04/24/2018 
 
 
 
Phase II Study of Lenalidomide in Combination with Nivolumab 
In Patients with Relapsed/Refractory Multiple Myeloma 
 
 
Clinical Lead (PI):    
 
Yvonne A. Efebera, M.D, MPH 
                                            
 E-mail: yvonne.efebera@osumc.edu   
 
Scientific Lead:  
 
 
Don M. Benson M.D. Ph.D. 
Email: Don.Benson@osumc.edu   
 
Clinical Site PI:  
Beth Israel Deaconess 
 
David E. Avigan, M.D 
Medical Center 
 
 
Email: davigan@bidmc.harvard.edu 
 
Study Sponsor: 
 
 
The Ohio State University 
IND #:  
 
 
 
135711 
 
Funding Entity: 
 
 
American Cancer Society 
Drug Supplied: 
 
 
Nivolumab 
Drug Supplier: 
 
 
Bristol-p Squibb 
 
Multi-Center Trial Program: 
Clinical Trials Office 
 
 
 
 
 
The Ohio State University Comprehensive Cancer Center 
 
 
 
 
 
Fax:  614-366-6652 
 
 
 
 
 
E: OSUCCC-CTO-MCTP@osumc.edu 
 
 
 
 
Initial: 
 
28 Apr 2017  
Amendment 1:  
28 Sep 2017 
Amendment 2: 
29 Nov 2017  
 
 
 
Amendment 3: 
19 Dec 2017 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
2 / 65 
 
PROTOCOL SYNOPSIS 
 
Study Title 
Phase II Study of Lenalidomide in Combination with Nivolumab 
in Patients with Relapsed/Refractory Multiple Myeloma 
 
Study ID 
 
Sponsor 
American Cancer Society 
Primary 
Objectives 
To determine the efficacy of Nivolumab in combination with lenalidomide 
(Revlimid) in terms of overall response rate in patients with relapse/refractory 
multiple myeloma (MM)  
 
Primary 
Endpoint 
• To determine the overall response rate (ORR) after 4 cycles and then at 8 
and 12 months in responding patients according to the International 
Myeloma Working Group (IMWG) response criteria in the phase II study. 
 
Secondary 
Endpoints 
 
 
• To determine time to progression (TTP) and progression free survival (PFS) 
• To determine overall survival (OS) 
• To assess Nivolumab correlative biologic studies to assess 
immunomonitoring of lymphocytes subsets including T and NK cell, and ex-
vivo assessment of immune functional activities. 
Safety 
parameters 
Infusion related and treatment emergent toxicities per National Cancer Institute 
Common Terminology Criteria for Adverse Events ( NCI CTCAE) v4.0 
 
Study Design 
Nivolumab will be administered intravenously as a 1-hour infusion, 240 mg every 2 
weeks (day 1 and 15) of each 28 day cycle. At the treating physician’s discretion,  
patients will receive pre-medication (Tylenol 650mg or Ibuprofen 800mg or related 
medication), and an antihistamine (phenergan 25mg or equivalent) before 
Nivolumab infusion. Lenalidomide will be given at starting dose of 25 mg days 1-
21 of a 28 day cycle. 
 
Patients will be assessed for response at the end of each cycle according to the 
IMWG response criteria.  
 
Patients will be monitored for safety by assessing toxicities as graded by the 
NCI CTCAE v4.0. Dose limiting toxicity (DLT) will be defined as one or more of the 
following toxicities considered to be at least possibly related to one of the study 
drugs during Cycle 1 
• Grade 3 or greater nonhematologic toxicity with the exception of Grade 3 
nausea, vomiting and diarrhea that responds to supportive therapy.  
• Grade 4 thrombocytopenia, or grade 3 thrombocytopenia with bleeding, or 
any requirement for platelets transfusion  
• Grade 4 neutropenia persisting for more than 5 days. 
• Grade 3 or greater febrile neutropenia (temperature ≥ 38.5 °C) 
• Grade 4 anemia, unexplained by underlying disease 
 
Patients that experience a lenalidomide-related hematologic DLT may continue on 
therapy if the event resolves, the investigator considers it in the best interest of the 
patient to continue and the patient qualifies for initiation of the next cycle with 
standard of care lenalidomide dose reduction.   


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
3 / 65 
 
 
Discontinuation of treatment due to disease progression will not constitute a DLT.  
 
After 4 cycles of therapy or earlier if clinically indicated, response determination 
will be assessed by the IMWG criteria. At the end of Cycle 4, if a subject has 
responded (complete or partial response) or has stable disease, dosing with 
Nivolumab and lenalidomide will continue for a minimum of 8 additional cycles or 
until disease progression or withdrawal. 
 
If disease progression is observed at the end of Cycle 4 evaluation, all study 
therapy will be discontinued. Confirmation of progression of disease will be done 
according to the IMWG criteria. 
 
Following the 30-day post-treatment follow-up assessment, additional evaluations 
will occur once per month (unless subject discontinued due to progression) until 
the earliest of the following events: disease progression, the time of initiation of 
new therapy, death or study completion. 
 
Study completion is defined as 30 days after the last subject remaining on study 
medication discontinues study medication. 
 
An independent Data Monitoring Committee will continue oversight of this trial. 
 
Treatment will continue until Progression of disease, death, unacceptable toxicity 
or patient or treating physician decision to discontinue therapy. 
 
Dosing 
Regimen 
Nivolumab will be given at a dose of 240 mg every 2 wks (Day 1 and 15) of a 28-
day cycle. Lenalidomide will be given at starting dose of 25 mg days 1-21 of a 28 
day cycle. Dexamethasone can be added after 2 cycles if stable disease. 
 
Planned 
Sample size 
18 patients will be recruited 
Duration of 
Study Period 
Patient will continue study treatment at the treating physician’s discretion.  
Patients achieving at least a stable disease can continue treatment until 
progression of disease, death, unacceptable toxicity, or patient decision.  Overall 
response will be assessed after 4, 8, and 12 cycles.  
 
The total study enrollment period is expected to be up to 12-18 months. 
 
Eligibility 
Inclusion criteria 
 
• Patients must be at least 18 years of age with evidence of progression, relapse 
or refractory disease from last line of therapy as defined by IMWG criteria and 
measurable disease as defined by any of the following: 
o Serum M-protein ≥0.5 g/dl (≥10 g/l) 
o Urine monoclonal protein ≥ 200 mg/24h 
o Involved FLC level ≥ 10mg/dl (≥ 100mg/l) and an abnormal serum 
free light chain ratio (<0.26, or >1.65) 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
4 / 65 
 
Measurable biopsy proven plasmacytoma (should be measured 
within 28 days of initial investigational agent dosing) 
• Patients must have exhausted all available therapies known to provide 
clinical benefit and has progressed, relapsed or is refractory to last line of 
treatment. 
• Patients must have had at least 4 prior lines of therapy. 
• Patient may be enrolled at any time from last line of therapy 
• Patients must have ANC > 1000/µL; Platelets ≥75,000/µL, if plasma cell 
percentage on bone marrow biopsy aspirate or core is > 30%, platelet 
eligibility requirement will be adjusted to 60,000/ul.   
• Patients must have adequate hepatic function as evidenced by: total 
bilirubin < 1.5 mg/dL, alkaline phosphatase < 3X the ULN, AST/ALT < 2X 
the ULN 
• Patients must have adequate renal function as evidenced by serum 
creatinine < 2mg/dL or calculated creatinine clearance of ≥ 40ml/min within 
14 days of registration using MDRD formula. 
• Patient must be able to swallow capsule or tablet. 
• Patients must provide informed consent.  
• Patients must have a left ventricular ejection fraction ≥ 30%, no 
uncontrolled arrhythmias or New York Heart Association class III-IV heart 
failure. 
• Patients must have a Karnofsky performance status > 70.  
• A negative pregnancy test will be required for all women of child bearing 
potential. Breast feeding is not permitted.  
• Fertility requirements 
o Female patients with child bearing potential must have a negative 
pregnancy test at least 7 days before starting treatment drugs. 
o Male patients must agree to use an adequate method of contraception for 
the duration of the study and for 7 months afterwards. 
o Female patients must be either post-menopausal, free from menses ≥2 yrs, 
surgically sterilized, willing to use two adequate barrier methods of 
contraception to prevent pregnancy, or agree to abstain from sexual activity 
starting from screening and for 5 months afterwards. 
o Female patients of child bearing potential must agree to comply with the 
fertility and pregnancy test requirements dictated by the Rev-Assist 
program. 
 
Exclusion Criteria 
 
• Patients with peripheral neuropathy > CTCAE grade 2 
• Patients receiving concurrent corticosteroids at the time protocol therapy is 
initiated other than for physiologic maintenance treatment. 
• History of allergic reaction (including erythema nodosum) to lenalidomide 
• Concurrent use of complementary or alternative medicines that would 
confound the interpretation of toxicities and antitumor activity of the study 
drugs. 
• Patients with contraindication to thromboprophylaxis 
• Unacceptable cardiac risk factors defined by any of the following criteria: 
Patients with congenital long QT syndrome, any history of ventricular fibrillation 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
5 / 65 
 
or torsade de pointes, bradycardia defined as HR< 50 bpm, Left ventricular 
ejection fraction < 30% 
• Patients who have received targeted or investigational agents within 2 weeks or 
within 5 half-lives of the agent and active metabolites (whichever is longer) and 
who have not recovered from side effects of those therapies. 
• Patients who have undergone major surgery ≤ 2 weeks prior to starting study 
drug or who have not recovered from the side-effects of surgery 
• Patients with known positivity for human immunodeficiency virus (HIV), or 
hepatitis C.  Baseline testing for HIV and hepatitis C is not required 
• Patients with a history of another primary malignancy that is currently  
      clinically significant or currently requires active intervention, other than non-   
melanoma skin cancer and carcinoma in situ of the cervix should not be    
enrolled. Patients are not considered to have a “currently active” malignancy  
      if they have completed therapy for a prior malignancy, are disease free from 
      a prior malignancy for ≥ 5 yrs and are considered by their physician to be less  
than 30% risk of relapse. 
• Patients with active (untreated or relapsed) CNS metastasis of the patient’s 
myeloma. 
• Patients with a history of gastrointestinal surgery or other procedure that  
      might, in the opinion of the investigator(s), interfere with the absorption or           
swallowing of the study drugs. 
• Patients with any significant history of non-compliance to medical regimens or 
unwilling or unable to comply with the instructions given to them by the study 
staff. 
• Any other medical condition, including mental illness or substance abuse, 
deemed by the investigator(s) to likely interfere with the patient’s ability to sign 
informed consent, cooperate and participate in the study, or interfere with the 
interpretation of the results. 
 
 
 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
6 / 65 
 
Contents 
1 
BACKGROUND AND RATIONALE ....................................................... 9 
1.1 
Multiple Myeloma ................................................................................................. 9 
1.2 
NK cells and MM................................................................................................... 9 
1.3 
Lenalidomide (Revlimid) ....................................................................................... 9 
1.3.1 
Clinical Experience in Relapsed Multiple Myeloma ........................................................ 9 
1.4 
Nivolumab............................................................................................................ 11 
1.4.1 
Nivolumab: Clinical studies in Hematologic Malignancy .............................................. 11 
1.4.2 
Toxicity of Nivolumab in Hematologic Malignancies .................................................... 12 
1.4.3 
Nivolumab and lenalidomide in multiple myeloma ........................................................ 13 
1.5 
Study rationale ..................................................................................................... 13 
2 
STUDY OVERVIEW AND OBJECTIVE .............................................. 14 
2.1 
Study Overview ................................................................................................... 14 
2.2 
Primary Objective ................................................................................................ 14 
2.3 
Primary Endpoints ............................................................................................... 14 
2.4 
Secondary Endpoints ........................................................................................... 14 
2.5 
Safety Parameters................................................................................................. 15 
3 
ELIGIBILITY CRITERIA ....................................................................... 15 
3.1 
Inclusion Criteria ................................................................................................. 15 
3.2 
Exclusion Criteria ................................................................................................ 16 
3.3 
Inclusion of Women and Minorities .................................................................... 16 
4 
SUBJECT REGISTRATION PROCEDURES ....................................... 16 
5 
STUDY DESIGN AND DURATION ....................................................... 17 
5.1 
Study Design ........................................................................................................ 17 
5.2 
Definition of Dose Limiting Toxicity .................................................................. 18 
5.3 
Duration of Treatment.......................................................................................... 18 
5.3.1 
Early Stopping Rules ...................................................................................................... 19 
5.4 
Study Accrual....................................................................................................... 19 
5.5 
Duration of Study Period ..................................................................................... 19 
6 
TREATMENT PLAN AND PROCEDURES ......................................... 19 
6.1 
Premedication ...................................................................................................... 20 
6.2 
Route and Method of Administration .................................................................. 20 
6.3 
Nivolumab infusional monitoring ........................................................................ 21 
6.4 
Lenalidomide  (RevlimidTM) ................................................................................ 21 
6.4.1 
Lenalidomide Administration and Schedule ................................................................... 21 
6.4.2 
Lenalidomide dose levels ................................................................................................ 21 
6.5 
Dexamethasone .................................................................................................... 22 
6.5.1 
Table 6.5.1 Adverse events and Dose Adjustment of drugs ............................................ 22 
6.5.2 
Table 6.5.2. Dose modifications for nivolumab related immune toxicities and  
adverse reactions ............................................................................................................. 23 
6.6 
Supportive Care ................................................................................................... 36 
6.6.1 
Thromboprophylaxis ....................................................................................................... 37 
6.6.2 
Growth factors ................................................................................................................ 37 
6.7 
Requirements at the beginning of each cycle ...................................................... 37 
6.8 
Patient Withdrawal............................................................................................... 37 
6.9 
Schedule of Tests and Observations .................................................................... 39 
6.9.1 
Screening......................................................................................................................... 39 
6.9.2 
Evaluation during treatment ............................................................................................ 39 
6.9.3 
Post-treatment Follow-up ................................................................................................ 39 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
7 / 65 
 
6.9.4 
Sample collection for immunologic correlative studies .................................................. 39 
6.9.5 
Schedule for correlative studies ...................................................................................... 39 
6.9.6 
Study Calendar Schedule of Events ................................................................................ 40 
7 
STATISTICAL CONSIDERATIONS ..................................................... 42 
7.1 
Overview of study design .................................................................................... 42 
7.1.1 
Statistical Rationale......................................................................................................... 42 
7.2 
Safety Endpoints .................................................................................................. 43 
7.3 
Clinical outcome definitions ................................................................................ 43 
7.4 
Prior and concomitant treatment .......................................................................... 43 
7.5 
Prohibited treatments ........................................................................................... 44 
8 
Correlative studies- .................................................................................... 44 
8.1 
Instructions for subsites handling correlative samples ........................................ 44 
8.2 
Correlative laboratory investigations ................................................................... 44 
8.3 
T-cell specific correlative science ........................................................................ 44 
8.4 
NK-cell specific correlative science .................................................................... 45 
8.5 
CD14(+) monocyte specific, correlative science ................................................. 45 
9 
Investigational drugs.................................................................................. 45 
9.1 
Nivolumab............................................................................................................ 45 
9.2 
LENALIDOMIDE (Revlimid) ......................................................................... 46 
10 
PATIENT SAFETY ................................................................................... 47 
10.1 
Monitoring of Adverse Events ............................................................................. 47 
10.2 
Definitions of Adverse Events and Causality ...................................................... 47 
10.3 
Serious Adverse Events ....................................................................................... 49 
10.3.1 
Subsite/External Participating Site SAE Reporting Requirement. .................................. 49 
10.4 
Reporting of Adverse Event Information Following Study Completion ............. 50 
10.5 
Pregnancy Statement and Use in Nursing Women .............................................. 50 
10.6 
Data Safety Monitoring Plan ............................................................................... 51 
10.7 
Data Submission .................................................................................................. 52 
10.8 
Auditing ............................................................................................................... 52 
10.9 
Study Termination ............................................................................................... 52 
11 
REFERENCES ........................................................................................... 53 
12 
Appendix: ECOG/KPS Scale .................................................................... 56 
13 
Appendix. IMWG Response Criteria ....................................................... 57 
14 
Appendix. NYHA Cardiac Disease ........................................................... 59 
15 
Appendix.  FACT/GOG-Neurotoxicity .................................................... 60 
16 
Appendix.  Ethical and regulatory ........................................................... 61 
16.1 
Ethical Principles ................................................................................................. 61 
16.2 
Protocol Compliance and Protocol Revisions...................................................... 61 
16.3 
Informed consent, Data Safety and Monitoring ................................................... 61 
16.4 
Institutional Review Board (IRB) Approval ........................................................ 61 
16.5 
Additional Responsibilities of the Investigator .................................................... 62 
16.6 
Use and Completion of Case Report Forms (CRFs) ............................................ 62 
16.7 
Confidentiality ..................................................................................................... 62 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
8 / 65 
 
17 
Appendix.  REV-ASSIST GUIDELINES ................................................ 63 
18 
Appendix: Instructions for sample collection, storage and shipment .. 65 
 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
9 / 65 
 
1 
BACKGROUND AND RATIONALE  
 Multiple Myeloma 
Multiple myeloma (MM) is the second most common hematological malignancy with approximately 
22,000 new cases diagnosed each year in the United States. MM is associated with profound and 
widespread disarray of both the adaptive and innate arms of the immune system1 specifically 
including:  loss of effector T cell function2,3,  defective maturation and function of antigen presenting 
cells,4,5  increased levels of regulatory T cells (Treg),6  humoral immune deficiency, as well as natural 
killer (NK) cell immunity.7,8 .  This immunosuppressive milieu, in turn, is crucial to promoting disease 
progression as both T cell8 and NK cell9 mediated tumor-specific immune responses have been 
demonstrated in early MM; however, these effects are lost in the inexorable progression of the 
disease.9,10  Moreover, most standard treatment options (including chemotherapy, radiation, and high-
dose corticosteroids) offer only modest benefit, and  also contribute to further immune suppression.  
Due to both disease-related and treatment-related immune compromise, infection remains the most 
common cause of death for pts with MM.11  Until recently, little has been known regarding the 
mechanisms by which immune dysfunction and immunoevasion occur.    
 
 NK cells and MM  
NK cells CD56(+),CD3(-) are large granular lymphocytes that comprise a key cellular compartment of 
the innate immune system,  and have been shown to exert anti-tumor activity against the malignant 
plasma cell clone in MM12-14.  In fact, both lenalidomide and bortezomib have been shown to confer 
anti-MM efficacy, in part, through recovery or enhancement of the NK cell versus MM effect15,16.   
However, as the disease progresses, the NK cell versus MM effect is attenuated through a number of 
established mechanisms including reduced NK cell activity and increased levels of soluble interleukin-
2 receptors and impaired NK cell function by inhibitory effect of M-component6,7,17.  
 
 Lenalidomide (Revlimid) 
Lenalidomide (Revlimid®), a thalidomide analogue, is an immunomodulatory agent with antiangiogenic 
properties.  It’s mechanism of action remains to be fully characterized. Lenalidomide inhibited the 
secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory cytokines from 
peripheral blood mononuclear cells. Of cell lines tested, lenalidomide was effective in inhibiting growth 
of Namalwa cells (a human B cell lymphoma cell line with a deletion of one chromosome 5) but was 
much less effective in inhibiting growth of KG-1 cells (human myeloblastic cell line, also with a deletion 
of one chromosome 5) and other cell lines without chromosome 5 deletions.  Lenalidomide inhibited 
the expression of cyclooxygenase-2 (COX-2) but not COX-1 in vitro.  Lenalidomide) is indicated for the 
treatment of patients with transfusion-dependent anemia due to Low- or Intermediate-1-risk 
myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without 
additional cytogenetic abnormalities.  lenalidomide in combination with dexamethasone is indicated for 
the treatment of newly diagnosed multiple myeloma patients  and those who have received at least one 
prior therapy. 
   
1.3.1 Clinical Experience in Relapsed Multiple Myeloma 
 
A multicenter, open-label, randomized phase 2 study evaluated 2 doses of lenalidomide for relapsed, 
refractory multiple myeloma patients.   Seventy patients were randomized to receive oral lenalidomide 
either 30 mg once-daily or 15 mg twice-daily for 21 days of every 28-day cycle. Patients with 
progressive or stable disease after 2 cycles received dexamethasone.  Analysis showed an increased 
grade 3/4 myelosuppression in patients receiving 15 mg twice daily as compared to those receiving 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
10 / 65 
 
30mg daily (41% versus 13%, P= .03). Responses were evaluated according to European Group for 
Blood and Marrow Transplantation (EBMT) criteria. Overall response rate (complete, partial, or minor) 
to lenalidomide alone was 25% (24% for once daily and 29% for twice-daily lenalidomide). Median 
overall survival (OS) in the 30-mg once-daily and twice-daily groups was 28 and 27 months, 
respectively. Median progression free survival was 7.7 months on once-daily versus 3.9 months on 
twice-daily lenalidomide (P = 0.2). Dexamethasone was added in 68 patients and 29% responded. 
Time to first occurrence of clinically significant grade 3 / 4 myelosuppression was shorter in the twice 
daily group (1.8 vs 5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis 
each occurred in only 3%. Lenalidomide was active and well tolerated in relapsed, refractory 
myeloma, with the 30-mg once-daily regimen providing the basis for future studies as monotherapy 
and with dexamethasone18. 
 
In a safety and efficacy study of single agent lenalidomide in relapsed and refractory multiple 
myeloma patients, lenalidomide 30 mg (days 1-21 of 28 day cycle) was given to 222 patients who had 
relapsed or progressed after 1 or more prior therapies19.  Sixty-seven percent of patients had had 
three or more prior therapies, and 45% had had one or more autologous stem cell transplants.  Eighty 
and 43% of patients had had thalidomide and bortezomib based therapies respectively. The median 
dose of lenalidomide was 25 mg (5-30mg) and the median duration of treatment was 4.2 months 
(0.06-38). The overall response rate (complete and partial) was 26% with 2% complete response19.  
 
Two phase III trials comparing lenalidomide + dexamethasone to single agent dexamethasone in 
patients with relapsed and/or refractory multiple myeloma were published20,21.  Patients who had 
received 1-3 prior therapies, and progressing on their last therapy were randomized to receive 
lenalidomide, 25 mg daily on days 1-21, placebo  on days 22-28 plus dexamethasone, 40 mg, d 1-4, 
9-12, 17-20, every 28 day cycle,  or placebo daily for 28 days plus dexamethasone, 40 mg, d 1-4, 9-
12, 17-20, every 28 days.    The responses reported are summarized in Table 1-1 while the incidence 
of DVT and pulmonary embolism are summarized in Table 1-2.  Anemia, thrombocytopenia, 
neutropenia, fatigue, neuropathy, and constipation were also observed more often in lenalidomide + 
dexamethasone group compared to dexamethasone only group, however these events were 
generally manageable. 
 
Table 1-1.   
 
Response Rates in Phase III Trials of Relapse refractory MM  
Weber et al (NEJM 2007) 
Dimopoulos et al (NEJM 2007) 
 
Lenalidomide 
+
Dexa (n=177) 
Dexa Alone 
(n=176) 
P Value Lenalidomide + Dexa 
(n=176) 
Dexa Alone   
(n=175) 
P Value 
Overall 
Response 
Rate (%) 
108 (61) 
35 (20) 
<0.001 
106 (60.2) 
42 (24) 
<0.001 
Complete 
Response  
14.1% 
0.6% 
<0.001 
15.9% 
3.4% 
<0.001 
Median TTP (mo.) 
11.1 
4.7 
<0.001 
11.3 
4.7 
<0.001 
Median OS (mo.) 
29.6 
20.2 
<0.001 
Not Reached 
20.6 
0.03 
 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
11 / 65 
 
Table 1-2 
DVT & PE Risks in Phase III Trials of Relapse refractory MM  
Weber et al 
Dimopoulos et al 
Lenalidomide 
+ 
Dexamethasone 
Dexamethasone 
Alone 
Lenalidomide 
+ 
Dexamethasone 
Dexamethasone 
Alone 
Deep Vein Thrombosis (%) 
11.9 
3.4 
4.0 
3.5 
Pulmonary Embolism (%) 
3.4 
0.6 
4.4 
1.2 
 
The dexamethasone used in the above two studies is considered high dose. A phase III study 
compared lenalidomide plus high-dose dexamethasone (doses and schedule as described above) to 
lenalidomide (dose and regimen as above)  plus low-dose dexamethasone (40 mg given on days 1, 
8, 15, 22 of 28 day cycle) in newly diagnosed multiple myeloma patients.  Overall survival at 1 year 
was 96% for the low-dose dexamethasone compared to 87% for the high-dose dexamethasone 
(P=0.0002). As a result, the trial was stopped and patients on the high-dose therapy were crossed 
over to the low-dose therapy22. Subsequently most therapies involving dexamethasone, uses low-
dose. 
 
 Nivolumab 
Nivolumab (BMS-936558, ONO-4538, or MDX1106, trade name Opdivo; Bristol-Myers Squibb, 
Princeton, NJ, USA) is the first-in-human immunoglobulin G4 (IgG4) PD-1 immune checkpoint 
inhibitor antibody that disrupts the interaction of the, PD-1 receptor with its ligands PD-L1 and PD-L2, 
thereby inhibiting the cellular immune response 23-25. Nivolumab binds PD-1 with high affinity (KD=2.6 
nmol/L by Scatchard analysis to polyclonally activated human T cells), blocks its interactions with 
both PD-L1 and PD-L2, and stimulates memory response to tumor antigen-specific T cell 
proliferation26,27. Nivolumab has been approved by the US Food and Drug Administration (FDA) for 
the treatment of melanoma, renal cell carcinoma, squamous cell and metastatic non-small cell lung 
cancer28,29. 
 
1.4.1 Nivolumab: Clinical studies in Hematologic Malignancy 
 
A phase 1 study of patients with relapsed or refractory hematologic cancers were treated with 
nivolumab at a dose of 1 mg per kilogram of body weight, with escalation of the dose to 3 mg per 
kilogram30. Since the maximum tolerated dose was not reached, a dose of 3 mg per kilogram was 
chosen for the expansion cohorts that included the 23 HL patients. Patients with relapsed or 
refractory HL received nivolumab at a dose of 3 mg per kilogram at week 1, week 4, and then every 2 
weeks until disease progression or complete response or for a maximum of 2 years. Drug-related 
adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively 
(Table). No grade 4 or 5 drug-related adverse events were reported. Two patients (9%) had infusion 
interruptions that were due to grade 1 hypersensitivity reactions. An objective response was reported 
in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the 
remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 
86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included 
stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 
patients) 30. 
 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
12 / 65 
 
1.4.2 Toxicity of Nivolumab in Hematologic Malignancies 
 
Adverse Events of 23 Hodgkins Lymphoma Patients 
Adverse Events(AE) 
Any grade (%) 
Grade 3 (%) 
Any adverse event 
18(78) 
5(22) 
Rash 
5(22) 
0 
Decreased platelet 
4(17) 
0 
Fatigue 
3(13) 
0 
Pyrexia 
3(13) 
0 
Diarrhea 
3(13) 
0 
Nausea 
3(13) 
0 
Cough 
2(9) 
0 
Hypothyroidism 
2(9) 
0 
Decreased lymphocyte count 
2(9) 
1(4) 
hypophosphatemia 
2(9) 
0 
Hypercalcemia 
2(9) 
0 
Increased Lipase  level 
2(9) 
1(4) 
Stomatitis 
2(9) 
1(4) 
Drug-related SAE 
 
 
Myelodysplastic syndrome 
1(4) 
1(4) 
Lymph node pain 
1(4) 
0 
Pancreatitis 
1(4) 
1(4) 
 
 
A phase I open-label dose escalation evaluated 81 patients with non-hodgkins lymphoma (31), T-cell 
lymphomas (23) and multiple Myeloma (27) with relapsed or refractory disease31. Patients were 
treated with nivolumab 1 or 3 mg/kg administered as a 1-h infusion at weeks 1 and 4 and then every 
2 weeks for up to 2 years. Because the maximum tolerated dose of nivolumab was not reached at the 
highest protocol specified dose, patients in the cohort expansion were treated with nivolumab 
3 mg/kg. Seventy-nine (96%) patients experienced at least one AE. Drug-related AEs of any grade 
were reported in 53 (65%) patients (Table). Fifteen (18%) patients had grade 3 drug related 
AEs, two had grade 4 AEs, and one had a grade 5 AE. Three patients (4%) had hypersensitivity or 
infusion reaction). The majority of response was stable disease in 17(63%) patients and 1(4%) 
complete response31. 
 
Drug-Related Adverse Events 
Adverse Events(AE) 
Any grade (%) 
Grade ≥3 (%) 
By tumor type 
 
 
B-cell NHL(n=31)* 
22(71) 
8(26) 
T-Cell (n=23) 
17(74) 
5(22) 
Multiple Myeloma(n=27) 
14(52) 
5(19) 
 
 
 
Any adverse event in ≥5% 
 
 
Fatigue 
14(17) 
0 
pneumonitis 
9(11) 
3(4) 
Decreased appetite 
7(9) 
0 
Pruritus 
7(9) 
0 
Rash 
7(9) 
1(1) 
Diarrhea 
6(7) 
0 
Pyrexia 
6(7) 
0 
Hypocalcemia 
5(6) 
0 
Blood creatine phosphokinase 
increase 
3(4) 
1(1) 
Lipase increase 
3(4) 
1(1) 
Mucosal inflammation 
3(4) 
1(1) 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
13 / 65 
 
Stomatitis 
2(2) 
1(1) 
Diplopia 
1(1) 
1(1) 
Pneumonia 
1(1) 
1(1) 
Pulmonary embolism 
1(1) 
1(1) 
Rash pustular 
1(1) 
1(1) 
Sepsis 
1(1) 
1(1) 
ARDS^ 
1(1) 
1(1) 
Hematologic 
 
 
Anemia 
5(6) 
3(4) 
Leukopenia 
4(5) 
3(4) 
Lymphopenia 
3(4) 
1(1) 
Neutropenia 
3(4) 
1(1) 
Eosinophilia 
1(1) 
1(1) 
Lymphocyte decrease 
1(1) 
1(1) 
Select AEs 
 
 
Skin(pruritis, rash) 
15(18) 
1(1) 
Pulmonary(pneumonitis) 
9(11) 
3(4) 
Gastrointestinal(diarrhea, 
enteritis) 
6(7) 
0 
Hypersensitivity(hypersensitivity, 
infusion reaction) 
3(4) 
0 
Hepatic(ALT or AST increase) 
2(2) 
0 
Renal(blood creatinine increase) 
2(2) 
0 
*One grade 5 event was observed (pneumonitis/ARDS). 
^ Event was grade 5 
 
1.4.3 Nivolumab and lenalidomide in multiple myeloma 
 
Lenalidomide (Revlimid ®, Celgene) exerts efficacy in part through enhancement of the NK cell 
versus MM effect an effect likely mediated through T cell production of interleukin (IL)-2 in response 
to the drug15,32.   Numbers of both T cells and NK cells are increased in patients receiving IMID 
therapy33.   NK cell killing is also enhanced including antibody-dependent cellular cytotoxicity (ADCC) 
and natural NK cell cytotoxicity33,34. These events correlate with clinical responses to IMID therapy in 
patients33. Preclinical studies support the combination of PD-1/PD-L1 antibodies with 
immunomodulatory (IMID) agents such as lenalidomide35.  Nivolumab, as a single-agent, has 
established safety and tolerability in patients with previously treated myeloma with disease 
stabilization observed in many patients31. One abstract suggests that the efficacy of nivolumab may 
be enhanced in the clinical setting in combination with IMIDs36. The combination of lenalidomide with 
another antibody that interacts with PD-1 ( CT-011; MDV9300) in relapsed and refractory MM showed 
an ORR 61.5%37.  lenalidomide/dexamethasone with another PD-1 blocking antibody 
(pembrolizumab) demonstrated an ORR of 50% in relapsed/refractory myeloma38.   
 
 Study rationale 
Two phase III studies have shown improved overall response rate (ORR), time to progression (TTP) 
or progression free survival (PFS), and overall survival (OS) in relapsed MM patients treated with 
lenalidomide (25mg days 1-21 q 28 days) and high dose dexamethasone (40mg days 1-4, 9-12 and 
17-20) as compared to dexamethasone alone20,21.  Using low dose dexamethasone (40mg days 1, 8, 
15, 22) with lenalidomide showed superior OS as compared to high dose dexamethasone with 
lenalidomide mainly due to much reduced toxicity39. The response to the combination was shown 
even in patients with prior thalidomide use40, however, response is better if used earlier than later41.  
While lenalidomide as a single agent has also shown some response in relapse MM patients, short of 
a randomized study, its effectiveness seems to be less than the combination with dexamethasone19. 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
14 / 65 
 
While the ORR, median PFS and median OS for relapsed MM patients have improved with agents 
like lenalidomide many patients still relapse. Hence newer agents to augment current ones are 
urgently needed.  
 
Myeloma cells express PD-L1 and effector lymphocytes express PD-1 in myeloma.  Preclinical 
studies support the combination of PD-1/PD-L1 antibodies with immunomodulatory (IMID) agents 
such as lenalidomide35.  Nivolumab, as a single-agent, has established safety and tolerability in 
patients with previously treated MM with disease stabilization observed in many patients31. In addition 
to the studies outlined previously, studies of lenalidomide / dexamethasone with nivolumab are 
recruiting in high-risk smoldering myeloma (NCT02903381), in relapsed/refractory MM 
(NCT01592370, NCT02726581). Studies of nivolumab with pomalidomide/dexamethasone in relapse 
and refractory MM (NCT03023527), and lenalidomide and nivolumab in lymphoma (NCT03015896) 
and are in process 
 
We seek to determine the response in relapse/refractory multiple myeloma patients using nivolumab 
in combination with lenalidomide.  Because decreased NK cell activity and enhancement may be 
seen with steroids42 (although less so at low doses), patients will receive nivolumab plus lenalidomide 
with an option to add low-dose dexamethasone after 2 cycles if stable disease. 
 
 
2 
STUDY OVERVIEW AND OBJECTIVE 
 Study Overview 
This is phase II Sargent one-stage, three-outcome design with the primary endpoint of overall 
response rate after 4 cycles by the IMWG criteria.  Secondary endpoints include assessment of 
overall response rate after 8 and 12 cycles of therapy, progression-free survival, time to progression, 
immunomonitoring of lymphocyte subsets, including T and NK cell subsets, and ex vivo immune 
functional assays. Dexamethasone 40 mg orally weekly may be added if only stable disease after 2 
cycles. Dexamethasone can be reduced to 20 mg based on tolerability or if patient is 70 years or 
older. 
 
 Primary Objective 
To determine the efficacy of Nivolumab in combination with lenalidomide (Revlimid) in terms of overall 
response rate in patients with relapse/refractory multiple myeloma (MM)  
 
 Primary Endpoints 
To determine the overall response rate (ORR) after 4 cycles and then at 8 and 12 months in 
responding patients according to the International Myeloma Working Group (IMWG) response criteria 
in the phase II study 
 
 Secondary Endpoints 
• To determine time to progression (TTP) and progression free survival (PFS) 
• To determine overall survival (OS) 
• To assess Nivolumab correlative biologic studies to assess immunomonitoring of lymphocytes 
subsets including T and NK cell, and ex-vivo assessment of immune functional activities. 
 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
15 / 65 
 
 Safety Parameters 
Infusion related and treatment emergent toxicities per National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v4.0 
 
3 
ELIGIBILITY CRITERIA 
 Inclusion Criteria 
 
• Patients must be at least 18 years of age with evidence of progression, relapse or refractory 
disease from last line of therapy as defined by IMWG criteria.  A line of therapy is defined as one 
or more cycles of a planned treatment program which may be one therapy or a sequence of 
treatments.  A new line of therapy begins when a planned course of therapy is modified due to 
disease progression, relapse or toxicity or when a planned period of observation off therapy. 
Measurable disease as defined by any of the following: 
o Serum M-protein ≥0.5 g/dl (≥10 g/l) 
o Urine monoclonal protein ≥ 200 mg/24h 
o Involved FLC level ≥ 10mg/dl (≥ 100mg/l) and an abnormal serum free light chain ratio 
(<0.26, or >1.65) 
o Measurable biopsy proven plasmacytoma (should be measured within 28 days of initial 
investigational agent dosing) 
• Patients must have exhausted all available therapies known to provide clinical benefit and has 
progressed, relapsed or is refractory to last line of treatment. 
• Patients must have had at least 4 prior lines of therapy. 
• Patient may be enrolled at any time from last line of therapy. 
• Patients must have ANC > 1000/µL; Platelets ≥75,000/µL, if plasma cell percentage on bone 
marrow biopsy aspirate or core is > 30%, platelet eligibility requirement will be adjusted to 
60,000/ul.   
• Patients must have adequate hepatic function as evidenced by: total bilirubin < 1.5 mg/dL, 
alkaline phosphatase < 3X the ULN, AST/ALT < 2X the ULN 
• Patients must have adequate renal function as evidenced by serum creatinine < 2mg/dL or 
calculated creatinine clearance of ≥ 40ml/min within 14 days of registration using MDRD 
formula. 
• Patient must be able to swallow capsule or tablet. 
• Patients must provide informed consent.  
• Patients must have a left ventricular ejection fraction ≥ 30%, no uncontrolled arrhythmias or 
New York Heart Association class III-IV heart failure. 
• Patients must have a Karnofsky performance status > 70.  
• A negative pregnancy test will be required for all women of child bearing potential. Breast feeding 
is not permitted.  
• Fertility requirements 
o Female patients with child bearing potential must have a negative pregnancy test at least 7 
days before starting treatment drugs. 
o Male patients must agree to use an adequate method of contraception for the duration of the 
study and for 7 months afterwards. 
o Female patients must be either posy-menopausal, free from menses ≥2 yrs, surgically 
sterilized, willing to use two adequate barrier methods of contraception to prevent pregnancy, 
or agree to abstain from sexual activity starting from screening and for 5 months afterwards. 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
16 / 65 
 
o Female patients of child bearing potential must agree to comply with the fertility and pregnancy 
test requirements dictated by the Rev-Assist program.\ 
 
 Exclusion Criteria 
 
• Patients with peripheral neuropathy > CTCAE grade 2 
• Patients receiving concurrent corticosteroids at the time protocol therapy is initiated other than for 
physiologic maintenance treatment. 
• History of allergic reaction (including erythema nodosum) to lenalidomide 
• Concurrent use of complementary or alternative medicines that would confound the interpretation 
of toxicities and antitumor activity of the study drugs. 
• Patients with contraindication to thromboprophylaxis. 
• Unacceptable cardiac risk factors defined by any of the following criteria: Patients with congenital 
long QT syndrome, any history of ventricular fibrillation or torsade de pointes, bradycardia defined 
as HR< 50 bpm, Left ventricular ejection fraction < 30% 
• Patients who have received targeted or investigational agents within 2 weeks or within 5 half-lives 
of the agent and active metabolites (whichever is longer) and who have not recovered from side 
effects of those therapies. 
• Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug  
      or who have not recovered from the side-effects of surgery. 
• Patients with known positivity for human immunodeficiency virus (HIV), or hepatitis C.  Baseline 
testing for HIV and hepatitis C is not required 
• Patients with a history of another primary malignancy that is currently clinically significant or 
currently requires active intervention, other than non- melanoma skin cancer and carcinoma in situ 
of the cervix should not be enrolled. Patients are not considered to have a “currently active” 
malignancy if they have completed therapy for a prior malignancy, are disease free from 
      a prior malignancy for ≥ 5 yrs and are considered by their physician to be less than 30% risk of 
relapse. 
• Patients with active (untreated or relapsed) CNS metastasis of the patient’s myeloma. 
• Patients with a history of gastrointestinal surgery or other procedure that might, in the opinion of 
the investigator(s), interfere with the absorption or swallowing of the study drugs. 
• Patients with any significant history of non-compliance to medical regimens or unwilling or unable 
to comply with the instructions given to them by the study staff. 
• Any other medical condition, including mental illness or substance abuse, deemed by the 
investigator(s) to likely interfere with the patient’s ability to sign informed consent, cooperate and 
participate in the study, or interfere with the interpretation of the results. 
 
 Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for the study. 
 
4 
SUBJECT REGISTRATION PROCEDURES 
For subsite patients, sites must send the signed consent form, documentation of the consent process, 
and the Screening Form (refer to Supplemental Forms Document) within 2 business days of initial 
consent. 
 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
17 / 65 
 
Patients will be registered after meeting all entry requirements and signing of the informed consent 
document. 
 
OSU patients will be registered by the OSU research coordinator, as per CTO standard practice. 
Subsite patients will have eligibility verified and will be entered on study centrally at The Ohio State 
University by the Multi-Center Trial Program (MCTP). All subsites must email the MCTP to verify slot 
availabilities prior to consenting patients. Once a patient signs consent, the signed consent document 
and documentation of the consenting process must be faxed or securely emailed to the MCTP. The 
required forms, including Eligibility Criteria Checklist and Registration Form, can be found in the 
Supplemental Forms Document. 
 
To register a subsite patient, the following documents must be completed by the subsite research 
team and faxed or securely e-mailed to the MCTP: 
• Copy of all baseline tests required per the protocol calendar. Tests must be within the specified 
window. 
• Signed Patient Consent Form, if not previously sent 
• Signed Patient HIPAA Authorization Form (if separate), if not previously sent 
• Consent Documentation Note, if not previously sent 
• Completed & Signed Eligibility Checklist (refer to Supplemental Forms Document) 
• Registration Form (refer to Supplemental Forms Document) 
• Source documents verifying every inclusion & exclusion criteria 
 
Upon receipt of registration documents, the MCTP will send an email confirming receipt. If 
confirmation of receipt is not received within 1 hour of submission, please contact the MCTP by 
phone and/or pager to confirm receipt. 
 
Upon receipt of all required registration documents and upon verification the subsite patient meets all 
eligibility criteria, the MCTP will: 
• Assign the patient a study sequence ID, if not already provided at time of consent 
• Register the patient on the study 
• Fax and/or e-mail the subsite the completed Registration Form with the assigned study 
sequence ID and registration date as confirmation of patient registration 
 
Following registration, patients should begin protocol treatment within 3 business days.  Issues that 
would cause treatment delays should be discussed with the Principal Investigator and MCTP as soon 
as possible. If a patient does not receive protocol therapy following registration, the PI and MCTP 
must be notified immediately within 1 business day. 
 
Each participating institution will order study agents directly.  Agents may be ordered by a 
participating site only after the required regulatory documents, including the initial IRB approval for 
the site, have been forwarded to the MCTP and all other study-specific requirements have been met 
(as outlined during site activation). 
 
5 
STUDY DESIGN AND DURATION 
 Study Design 
This is a non-randomized open-label phase II study for patients with relapsed and refractory multiple 
myeloma. Given the established 3 mg/kg dose in hematologic malignancies, nivolumab will be given 
at a flat dose of 240 mg every 2 wks (Day 1 and 15) of a 28-day cycle. Lenalidomide will be given at 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
18 / 65 
 
starting dose of 25 mg days 1-21 of a 28 day cycle. Dexamethasone can be added after 2 cycles if 
stable disease. Patients will be assessed for response at the end of each cycle according to the 
IMWG response criteria.  
 
 Definition of Dose Limiting Toxicity  
Patients will be monitored for safety by assessing toxicities as graded by the 
NCI CTCAE v4.0. Dose limiting toxicity (DLT) will be defined as one or more of the following toxicities 
considered to be at least possibly related to one of the study drugs during Cycle 1 
• Grade 3 or greater nonhematologic toxicity with the exception of Grade 3 nausea, vomiting and 
diarrhea that responds to supportive therapy.  
• Grade 4 thrombocytopenia, or grade 3 thrombocytopenia with bleeding, or any requirement for 
platelets transfusion  
• Grade 4 neutropenia persisting for more than 5 days. 
• Grade 3 or greater febrile neutropenia (temperature ≥ 38.5 °C) 
• Grade 4 anemia, unexplained by underlying disease 
 
Patients that experience a lenalidomide-related hematologic DLT may continue on therapy if the 
event resolves, the investigator considers it in the best interest of the patient to continue and the 
patient qualifies for initiation of the next cycle with standard of care lenalidomide dose reduction.   
 
Discontinuation of treatment due to disease progression will not constitute a DLT.  
 
After 4 cycles of therapy or earlier if clinically indicated, response determination will be assessed by 
the IMWG criteria. At the end of Cycle 4, if a subject has responded (complete or partial response) or 
has stable disease, dosing with Nivolumab and lenalidomide will continue for a minimum of 8 
additional cycles or until withdrawal. 
 
If disease progression is observed at the end of Cycle 4 evaluation, all study therapy will be 
discontinued. Confirmation of progression of disease will be done according to the IMWG criteria. 
 
Following the 30-day post-treatment follow-up assessment, additional evaluations will occur once per 
month (unless subject discontinued due to progression) until the earliest of the following events: 
disease progression, the time of initiation of new therapy, death or study completion. 
 
Study completion is defined as 30 days after the last subject remaining on study medication 
discontinues study medication. 
 
An independent Data Monitoring Committee will continue oversight of this trial. 
 
Treatment will continue until Progression of disease, death, unacceptable toxicity or patient or treating 
physician decision to discontinue therapy. 
 
 Duration of Treatment 
Patient can continue study treatment at the treating physician’s discretion.  Patients achieving at least 
a stable disease can continue treatment until one of the following is reached: 
• Progression of disease  
• Death 
• Unacceptable toxicity 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
19 / 65 
 
• Patient decision  
• Treatment delay greater than 4 weeks.   
 
Overall response will be assessed after 4, 8, and 12 cycles. If disease progression is observed at the 
end of Cycle 4 evaluation, all study therapy will be discontinued. In addition, study therapy will be 
discontinued at the time of disease progression as noted above.  
 
For subjects who withdraw consent, there must be clear documentation of whether the subject 
withdraws consents to treatment only (i.e. agrees to follow-up) or withdraws consent to treatment and 
follow-up. 
 
Following the 30-day post-treatment follow-up assessment, additional evaluations will occur once per 
month (unless subject discontinued due to progression) until the earliest of the following events:  
• Disease progression,  
• The time of initiation of new therapy,  
• Death. 
 
5.3.1 Early Stopping Rules 
 
The study may be suspended or terminated prematurely with sufficient concern for excessive toxicity.  
Frequency, nature, and severity of adverse events will be reviewed by the PI and study team and 
compared to what is known about lenalidomide and nivolumab from other sources, including 
published literature, scientific meetings and discussion with Bristol Myers Squibb to determine if the 
trial should be terminated before completion. If n=3 subjects experience an infection of grade 3 and 
higher or an adverse event of grade 3 or greater which is determined to be immune-mediated,and 
possibly, probably or definitely related to nivolumab and/or lenalidomide, the study will be suspended 
to allow assessment of whether to  continue further enrollment or terminate the trial. If any subject 
dies while getting treatment, enrollment will be halted to determine relationship to study drugs. 
Enrollment will resume if determined not to be related to study drugs. If determined to be related to 
study drugs, the study will be suspended to allow assessment of whether to continue further 
enrollment or terminate the trial. If N=3 dies and determined to be related to study drugs, the study 
will be terminated. 
 
 Study Accrual  
Eighteen patients will be accrued. 
 
 Duration of Study Period 
The total study enrollment period is expected to be 12-18 months. 
 
6 
TREATMENT PLAN AND PROCEDURES 
Nivolumab will be administered intravenously as a 1-hour infusion, 240 mg every 2 weeks (day 1 and 
15) of each 28 day cycle. The Nivolumab infusion scheduling window is +/- 3 days.  Lenalidomide will 
be given at starting dose of 25 mg days 1-21 of a 28 day cycle.  Lenalidomide may be consumed at 
any time during a dosing day – there is no hourly window. 
 
Dexamethasone 40 mg orally weekly may be added if only stable disease after 2 cycles according to 
the IMWG response criteria (section 13-0). Dexamethasone can be reduced to 20 mg based on 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
20 / 65 
 
tolerability or if patient is 70 years or older. There is no required dosing order for all three 
medications. 
 
 Premedication 
All patients may receive pre-medication (Tylenol 650mg or Ibuprofen 800mg or related medication), 
and an antihistamine (diphenhydramine 25mg or equivalent) before Nivolumab infusion at the 
investigator’s discretion. In cases where patients cannot tolerate diphenhydramine hydrochloride, or 
cases where this medication is not available at the site’s pharmacy, an alternative would be to use 
one of the following as anti-histamine: promethazine at 25mg I.V. administered 20-50 minutes prior to 
nivolumab dose, chlorpheniramine administered at 10mg I.V 20-50 minutes prior to nivolumab dose, 
oral chlorpheniramine taken 2 hours prior to nivolumab dose or oral diphenhydramine taken 2 hours 
prior to nivolumab dose. Anti-histamines given I.V. should be administered as slow IV (NOT as 
“push”).  H2 blockers may be given in addition to H1 at the investigator’s discretion but cannot 
substitute for an H1 anti-histamine. Patients who develop severe infusion reaction requiring intubation 
will be taken off study. 
 
 Route and Method of Administration 
Nivolumab 240 mg will be administered intravenously. The Nivolumab infusion scheduiling window is 
+/- 3 days.  The drug is diluted into a 250mL saline bag and will be administered over one-hour every 
2 wks. (day 1 and 15) of a 28 day cycle. Nivolumab is to be administered using a peripheral line or a 
central device if such has been inserted.  
 
In the event that Grade 3 or higher infusion-related toxicity occurs during infusion, administration of 
nivolumab should be stopped immediately. Administration of nivolumab could be resumed only after 
the toxicity has resolved using the slowest rate of infusion (50mL/hr). Once the infusion is resumed, 
vital signs will be checked every 15 minutes for the first hour, then every 30 minutes till the end of the 
infusion and then one hour from end of infusion.  The window for vital sign collection will be per 
institutional standard of practice. 
 
The maximal administration rate is approximately 250 mg/hr. The total dose administered and the 
dosing rate will be documented in the patient’s medical records. 
 
To ensure complete delivery of nivolumab, the IV infusion line must be flushed with 0.9% sodium 
chloride. The following are three recommended methods for flushing the nivolumab IV infusion line: 
 
1) When the nivolumab infusion is complete, add an additional 50mL of 0.9% sodium chloride for 
injection to the nivolumab infusion bag. Continue the infusion until a volume equal to that of the 
volume contained in the tubing has been administered. 
2) Replace the empty nivolumab infusion bag with a 50mL bag of 0.9% sodium chloride for injection 
and infuse a volume equal to the volume contained in the tubing.  Please note: the flush is not 
included in the total recommended infusion times. 
3) When the nivolumab infusion is complete (IV bag is empty), hang a 50 mL bag of 0.9% sodium 
chloride for injection and attach it to the primary line port above the pump.  Flush the tubing with 
30 mL of 0.9% sodium chloride for injection at the same rate as the infusion. 
 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
21 / 65 
 
 Nivolumab infusional monitoring 
The potential risks that may be related to the administration of monoclonal antibodies in general, 
adverse events that were possibly related to nivolumab administration in the Phase 1 study, and a 
few theoretical risks for nivolumab included infusion-related effects.   
 
Vital signs (temperature, blood pressure, pulse rate, respiratory rate) and ECG will be closely 
monitored prior to, during, and after first drug infusion to avoid general infusion-related toxicity. In the 
event that severe allergic or hypersensitivity develop, first-line treatment is epinephrine given 
intramuscularly (0.2 to maximum 0.5 mL aqueous epinephrine 1:1000). Subsequent management of 
hypersensitivity reactions should follow the institution’s protocol. Other known infusion related effects 
are milder and typically include chills, fever, throat irritation and nausea, which are treated 
symptomatically. Patients who develop severe infusion reaction requiring intubation will be taken off 
study. 
 
 Lenalidomide  (RevlimidTM) 
 
6.4.1 Lenalidomide Administration and Schedule 
Lenalidomide will be given orally. The starting dose is 25 mg days 1-21 of a 28 day cycle. 
If a dose is missed or vomited up, the dose will not be made up.  Lenalidomide doses may be consumed at any 
time during a dosing day without being considered ‘delayed’ or ‘missed.’ 
 
In the event of a dose hold due to toxicity, the patient’s treatment will be considered delayed and not 
missed.    
 
Beginning on day 1 of cycle #2 and on day 1 of every cycle thereafter, while all conditions below have 
been met, patients will be evaluated for lenalidomide dose reduction.  
For patients that: 
• Never had a lenalidomide dose reduction due to a toxicity that was probable or definitely 
related to lenalidomide.   
• Maintained platelet count ≥50,000 at all times in the previous cycle 
• Minimum ANC ≥1,000 at all times in the previous cycle 
• No clinically significant grade 2 or greater non-hematologic toxicities in the previous cycle 
 
If all conditions are met, no dose reduction will occur. If any of the above conditions is not met, the 
patient’s dose for lenalidomide will be reduced by 5 mg. 
 
Per lenalidomide prescribing information, the starting dose of lenalidomide for patients enrolled with 
creatinine clearance (Clcr) < 50 mL/min will be 10mg days 1-21 of a 28 day cycle. 
 
Dose reductions are not permanent.  Lenalidomide may be increased again per treating physician 
discretion.  In the event a patient is dose reduced to 0mg, patient may continue on study, and may 
still receive Nivolumab as scheduled. 
 
6.4.2 Lenalidomide dose levels 
Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after 
the previous dose(s).  Toxicities are to be assessed according to the NCI Common Terminology Criteria 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
22 / 65 
 
for Adverse Events (CTCAE), Version 4.0.  Dose modifications or delays will be done based on the 
toxicity experienced during a cycle of therapy or newly encountered on day one of a cycle. 
 
 Dexamethasone 
Dexamethasone 40 mg orally weekly (days 1,8,15, 22) may be added if only stable disease after 2 
cycles according to the IMWG response criteria (section 13-0). Dexamethasone can be reduced to 20 
mg based on tolerability or if patient is 70 years or older. 
 
6.5.1 Table 6.5.1 Adverse events and Dose Adjustment of drugs 
 
Neutropenia 
Grade 3 or greater on day 1 of cycle: delay and monitor CBC weekly; 
if resolves to ≤ grade 2 within 4 weeks, resume lenalidomide with 5mg 
dose reduction.  If grade 3 or greater during a cycle, hold lenalidomide 
for the remainder of the cycle. Resume with 5mg dose reduction for 
subsequent cycles.  G-CSF or GM-CSF are not to be used to avoid 
dose reductions but can be used for treatment of febrile neutropenia 
 
Febrile Neutropenia 
Hold lenalidomide for the remainder of the cycle. Consider G-CSF 
administration until there is adequate count recovery ANC≥1000/µL + 
absence of fever.  If neutropenia resolves ≤ grade 2, resume 
lenalidomide at 5 mg dose reduction for subsequent cycles. 
 
Thrombocytopenia 
If grade 3 or greater, hold lenalidomide for the remainder of the cycle 
and until platelets ≥ 50,000/µL. Then resume lenalidomide at 5 mg 
dose reduction for subsequent cycles. 
 
Anemia 
For grade 3 or greater, hold lenalidomide for the remainder of the cycle 
and until hemoglobin recovers to ≤ grade 2. 
 
Fatigue (asthenia, 
malaise) 
Lenalidomide or 
dexamethasone 
 
For intolerable grade 2 or grade 3-4, hold the protocol therapy thought 
to be probable or definitely related to the reaction until resolves to ≤ 
grade 1, then resume protocol therapy with dose reduction of 
implicated protocol therapy by one dose level (5 mg for lenalidomide 
and/or 50% for dexamethasone). 
Rash 
Lenalidomide  
If grade 3 or greater, hold lenalidomide until resolves to ≤ grade 2, then 
resume protocol therapy. In the instance of intolerable recurrent rash, 
stop implicated drug but may continue on study. 
 
 
Renal insufficiency 
For patients with calculated or measured GFR <30ml/min, 
lenalidomide should be held until creatinine returns to baseline.  If the 
calculated or measured GFR falls under 50 ml/min, the dose of 
lenalidomide will be reduced to 10mg if the patient began therapy with 
25mg dosage. 
 
Venous 
Thromboembolism 
 
All protocol should be held until the patient is adequately anti-
coagulated. Patients with recurrent thrombosis despite adequate anti-
coagulation should be removed from protocol therapy. 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
23 / 65 
 
Suspected Pregnancy 
Protocol therapy should be held until pregnancy is ruled out. 
Discontinue all protocol therapy if pregnancy is positive 
 
Dyspepsia, gastric or 
duodenal ulcer, gastritis 
Grade 1-2 (requiring 
medical management) 
Treat with H2 blockers, sucralfate, or omeprazole. If symptoms persist 
despite above measures, decrease dexamethasone dose by 1 dose 
level 
> Grade 3 (requiring 
hospitalization or 
surgery) 
 
Hold dexamethasone until symptoms adequately controlled. Restart 
and decrease one dose level of current dose along with concurrent 
therapy with H2 blockers, sucralfate, or omeprazole. If symptoms 
persist despite above measures, discontinue dexamethasone and do 
not resume. 
Acute pancreatitis 
Discontinue dexamethasone and do not resume 
 
Edema > Grade 3 
(limiting function and 
unresponsive to therapy 
or anasarca) 
Diuretics as needed, and decrease dexamethasone dose by 1 dose 
level; if edema persists despite above measures, decrease dose 
another dose level. Discontinue dexamethasone and do not resume if 
symptoms persist despite second reduction. 
Confusion or mood 
alteration > Grade 2 
(interfering with function 
+/- interfering with 
activities of daily living) 
Hold dexamethasone until symptoms resolve. Restart with one dose 
level reduction. If symptoms persist despite above measures, 
permanently discontinue dexamethasone. 
Muscle weakness > 
Grade 2 (symptomatic 
and 
interfering with function 
+/- 
interfering with activities 
of daily living) 
Decrease dexamethasone dose by one dose level. If weakness 
persists despite above measures decrease dose by one dose level 
Discontinue dexamethasone and do not resume if symptoms persist. 
Hyperglycemia > Grade 
3 or higher 
Treatment with insulin or oral hypoglycemics as needed. If uncontrolled 
despite above measures, decrease dose by one dose level until levels 
are satisfactory 
 
6.5.2 Table 6.5.2. Dose modifications for nivolumab related immune toxicities and adverse 
reactions 
 
AE 
Grade 
of 
Event 
(CTCAE 
v4.03) 
Dose modifications 
Toxicity management 
Overall 
management 
for immune-
related AE 
 
Drug administration modifications 
of Nivolumab will be made to 
manage potential immune-related 
AEs based on severity of 
treatment-emergent toxicities 
graded per NCI CTCAE v4.03. 
It is recommended that 
management of AEs follow the 
guidelines presented in this table: 
• Subjects should be thoroughly 
evaluated to rule out any 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
24 / 65 
 
In addition to the criteria for 
permanent discontinuation of 
Nivolumab based on CTC 
grade/severity, permanently 
discontinue Nivolumab for the 
following: 
• Recurrence of a previously 
experienced Grade 3 
treatment-related AE following 
resumption of dosing 
alternative etiology (e.g. 
disease progression, 
concomitant medications, 
infections, etc) 
• In the absence of a clear 
alternative etiology, all events 
should be considered 
potentially immune related 
• Symptomatic and topical 
therapy should be considered 
for any low grade events 
(Grade 1 or 2, unless otherwise 
specified) 
• For persistent (greater than 3-5 
days) low grade (Grade 2) or 
severe (Grade > 3) events 
promptly start prednisone PO 1-
2 mg/kg/day or IV equivalent 
• If symptoms recur or worsen 
during corticosteroid tapering 
(28 days), increase the 
corticosteroid dose (e.g. up to 
2-4 mg/kg/day or IV equivalent) 
until stabilization or 
improvement of symptoms, 
then resume corticosteroid 
tapering at a slower rate (> 28 
days of taper) 
• More potent 
immunosuppressives such as 
TNF inhibitors should be 
considered for events not 
responding to systemic steroids 
• Discontinuation of Nivolumab is 
not mandated for Grade 3/4 
inflammatory reactions 
attributed to local tumor 
response (e.g. inflammatory 
reaction at sides of 
plasmacytomas). Continuation 
of study drug in this situation 
should be based upon a 
benefit/risk analysis for that 
subject 
Grade 1 No dose modification 
Grade 2 
Hold Nivolumab dose until grade 2 
resolution to grade 1 
• If toxicity worsens then treat as 
Grade 3 or Grade 4 
• If toxicity improves to baseline 
then resume treatment as seen 
best by treating physician 
• 
Nivolumab can be resumed 
once event stabilizes to grade 
1 and 5-7 days have passed 
after completion of steroid 
taper. 
Subjects with endocrinopathies 
who may require prolonged or 
continued steroid replacement can 
be retreated with Nivolumab on the 
following conditions: 1) the event 
stabilizes and is controlled, 2) the 
subject is clinically stable as per 
investigator or treating physician’s 
clinical judgement, and 3) doses of 
prednisone are at less than or 
equal to 10 mg/day or equivalent 
Grade 3 
Depending on the individual 
toxicity, may permanently 
discontinue Nivolumab 
Grade 4 Permanently discontinue 
Nivolumab 
Note: For Grade 3 and above asymptomatic 
amylase or lipase levels hold Nivolumab and 
if complete work-up shows no evidence of 
pancreatitis, may continue or resume 
Nivolumab 
Pneumonitis / 
ILD 
Any 
Grade 
 
• Monitor subjects for signs and 
symptoms of pneumonitis or 
ILD (new onset or worsening 
shortness of breath or cough). 
Subjects should be evaluated 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
25 / 65 
 
with imaging and/or pulmonary 
functions tests as indicated by 
treating physician. Initial work-
up may include clinical 
evaluation, monitoring of 
oxygenation via pulse oximetry 
(resting and exertion), 
laboratory work-up and high-
resolution CT scan 
Grade 1  
No dose modification required. 
However, holding Nivolumab 
dosing as clinically appropriate 
and during diagnostic work-up for 
other etiologies 
For radiographic changes only: 
• Monitor and closely follow up in 
2-4 days for clinical symptoms, 
pulse oximetry (resting and 
exertion) and laboratory work-
up and then as clinically 
indicated 
• Consider pulmonary and 
infectious disease consult 
Grade 2  
• Hold Nivolumab until G2 
resolution to < G1 
• If toxicity worsens then treat as 
G3 or G4 
• If toxicity improves to baseline 
then the decision to reinitiate 
Nivolumab will be based on 
physician discretion 
• 
Nivolumab can be resumed once 
event stabilizes to grade 1 and 
5-7 days have passed after 
completion of steroid taper. 
 
For Grade 2 (mild to moderate new 
symptoms): 
• Monitor symptoms daily and 
consider hospitalization 
• Promptly start systemic steroids 
(e.g. prednisone 1- 2 mg/kg/day 
or IV equivalent) 
• Reimaging as clinically 
indicated 
• If no improvement within 3-5 
days, additional workup should 
be considered and prompt 
treatment with IV 
methylprednisone 2-4 
mg/kg/day started 
• If still no improvement within 3-
5 days despite IV 
methylprednisone, promptly 
start immunosuppressive 
therapy such as TNF inhibitors. 
• Once improving, gradually 
taper steroids over > 4 weeks 
and consider prophylactic 
antibiotics, antifungal, or anti-
PCP treatment 
• Consider pulmonary and 
infectious disease consult 
• Consider as necessary 
discussing with study physician 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
26 / 65 
 
Grade 3 
Grade 4 
Permanently discontinue 
Nivolumab 
For Grade 3 or 4 (severe or new 
symptoms, new/worsening 
hypoxia, life threatening): 
• Promptly initiate empiric IV 
methylprednisolone 1 – 4 
mg/kg/day or equivalent 
• Obtain pulmonary and 
infectious disease consult 
• Hospitalize the patient 
• Supportive care including 
oxygen 
• If no improvement within 3-5 
days, additional workup should 
be considered and prompt 
treatment with additional 
immunosuppressive therapy 
such as TNF inhibitors 
• Once improving, gradually 
taper steroids over > 4 weeks 
and consider prophylactic 
antibiotics, antifungal, or anti-
PCP treatment 
Diarrhea / 
enterocolitis 
Any 
grade 
 
• Monitor for symptoms that may 
be related to 
diarrhea/enterocolitis 
(abdominal pain, cramping, or 
changes in bowel habits such 
as increased frequency over 
baseline or blood in stool) or 
related to bowel perforation 
(such as sepsis, peritoneal 
signs, and ileus) 
• Subjects should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g. 
disease progression, other 
medications, infections 
including testing for clostridium 
difficile toxin, etc) 
• Steroids should be considered 
in the absence of clear 
alternative etiology, even for 
low grade events, in order to 
prevent potential progression to 
higher grade event 
• Use analgesics carefully; they 
can mask symptoms of 
perforation and peritonitis 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
27 / 65 
 
Grade 1 
diarrhea No dose modification 
For grade 1 diarrhea: 
• Close monitoring for worsening 
symptoms 
• Consider symptomatic 
treatment including hydration, 
electrolyte replacement, dietary 
changes, and loperamide 
Grade 2 
diarrhea 
• Hold Nivolumab until resolution 
to < Grade 1 
• If toxicity worsens then treat as 
Grade 3 or 4 
• If toxicity improves to baseline 
then treat at next scheduled 
treatment date 
• 
Nivolumab can be resumed 
once event stabilizes to grade 
1 and 5-7 days have passed 
after completion of steroid 
taper. 
 
For Grade 2 diarrhea: 
• Consider symptomatic 
treatment including hydration, 
electrolyte replacement, dietary 
changes, and loperamide 
and/or budesonide 
• Promptly start prednisone 1 – 2 
mg/kg/day or IV equivalent 
• If event not responsive within 3-
5 days or worsens despite 
prednisone at 1-2 mg/kg/day or 
IV equivalent, GI consults 
should be obtained for 
consideration of further workup 
such as imaging and/or 
colonscopy to confirm colitis 
and rule out perforation, and 
prompt treatment IV 
methylprednisolone 2-4 
mg/kg/day started 
• If still no improvement within 3-
5 days despite 2-4 mg/kg 
methylprednisolone, promptly 
start immunosuppressives such 
as a TNF inhibitor 
• Consult study physician if no 
resolution to < Grade 1 in 3-4 
days 
• Once improving, gradually 
taper steroids over > 28 days 
and consider prophylactic 
antibiotics, antifungals, and 
anti-PCP treatment 
Grade 3 
or 4 
diarrhea 
Permanently discontinue 
Nivolumab 
For Grade 3 or 4 diarrhea: 
• Promptly initiate empiric IV 
methylprednisolone 1 – 4 
mg/kg/day or equivalent 
• Monitor stool frequency and 
volume and maintain hydration 
• Urgent GI consult and imaging 
and/or colonoscopy as 
appropriate 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
28 / 65 
 
• If still no improvement within 3-
5 days of IV 
methylprednisolone 2-4 
mg/kg/day or equivalent, 
promptly start further 
immunosuppressives 
• Once improving, gradually 
taper steroids over > 28 days 
and consider prophylactic 
antibiotics, antifungals, and 
anti-PCP treatment 
Hepatitis 
(elevated 
LFTs) 
Any 
Grade  
 
• Monitor and evaluate liver 
function test: AST, ALT, ALP, 
and total bilirubin 
• Evaluate for alternative 
etiologies (e.g. viral hepatitis, 
disease progression, 
concomitant medications) 
Grade 1 No dose modification, if it worsens, 
treat as Grade 2 event 
For Grade 1 AST or ALT and/or 
total bilirubin elevation 
• Continue LFT monitoring per 
protocol 
Grade 2 
Hold Nivolumab until Grade 2 
resolution to < Grade 1 
• If toxicity worsens then treat as 
Grade 3 or 4 
• If improves to baseline then 
treat at next scheduled 
treatment date 
• 
Nivolumab can be resumed 
once event stabilizes to grade 
1 and 5-7 days have passed 
after completion of steroid 
taper. 
 
For Grade 2 AST or ALT and/or 
total bilirubin elevation 
• Regular and frequent checking 
of LFTs (every 1-2 days) until 
elevations of these are 
improving or resolved 
• If no resolution to < grade 1 in 
1-2 days, discuss with study 
physician 
• If event is persistent (> 3-5 
days) or worsens, promptly 
start prednisone 1-2 mg/kg/day 
or IV equivalent 
• If still no improvement within 3-
5 days despite 1-2 mg/kg/day 
of prednisone or equivalent, 
consider additional workup and 
prompt treatment with IV 
methylprednisolone 2-4 
mg/kg/day started 
• If still no improvement within 3-
5 days despite 2-4 mg/kg/day 
methylprednisolone, promptly 
start other 
immunosuppressives 
(mycophenolate mofetil) 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
29 / 65 
 
• Once improving, gradually 
taper steroids over > 28 days 
and consider prophylactic 
antibiotics, antifungals, and 
anti-PCP treatment 
Grade 3 
For elevations in transaminases < 
8 x ULN, or elevations in bilirubin < 
5 x ULN: 
• Hold Nivolumab until resolution 
to < grade 1 or baseline 
• Resume Nivolumab if 
elevations downgrade to < 
grade 1 or baseline within 14 
days 
• For elevations in 
transaminases > 8 x ULN or 
elevations in bilirubin > 5 x 
ULN, discontinue Nivolumab 
 
For Grade 3 or 4 AST or ALT 
and/or total bilirubin elevation: 
• Promptly initiate empiric IV 
methylprednisolone at 1-4 
mg/kg/day or equivalent 
• If still no improvement within 3-
5 days despite 1-4 mg/kg/day 
methylprednisolone IV or 
equivalent promptly start 
immunosuppressive treatment 
(mycophenolate mofetil) 
• Hepatology consult, abdominal 
workup, and imaging as 
appropriate 
• Once improving, gradually 
taper steroids over > 28 days 
and consider prophylactic 
antibiotics, antifungals, and 
anti-PCP treatment 
Grade 4 Permanently discontinue 
Nivolumab 
Nephritis / 
renal 
dysfunction 
Any 
grade 
 
• Consult with nephrologist 
• Monitor for signs and 
symptoms that may be related 
to changes in renal function 
(e.g. UA, elevated BUN and Cr, 
decreased CrCl, electrolyte 
imbalance, decrease in urine 
output, proteinuria, etc) 
• Subjects should be thoroughly 
evaluated to rule out any 
alternative etiology (i.e. disease 
progression, infections, etc) 
• Steroids should be considered 
in the absence of clear 
alternative etiology even for low 
grade events (Grade 2), in 
order to prevent potential 
progression to higher grade 
event 
Grade 1 No dose modification 
For Grade 1 elevated creatinine: 
• Monitor serum creatinine 
weekly and any accompanying 
symptom 
• If creatinine returns to 
baseline, resume its regular 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
30 / 65 
 
monitoring per study 
protocol 
• If it worsens, depending on 
the severity, treat as Grade 
2 or Grade 3/4 
• Consider symptomatic 
treatment including hydration, 
electrolyte replacement, 
diuretics, etc. 
Grade 2  
Hold Nivolumab until resolution to 
< Grade 1 
• If toxicity worsens then treat as 
Grade ¾ 
• If toxicity improves to baseline 
then resume treatment 
•  Nivolumab can be resumed 
once event stabilizes to grade 
1 and 5-7 days have passed 
after completion of steroid 
taper. 
 
For Grade 2 elevated creatinine: 
• Consider symptomatic 
treatment including hydration, 
electrolyte replacement, 
diuretics, etc. 
• Carefully monitor serum 
creatinine every 2-3 days and 
as clinically warranted 
• Consult nephrologist and 
consider renal biopsy if 
clinically indicated 
• If event is persistent (> 3-5 
days) or worsens, promptly 
start prednisone 1-2 mg/kg/day 
or IV equivalent 
• If event if not response within 3-
5 days or worsens despite 
prednisone at 1-2 mg/kg/day or 
IV equivalent, additional workup 
should be considered and 
prompt treatment with IV 
methylprednisolone at 2-4 
mg/kg/day started. 
• Once improving, gradually 
taper steroids over > 28 days 
and consider prophylactic 
antibiotics, antifungals, and 
anti-PCP treatment 
• When event returns to baseline, 
resume Nivolumab and routine 
serum creatinine monitoring per 
study protocol 
Grade 3 
or 4 
Permanently discontinue 
Nivolumab 
• Carefully monitor serum 
creatinine on a daily basis 
• Consult nephrologist and 
consider renal biopsy if 
clinically indicated 
• Promptly start prednisone 1-2 
mg/kg/day or IV equivalent 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
31 / 65 
 
• If event if not response within 3-
5 days or worsens despite 
prednisone at 1-2 mg/kg/day or 
IV equivalent, additional workup 
should be considered and 
prompt treatment with IV 
methylprednisolone at 2-4 
mg/kg/day started. 
• Once improving, gradually 
taper steroids over > 28 days 
and consider prophylactic 
antibiotics, antifungals, and 
anti-PCP treatment 
Rash 
Any 
Grade 
 
• Monitor for signs and 
symptoms of dermatitis (rash 
and pruritis) 
• If there is any bullous 
formation, the study physician 
should be contacted and 
Nivolumab discontinued 
Grade 1 No dose modification 
For Grade 1: 
• Consider symptomatic 
treatment including oral 
antipruritics (e.g. 
diphenhydramine or 
hydroxyzine) and topical 
therapy (e.g. urea cream) 
Grade 2 
For persistent (> 1-2 weeks) 
Grade 2 events, hold Nivolumab 
until resolution to < Grade 1 or 
baseline 
• If toxicity worsens then treat as 
Grade 3 
• If toxicity improves then 
resume Nivolumab treatment. 
• 
Nivolumab can be resumed 
once event stabilizes to grade 
1 and 5-7 days have passed 
after completion of steroid 
taper. 
 
For Grade 2: 
• Obtain dermatology consult 
• Consider symptomatic 
treatment including oral 
antipruritics (e.g. 
diphenhydramine or 
hydroxyzine) and topical 
therapy (e.g. urea cream) 
• Consider moderate strength 
topical steroid 
• If no improvement of rash/skin 
lesions occurs within 3-5 days) 
or is worsening despite 
symptomatic treatment and/or 
use of moderate strength 
topical steroid, discuss with 
study physician and promptly 
start systemic steroids with 
prednisone 1-2 mg/kg/day or IV 
equivalent 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
32 / 65 
 
• Consider skin biopsy if 
persistent for > 1-2 weeks or 
recurs 
Grade 3 
• Hold Nivolumab until resolution 
to < Grade 1 or baseline 
• If temporarily holding 
Nivolumab does not provide 
improvement of the Grade 3 
skin rash to Grade 1 or 
baseline within 30 days, then 
permanently discontinue 
Nivolumab 
For Grade 3 or 4: 
• Consult dermatology 
• Promptly initiate empiric IV 
methylprednisolone 1-4 
mg/kg/day 
• Consider hospitalization 
• Monitor extent of rash (Rule of 
Nines) 
• Consider skin biopsy 
(preferably > 1) as clinically 
feasible 
• Once improving, gradually 
taper steroids over > 28 days 
and consider prophylactic 
antibiotics, antifungals, and 
anti-PCP treatment 
• Discuss with study physician 
Grade 4 Permanently discontinue 
Nivolumab 
Endocrinopathy 
Any 
Grade 
 
• Consult endocrinologist 
• Monitor subjects for signs and 
symptoms of endocrinopathies. 
Non-specific symptoms include 
headache, fatigue, behaviour 
changes, changes mental 
status, vertigo, abdominal pain, 
unusual bowel habits, 
hypotension, and weakness 
• Subjects should be thoroughly 
evaluated to rule out any 
alternative etiology (e.g. 
disease progression including 
CNS involvement and 
infections) 
• Monitor and evaluate thyroid 
function tests: TSH, free T3 and 
T4, and other relevant 
endocrine labs depending on 
the suspected endocrinopathy 
• If a subject experiences an AE 
that is thought to be possibly of 
autoimmune nature (e.g. 
thyroiditis, pancreatitis, 
hypophysitis, diabetes 
insipidus), the investigator 
should send a blood sample for 
appropriate autoimmune 
antibody testing 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
33 / 65 
 
Grade 1 No dose modification 
For Grade 1 (including those with 
asymptomatic TSH elevation): 
• Monitor subject with 
appropriate endocrine function 
tests 
• If TSH < 0.5x LLN, or TSH > 2X 
ULN or consistently out of 
range in 2 subsequent 
measurements, include FT4 at 
subsequent cycles as clinically 
indicated and consider 
endocrinology consult 
Grade 2 
For Grade 2 endocrinopathy other 
than hypothyroidism, hold 
Nivolumab dose until subject is 
clinically stable 
• If toxicity worsens then treat as 
Grade 3 or 4 
If toxicity improves to baseline 
then resume  treatment  
Nivolumab can be resumed once 
event stabilizes to grade 1 and 5-7 
days have passed after 
completion of steroid taper. 
. 
Subjects with endocrinopathies 
who may require prolonged or 
continued steroid replacement can 
be retreated with Nivolumab on 
the following conditions: 1) the 
event stabilizes and is controlled, 
2) the subject is clinically stable as 
per Investigator or treating 
physician’s clinical judgement, and 
3) doses of prednisone are at less 
than or equal to 10 mg/day or 
equivalent 
For Grade 2 (including those with 
symptomatic endocrinopathy): 
• Isolated hypothyroidism may be 
treated with replacement 
therapy without treatment 
interruption and without 
corticosteroids 
• Initiate hormone replacement 
as needed for management 
• Evaluate endocrine function, 
and as clinically indicated, 
consider pituitary scan 
• For subjects with abnormal 
endocrine workup, except for 
those with isolated 
hypothyroidism, consider short-
term, corticosteroids (e.g. 1-2 
mg/kg/day methylprednisolone 
or IV equivalent) and prompt 
initiation of treatment with 
relevant hormone replacement 
(e.g. levothyroxine, 
hydrocortisone, or sex 
hormones) 
• Once improving, gradually 
taper steroid over > 28 days 
and consider prophylactic 
antibiotics, antifungals, and anti 
PCP treatment 
• For subjects with normal 
endocrine workup (lab or MRI 
scans), repeat labs/MRI as 
clinically indicated 
Grade 3 
or 4 
• For Grade 3 or 4 
endocrinopathy other than 
hypothyroidism, hold 
Nivolumab until 
For Grade 3 or 4: 
• Consult endocrinologist 
• Isolated hypothyroidism may be 
treated with replacement 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
34 / 65 
 
endocrinopathy symptom(s) 
are controlled 
• Resume Nivolumab if 
controlled  
• 
Nivolumab can be resumed 
once event stabilizes to grade 
1 and 5-7 days have passed 
after completion of steroid 
taper. 
 
therapy without treatment 
interruption and without 
corticosteroids 
• Promptly initiate empiric IV 
methylprednisolone 1-2 
mg/kg/day or equivalent 
• Administer hormone 
replacement therapy as 
necessary 
• For adrenal crisis, severe 
dehydration, hypotension, or 
shock: immediately initiate IV 
corticosteroids with 
mineralcorticoid activity 
• Once improving, gradually 
taper immunsuppressive 
steroids over > 4 weeks and 
consider prophylactic 
antibiotics, antifungals, and 
anti-PCP treatment 
• Discuss with study physician 
Immune-
mediated 
neurotoxicity 
Any 
Grade 
 
• Subjects should be evaluated 
to rule out any alternative 
etiology (e.g. disease 
progression, infections, 
metabolic syndrome, and 
medications, etc) 
• Monitor subject for general 
symptoms (headache, nausea, 
vertigo, behavior change, or 
weakness) 
• Consider appropriate 
diagnostic testing (e.g. 
electromyogram and nerve 
conduction investigations) 
• Symptomatic treatment with 
neurological consult as 
appropriate 
Grade 1 No dose modifications 
See “Any Grade” 
recommendations 
Grade 2 
• For acute motor neuropathies 
or neurotoxicity, hold 
Nivolumab until resolution to < 
grade 1 
• For sensory 
neuropathy/neuropathic pain, 
consider holding Nivolumab 
until resolution to < grade 1 
• Discuss with the study 
physician 
• Obtain a neurology consult 
• Sensory 
neuropathy/neuropathic pain 
may be managed by 
appropriate medications 
(gabapentin, duloxetine, etc) 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
35 / 65 
 
• If toxicity worsens then 
treat as Grade 3 or 4 
• If toxicity improves to 
baseline then resume 
treatment 
• 
Nivolumab can be resumed 
once event stabilizes to 
grade 1 and 5-7 days have 
passed after completion of 
steroid taper. 
•  
• Promptly start systemic 
steroids prednisone 1-2 
mg/kg/day or IV equivalent 
• In no improvement within 3-5 
days despite 1-2 mg/kg/day 
prednisone or IV equivalent 
consider additional workup and 
promptly treat with additional 
immunosuppressive therapy 
(e.g. IVIG) 
Grade 3 
• Hold Nivolumab until resolution 
to < grade 1 
• Permanently discontinue 
Nivolumab if Grade 3 irAE 
does not resolve to < grade 1 
within 30 days 
For Grade 3 or 4: 
• Discuss with study physician 
• Obtain neurology consult 
• Consider hospitalization 
• Promptly initiate empiric IV 
methylprednisolone 1-2 
mg/kg/day or equivalent 
• If no improvement within 3-5 
days despite IV corticosteroids, 
consider additional workup and 
promptly treat with additional 
immunosuppressants (e.g. 
IVIG) 
• Once stable, gradually taper 
steroids > 4 weeks 
Grade 4 
• Permanently discontinue 
Nivolumab 
Infusion-related 
reactions 
Any 
Grade 
 
• Management per institutional 
standard at the discretion of the 
investigator 
• Monitor subjects for signs and 
symptoms of infusion-related 
reactions (e.g. fever and/or 
shaking chills, flushing and/or 
itching, alterations in heart rate 
and blood pressure, dyspnea or 
chest discomfort, skin rashes, 
etc) and anaphylaxis (e.g. 
generalized urticarial, 
angioedema, wheezing, 
hypotension, tachycardia, etc) 
Grade 1 
The infusion rate of Nivolumab 
may be decreased by 50% or 
temporarily interrupted until 
resolution of the event 
For Grade 1 or 2: 
• Acetaminophen and/or 
antihistamines may be 
administered per institutional 
standard at the discretion of the 
investigator 
• Consider premedication per 
institutional standard prior to 
subsequent doses 
Grade 2 
The infusion rate of Nivolumab 
may be decreased 50% or 
temporarily interrupted until 
resolution of the event. 
Subsequent infusions may be 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
36 / 65 
 
given at 50% of the initial infusion 
rate 
Grade 3 
or 4 
The administration of Nivolumab 
should be stopped immediately. 
Administration of Nivolumab could 
be resumed only after the toxicity 
has resolved using the slowest 
rate of infusion (50mL/hr). Once 
the infusion is resumed, vital signs 
will be checked every 15 minutes 
for the first hour, then every 30 
minutes till the end of the infusion, 
and then one hour from end of 
infusion.  The window for vital sign 
collection will be per institutional 
standard of care. 
For Grade 3 or 4: 
• Manage severe infusion-related 
reactions per institutional 
standards including IV 
glucocorticoid, IV 
diphenhydramine, and IM 
epinephrine for 
bronchospasm/edema. 
Non-immune 
mediated 
reactions 
Any 
grade 
Note: dose modifications are not 
required for adverse events not 
deemed to be related to study 
treatment (ie. events due to 
underlying disease) or for 
laboratory abnormalities not 
deemed to be clinically significant 
Treat according to institutional 
standard 
Grade 1 No dose adjustment 
Grade 2 
Hold study drug/study regimen 
until resolution to Grade < 1 or 
baseline 
Grade 3 
Hold study drug/regimen until 
resolution to Grade < 1 or baseline 
 
For AEs that downgrade to Grade 
< 2 within 7 days or resolve to 
Grade < 1 or baseline within 14 
days, resume study drug/study 
regimen  
Grade 4 
Discontinue study drug/study 
regimen (Note for Grade 4 labs, 
decision to discontinue would be 
based on accompanying clinical 
signs/symptoms and as per 
Investigator’s clinical judgement 
and in consultation with sponsor) 
 
 Supportive Care 
Patients will receive full supportive care while on this study. This includes blood product support, 
antibiotic treatment and treatment of other newly diagnosed or concurrent medical conditions. All blood 
products and concomitant medications such as anti-diarrheal, analgesics, anti-emetics received from 
the first administration of study drugs until 30 days after the final dose are to be recorded in the medical 
record. 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
37 / 65 
 
All patients may receive prophylaxis with either an H-2 blocker or proton pump inhibitor while on study 
medications if needed or if dexamethasone is added. Suggested medications included ranitidine 150 
mg oral twice daily or omeprazole 20 mg oral daily or equivalent. 
 
Patients may receive bisphosphonates at physician’s discretion. 
 
Patients may receive local radiation for pain control. 
 
6.6.1  Thromboprophylaxis 
 
 Lenalidomide increases the risk of thrombotic events in patients who are at high risk or with a history 
of thrombosis, in particular when combined with other drugs known to cause thrombosis. When 
lenalidomide is combined with other agents such as steroids (e.g. dexamethasone, prednisone), 
anthracyclines (doxil, adriamycin) and erythropoietin, the risk of thrombosis is increased. 
It is required that patients receive 81-325 mg of aspirin (enteric-coated is preferred) as 
thromboprophylaxis, equivalent or more intensive anticoagulation strategies with low molecular weight 
heparins or full-dose warfarin are permitted.   
 
 
 
6.6.2 Growth factors 
Prophylactic use of growth factors is not recommended. 
 
 Requirements at the beginning of each cycle 
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
• The ANC is ≥ 1,000/μL; 
• The platelet count is ≥ 50,000/μL; 
• Any lenalidomide-related allergic reaction/hypersensitivity or sinus bradycardia/ other cardiac 
arrhythmia adverse event that may have occurred has resolved to ≤ grade 1 severity; 
• Any other lenalidomide-related adverse event that may have occurred has resolved to ≤ grade 
2 severity. 
 
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated weekly and a 
new cycle of therapy will not be initiated until the toxicity has resolved as described above.  Patients 
unable to initiate a new cycle of therapy within 4 weeks due to treatment related toxicity will be 
removed from study. 
 
• If lenalidomide dosing was held during the previous cycle and was restarted with a one-level dose 
reduction without requiring an interruption for the remainder of the cycle, then that reduced dose 
level will be initiated on Day 1 of the new cycle.  
• If lenalidomide dosing was omitted for the remainder of the previous cycle or if the new cycle is 
delayed due to lenalidomide related toxicity newly encountered on the scheduled Day 1, then the 
new cycle will be started with a one-level dose reduction of lenalidomide. 
 
 Patient Withdrawal 
A patient should be removed from the study whenever it is necessary to safeguard his/her welfare. 
Occurrence of a significant adverse event or laboratory abnormalities unexpected for these patients 
may also necessitate discontinuation from the study.   Additional reasons for removing a patient from 
the study are: 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
38 / 65 
 
 
• Patients who participate in another investigational drug trial. 
• The occurrence of unacceptable toxicity indicating the need for cessation of treatment.  
Patients may continue with correlative studies. 
• Patient has progressive disease while receiving treatment. 
• The physician feels it is in the best interest of the patient to stop treatment and the physician 
may determine whether to continue with correlative studies. 
• Patients who express a desire to withdraw from the study (the patient has the right to withdraw 
for any reason without prejudice). 
• Non-compliance by the patient with protocol requirements. 
• Patient is lost to follow-up.  If a patient does not return for scheduled visits, every effort should 
be made to re-establish contact.  In any circumstance, every effort should be made to 
document patient outcome, if possible. 
• Patient becomes pregnant. 
• Any other reasons deemed by the principal investigator and treating physician. 
• Termination of the study. 
 
The reason for any patient withdrawal from the study should be recorded on the case report form 
(CRF) and the occurrence should be reported to the OSU principal investigator by email. These 
patients who withdraw from the study in the phase II portion of the trial will not be replaced. When a 
patient is removed from the study, he/she will receive treatment according to the standard of care 
(SOC) in the medical center and will be followed-up according to the study schedule whenever 
possible.  
 
The investigator should complete all end of treatment procedures when a patient withdraws from 
treatment.  A patient who is removed from the study by the investigator due to an adverse event (AE) 
or serious adverse event (SAE) will be followed until resolution of the toxicity to Grade 1 or baseline.  
All the tests that are required to assess the patient condition will be made as frequent as necessary 
until the AE or SAE has been resolved. Samples that have already been obtained will be processed. 
 
A patient who withdraws consent before starting the study will not be followed.  
 
A patient who is removed from the study by the investigator since he/she did not keep the 
appointments will be hard to follow given the circumstances. The extreme situation of this occurrence 
is a patient who is defined as “lost to follow-up”. Attempts to follow up on the subject will be made as 
long as the consent has not been withdrawn by the subject. Samples that have already been obtained 
will be processed. 
 
A patient who initiated another treatment not allowed in the protocol is to be removed from the study 
by the investigator. Follow up will be only for safety per above. Attempts to continue the follow up of 
the patient by monthly phone calls or other means will be made to collect information on the patient's 
survival. Samples that have already been obtained will be processed. 
 
For patients who withdraw consent, there must be clear documentation of whether the subject 
withdraws consents to treatment only (i.e. agrees to follow-up) or withdraws consent to treatment and 
follow-up. 
 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
39 / 65 
 
 Schedule of Tests and Observations  
6.9.1 Screening  
 
All screening tests must be performed within 4 weeks prior to starting protocol-based therapy with the 
exception of obtaining informed consent, which should be conducted within the timeframe outlined in 
local policy (if applicable).  
 
6.9.2 Evaluation during treatment  
 
Clinical examination, ECOG/WHO PS, vital signs, toxicity assessment and documentation of 
concomitant medications will be performed at each outpatient visit. Toxicity will be assessed 
according to the NCI CTCAE  
 
6.9.3 Post-treatment Follow-up  
 
After the end of study treatment (whatever the reason for discontinuation), the patient will be followed 
for at least 30 days, during which time all procedures for the reporting of SAEs will be followed.  
All patients who discontinue the trial secondary to an adverse event thought to be related to protocol 
therapy (probably, possible, or definite) should be followed until resolution, stabilization, return to a 
baseline condition, or death.   Overall and progression free survival will be determined through clinic 
visits or phone interviews with clinical research staff. 
 
6.9.4 Sample collection for immunologic correlative studies 
 
All patients enrolled on this trial will have samples procured for all proposed laboratory correlative 
studies as summarized below.  With each cycle, approximately 30-mL of blood will be collected and 
sent to Don Benson’s lab for processing. Upon receipt, each sample will be recorded and coded with 
a unique sample number to keep patient identification confidential. PBMCs and plasma (and/or 
serum) will be aliquoted and cryopreserved. The vials of viably frozen cells for all time points for each 
patient will be thawed at the same time whenever possible to avoid inter-experimental variability.   
 
6.9.5 Schedule for correlative studies 
 
Laboratory correlative studies will be obtained at screening, days 1 and 15 of the cycles and off study.  
Off-study correlates should be obtained at the time the patient is removed from protocol for any 
reason. In addition, continued T-cell correlate will be done at 1, 3, and 6 months after removal from 
study.  Specimens obtained include BM aspirate (10-15 ml in green-top tubes using heparinized 
syringe) and peripheral blood (Three-10 ml green top tubes, 2 for cells and 1 for plasma).  
 
 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
40 / 65 
 
6.9.6 Study Calendar Schedule of Events  
 
Investigations 
Screening 
C1D1a 
C1D15a 
C2D1a 
C2D15 a 
CxD1a 
CxD15a 
C12D1a 
Off studyb 
History, physical 
examination, concomitant 
medication review 
X 
X 
 
X 
 
X 
 
X 
X 
Informed written consent 
X 
 
 
 
 
 
 
 
 
Confirmation of disease 
relapse and prior 
treatment 
X 
 
 
 
 
 
 
 
 
Skeletal survey (CT or 
MRI as clinically 
indicated)c 
X 
 
 
 
 
 
 
 
X 
MUGA or ECHO 
X 
 
 
 
 
 
 
 
 
β-hCGd 
X 
 
 
 
 
 
 
 
 
Toxicity evaluation 
X 
X 
 
X 
 
X 
X 
 
X 
CBC / differential / 
plateletse 
X 
X 
X 
X 
X 
X 
Xf 
 
Xf 
PTT, INR, TSHe 
X 
 
 
 
 
 
 
 
 
BMP, glucose, 
magnesiume 
X 
X 
 
X 
 
X 
X 
 
 
LFTs 
X 
X 
 
X 
 
X 
X 
 
 
Beta 2 microglobuling 
X 
 
 
 
 
 
 
 
X 
12-lead ECGh 
X 
 
 
 
 
 
 
 
 
Serum monoclonal 
protein assessmentsi 
X 
Xi 
 
Xi 
 
Xi 
 
 
Xi 
24hr urine for creatinine 
clearance 
X 
 
 
 
 
 
 
 
 
24hr urine monoclonal 
protein and 
immunofixationj 
X 
Xj 
 
Xj 
 
Xj 
X 
 
Xj 
BM biopsy, unilateralk    
X 
 
 
 
 
 
Xk 
 
Xk  
nivolumab Given 
 
X 
X 
X 
X 
X 
X 
X 
 


OSU-17160 Protocol Amd 3 – 19 Dec 2017 
41 / 65 
 
Prescribe lenalidomide 
via RevAssistl 
X 
 
 
 
 
     
 
 
 
Dexamethasonem 
X 
 
 
 
 
 
 
 
 
 Pregnancy testn 
X 
 
 
 
 
 
 
 
 
Correlative studies, 
periphereal bloodo 
 
Xo 
X 
X 
X 
X 
X 
X 
X 
Correlative studies, bone 
marrow aspirateq 
X 
 
 
 
 
Xq 
 
 
X 
Monitoring p 
X 
 
 
 
 
 
 
 
 
a. Time points in the preceding table have a +/- 4 day window to accommodate weekends, holidays, and for patient convenience. 
b. Off study correlates will be done. In addition, continued T-cell correlate will be done at 1,3,and 6 months after removal from study  
c. Skeletal survey will be done at baseline and may be done at evidence of progression of disease.  CT scan will be done to document size of plasmacytoma if 
this is the only measurable disease. 
d. Female patients of childbearing potential (FCBP, defined in section 8.5) must have a negative pregnancy test (β-hCG) as required by the RevAssist 
program.        
e. CBC d/p will be monitored biweekly in cycles 1 to 4, then monthly thereafter. Chemistry tests, including electrolytes, glucose and serum creatinine, should 
be performed every 2 weeks during the first 2 months of therapy and once a month thereafter.  Serum electrolyte monitoring should include potassium, 
magnesium and calcium. PTT, INR and TSH will be checked every 2 months. 
f. Starting C5D1, CBC will be done monthly on D1 of each cycle. 
g. Beta 2 microglobulin will be done after every 2 cycles and at evidence of progression of disease. 
h. Baseline and periodic ECGs should be performed during treatment as indicated in the flow chart.  In patients who have ECG abnormalities, ECGs should 
be performed more routinely as clinically indicated.  ECGs post-baseline should be performed as indicated 
i. 
Myeloma monoclonal protein assessments (Serum protein electrophoresis & immunofixation, immunoglobulin levels, serum free light chain assay) will be 
performed on day 1 of each cycle as well as off study.   
j. 
24hr urine monoclonal protein assessment (Urine protein electrophoresis & immunofixation) will be performed at screening and as required for response 
assessment. 
k. Unilateral bone marrow (BM) biopsy will be done at baseline and at end of 4th cycle  and evidence of progression for patients with non-secretory multiple 
myeloma 
l. 
Lenalidomide must be prescribed through and in compliance with Celgene’s RevAssist® program.  Prescriptions must be filled within 7 days.  Any unused 
lenalidomide should be returned to the patient for disposition in accordance with the RevAssist® program.   
m. Dexamethasone will be started on cycle 3 only if stable disease after 2 cycles. 
n. Lenalidomide and dexamethasone will start on day 1 of each cycle.  Patients will do not need to be in clinic to initiate this as all patients would have been 
exposed to both. Lenalidomide will be ordered for the next cycle. A pregnancy test (urine or B-HCG) will also be ordered at this time and must be negative 
prior to starting treatment. 
o. Laboratory correlative studies will be obtained. This will be collected through C5D1, at the off study visit, and at 1, 3, and 6 months post off-study.  Off-
study correlates should be obtained at the time the patient is removed from protocol for any reason.  
p. Vital signs (temperature, blood pressure, pulse rate, respiratory rate) and ECG will be closely monitored prior to, during, and after first drug infusion to 
avoid general infusion-related reactions. Routine vital signs with subsequent infusions, unless indicated otherwise. 
q. Correlative studies for the bone marrow aspirate will be done at screening, cycle 5 day 1, and at the off study visit.


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
42 / 65 
 
7 
STATISTICAL CONSIDERATIONS 
 Overview of study design 
This is a phase 2 trial to explore the combination of lenalidomide (without dexamethasone) and 
nivolumab in relapsed/refractory MM. We hypothesize that the direct anti-myeloma effect of 
lenalidomide in conjunction with the potential, combinatorial effect on favorable immune modulation 
with lenalidomide and nivolumab without deleterious effects of corticosteroid administration may 
improve outcomes. 
 
7.1.1 Statistical Rationale 
The purpose of the clinical trial per se is to reject the combination of lenalidomide and nivolumab from 
further clinical development if the therapy is insufficiently active.  The trial is designed as a Sargent 
one-stage, three-outcome design43  with the following assumptions: the inactivity cut off of the 
combination is 26% (the previously published, single-agent, objective response rate of lenalidomide in 
relapsed MM) and the activity cut off is 60% (the previously published, objective response rate of 
lenalidomide in combination with dexamethasone in the setting of relapsed MM).  The type 1 (alpha) 
and type 2 (beta) error rates are both set to 5%, the probability of correctly rejecting an ineffective 
treatment is set to 80%.  Under these assumptions, the three-outcome design specifies treatment of 
n=18 pts in this phase II trial.  If n=7 or fewer show response to treatment, the combination will be 
declared ineffective.  If n=10 or more pts show objective response, the treatment will be declared 
effective.  If n=8 or 9 pts show response, the trial will be deemed inconclusive and additional pts may 
be enrolled.   
 
The proportion of responses (partial and complete) will be calculated out of all eligible patients who 
receive any treatment in that disease group who are included in the phase II assessment. Assuming 
the number of responses is binomially distributed, 95% binomial confidence intervals will also be 
calculated for the estimate of the proportion of responses. All adverse events will be summarized by 
the NCI CTCAE v. 4 criteria, and tabulated across all patients who received any treatment with a focus 
on severe (grade 3+) adverse events and toxicities (i.e. those deemed at least possibly related to study 
treatment). In addition, we will summarize the proportion of patients who received dexamethasone after 
being stable disease but without response after 2 cycles of therapy. We will descriptively summarize 
how many of these patients were converted to response after the addition of dexamethasone. Since 
the addition of dexamethasone is part of the overall treatment regimen that is dependent on treatment 
outcome at a certain time point, we will not make other adjustments to the study design to evaluate 
these patients separately outside of this descriptive summarization of whether or not they received the 
dexamethasone. We will evaluate other clinical outcomes such as progression-free survival and overall 
survival using the methods of Kaplan-Meier, although these analyses will be exploratory and primarily 
to help describe the cohort itself.  
 
Correlative analyses will also be done, including analysis of markers of the immunogenicity of 
nivolumab. In particular, we will evaluate biological and cellular markers in patients treated with 
nivolumab, measure PD-L1 expression on MM cells, percentage increase in NK cell activity, migration, 
immune complex formation, and cytotoxicity. Other markers such as plasma cell IHC baseline 
expression to characterize immunologic markers of MM cells that are responsive to nivolumab such as 
TNF-alpha, IFN-gamma, CD4, CD8, and granzyme B will be evaluated in addition to markers of MM 
cells responsive to lenalidomide (Sparc, IRF-4). Changes in these markers before and after therapy will 
be explored using graphical analyses as well as summarized quantitatively. We will also explore how 
changes in these correlative markers may differ based on whether or not the patient achieved a 
response or not; to accomplish this, we will utilize different plotting characters and colors for successes 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
43 / 65 
vs. not in the graphical analyses to help identify potential patterns, and summarize the changes 
quantitatively between successes vs. not. Given the total sample size available, we expect that these 
analyses will be exploratory at best, but will provide important insights into mechanisms of action and 
vital preliminary data for future studies and hypothesis generation. 
 
 Safety Endpoints 
We will describe the safety profile of treatment by the recording of adverse events experienced by 
patients in the trial and by the monitoring of clinical laboratory values.  The safety analysis will be 
performed on the safety population, as defined below.  Adverse events will be described using the 
NCI CTCAE V 4.0 criteria.   
 
Laboratory assessments will also be described according to the NCI CTCAE criteria, with separate 
descriptions for grade 3 or 4 laboratory abnormalities.  Clinically significant laboratory abnormalities 
will be described as well. 
 
 Clinical outcome definitions 
Time to progression: TTP will be defined as the time from start of treatment until the date he or she 
has progression or dies. Any subject who has received study treatment but has neither progressed 
nor died will be censored on the date of his or her last tumor assessment. A subject who has not 
received study treatment and who has neither progressed nor died will be censored on the day he or 
she was enrolled. 
  
Progression Free Survival: PFS will be defined as the time from study entry until disease 
progression or death at trial closure for the per protocol population.  Patients who withdraw from the 
trial prior to disease progression and who are either lost to follow-up, die or who begin alternative 
treatments prior to progression, will have their data censored as of the date considered to be lost to 
follow-up, date of death, or the first day of alternative therapy. 
 
Time to Response: A subject’s time to response is defined as the time from first dose of study 
therapy until measurement criteria are first met for [VG]PR or CR or SD (whichever status is recorded 
first). Time to response is computed only for subjects whose best response is [VG] PR or CR. 
 
Duration of Overall Response: The duration of overall response will be computed for subjects 
whose best response is either [VG] PR or CR or SD. It will be measured from the time measurement 
criteria are first met for complete response or partial response (whichever status is recorded first) until 
the first date of progressive disease or death. Subjects who neither progress nor die will be censored 
on the date of their last tumor assessment. 
 
Overall Survival: A subject’s survival time will be defined as the time from start of treatment to the 
date of his or her death. If the subject has not died, survival will be censored on last date the subject 
was known to be alive. 
 
Response Rate: The tumor response rate will be defined as the total number of subjects whose best 
response is PR or VGPR or CR or SD, divided by the number of per protocol patients. 
 
 Prior and concomitant treatment  
The type (brand name and active ingredient) and duration of administration of all medications taken at 
the time of the inclusion or during the study will be recorded on the Case Report Form (CRF). 
Dosage, route of administration, and indication will also be specified. 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
44 / 65 
 
 Prohibited treatments 
The use of concomitant chemotherapy, radiotherapy, biological therapy (including cytokines, however 
erythropoietin is allowed), and steroid therapy (inhaled, oral or topical steroids for treating mild to 
moderate asthma, allergies or ocular inflammations, typically at ≤500ug/day of fluticasone or 
equivalent are allowed), is prohibited as long as the patient is on the study and must have been 
stopped at least 2 weeks prior to first dose administration. Radiation for palliation of pain is 
acceptable. Participation in any clinical study involving any medications or treatments, whether 
approved or investigational, is prohibited. 
 
8 
Correlative studies- 
To assess nivolumab correlative biologic studies to assess immunomonitoring of lymphocytes 
subsets including T and NK cells and ex-vivo assessment of immune functional activities.  If possible, 
similar studies will be conducted on the bone marrow aspirates as well.  
 
 Instructions for subsites handling correlative samples 
 
Subsites are requested to procure correlative samples at specified time points.  Peripheral blood 
mononuclear cells (PBMC) and bone marrow samples are to be ficolled and cryopreserved in 
freezing media aliquots with subject number and cycle/day of collection marked.  These may be 
batched shipped quarterly, Monday - Thursday.  The address to which to send samples is: 
 
Benson Laboratory 
898 Biomedical Research Tower 
460 W 12th Ave Columbus OH 43210 
 
 Correlative laboratory investigations 
We will conduct extensive immunomonitoring of T and NK cell subsets at baseline and upon 
completion of each 28-d cycle of therapy.  We will focus our analyses principally on the absolute 
and relative percentage of CD8(+) T cells and CD4(+) T cell subsets including:  
CD4(+)C45RO(+)CD62L(-)CCR7(-) effector/memory T cells, CD4(+)CD62L(-)CD127(+) peripheral 
memory T cells, and CD4(+)CD25brightFOXP3(+),CD127low/absent regulatory T cells.  We will study 
Th1/Th2/Th17 polarization in T cells (by expression of CD3, CD4, CD193, CD293, CXCR3, CCR4, 
and CD45).   
 
 T-cell specific correlative science 
Immunologic assessments will be performed prior to each cycle of therapy, and at 1, 3, and 6 months 
following the last cycle of therapy.  At each time point, PBMC will be isolated from peripheral blood by 
ficoll density centrifugation and cryopreserved.  Following completion of the study, PBMC will be thawed 
and 1 x 106 PBMC will be cultured with lysate generated by freeze thaw cycle of 1 x105 unselected MM 
cells.  As a control, PBMC will be cultured with tetanus toxoid (10 ug/ml) or media alone.  Following 5 
days of coculture, expression of IFN-γ by CD4(+) and CD8(+) populations will be determined by 
intracellular FACS analysis.  Cells will be restimulated with tumor lysate for 6 h and cultured overnight 
with 1 ug/ml GolgiStop. The cells will be stained with CD4 or CD8 antibodies conjugated to FITC and 
permeabilized with Cytofix/Cytoperm plusTM.  Cells will be stained with PE-conjugated anti-human 
IFN-γ, fixed in 2% paraformaldehyde and analyzed by flow cytometry.  The effect of therapy on levels 
of circulating tumor reactive T cells will be determined by quantifying IFN- γ expressing CD4(+) and 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
45 / 65 
CD8(+) T cells.  The impact of nivolumab and Len on tumor reactive T cells will be determined by 
comparing the pre-treatment levels with the peak level observed following therapy.  The cytolytic 
capacity of tumor reactive lymphocytes will be determined by measuring expression of granzyme B and 
perforin in CD8(+) T cells following ex vivo exposure to autologous tumor lysate. The presence of naïve, 
memory effector, and central memory cells in the tumor reactive population will be determined by 
multichannel FACS analysis. The percentage of activated effector cells will be elucidated by quantifying 
the percentage of CD4(+)CD25(+) CD69(+) cells.  Tregs will be quantified by assessing expression of 
FOXP3 for the CD4(+)CD25(+)CD127low/absent population.  When cell yields allow, we will assess the 
capacity of T cells to lyse autologous tumor cells in a standard chromium release assay.   We will also 
examine the effect of nivolumab and Len on immunologic responses against previously identified tumor 
antigens. XBP-1, OFD-1, SOX2, MUC1, and CD138 have been identified as MM associated antigens.  
In HLA-A2.1 patients, we will quantify the number of CD8(+) T cells binding tetramer constructed from 
these antigens (as cell yields allow) at serial time points in the circulation.  The persistence of 
tetramer(+) cells in the circulation will be determined.  Functional characteristics of the tetramer positive 
population will be determined by measuring IFN-γ, granzyme B, IL-4, and IL-10 expression in the 
tetramer(+) cells by intracellular FACS staining.   
 
 NK-cell specific correlative science 
We will quantitate CD56bright and CD56dim NK cell subsets in PBMC and other markers of NK cell 
maturity (proportion of NK cells expressing CD16 and CD117) and developing intermediates in 
peripheral blood.  We will also perform immunophenotyping of NK cell subsets for expression of 
trafficking antigens (in particular CXCR4 which we have shown to be modulated by nivolumab on NK 
cells) and markers of activation (CD158, CD69) and degranulation (LAMP-1, LAMP-3, CD107a, 
CD107b, CD159, and CD314) which may be influenced by nivolumab and Len.  Notably, our group has 
optimized an “immunome” flow cytometry-based profiling technique to allow these characterizations 
from a very modest amount of pt PBMC to minimize volume of blood collected for correlative science 
studies.  Finally, we will perform ex vivo functional assays against MM cell line targets and purified, 
autologous MM tumor samples obtained at baseline and after each cycle of therapy including trafficking, 
immune complex and cytotoxicity assays as described by our group previously.44  We will also attempt 
to verify our preclinical finding regarding down modulation of PD-L1 on MM tumor cells by Len by 
comparing PD-L1 expression on pt MM tumor cells at baseline and after one cycle of therapy.  We will 
purify CD138 (+) MM cells from bone marrow aspirates of pts obtained at baseline and after 4 cycles 
of treatment and assess PD-L1 expression by flow cytometry.   
 
 CD14(+) monocyte specific, correlative science 
We will evaluate the expression of PD-L1 and PD-L2 on CD14 (+) monocytes at baseline and after 
treatment with nivolumab after each cycle of therapy.  We will specifically study the induction of these 
antigens on CD14 (+) cells as a consequence of nivolumab administration.  We will attempt to correlate 
the expression PD-L1 on CD14 (+) cells with clinical activity determined by response rate and 
progression-free survival if allowable by sample size power.  Otherwise, we will limit these analyses to 
hypothesis-generating, descriptive evaluation.   
 
9 
Investigational drugs  
 Nivolumab 
Nivolumab (humanized monoclonal antibody) for parenteral administration is supplied as a 10 mg/mL 
clear solution and is preservative-free. Each vial consists of 100 mg in 10 ml solutions.  
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
46 / 65 
Label of the Drug:  The container label and the immediate outer carton label of the investigational 
product to be used in the clinical study will contain the following information: product name and 
strength, lot number, protocol number, vial number, manufacturer’s name and address, 
recommended storage conditions, and an investigational caution statement. 
 
Storage of the Drug: Vials of nivolumab injection must be stored at 2oC to 8oC (36oF to 46oF) and 
protected from light and freezing.  
 
Preparation of Nivolumab for Administration: The solution will be prepared by a pharmacist, the 
Investigator, or a study nurse. Appropriate aseptic techniques should be used. Each vial contains 
approximately 100 mg/10 ml nivolumab. The bag will be identified with the patient number. 
Parenteral solutions should be inspected visually for particulates and discoloration prior to 
administration. Once the infusion is prepared, it should be administered within 24 hours. If 
Not used immediately, the infusion solution may be stored under refrigeration conditions (2°C to 
8°C, 36°F to 46°F) for up to 24 hours, and a maximum of 8 hours of the total 24 hours can be at room 
temperature (20oC to 25oC, 68oF to 77oF) and room light. The maximum 8-hour period under room 
temperature and room light conditions includes the product administration period. 
 
Method of Administration:  nivolumab will be administered intravenously on day 1 and 15 of each 
28 day cycle. The drug is diluted into a 250mL saline bag and will be administered over one-hour. 
In the event that Grade 3 or higher toxicity occurs during infusion, administration of nivolumab should 
be stopped immediately. Administration of nivolumab could be resumed only after the toxicity has 
resolved using the slowest rate of infusion (50mL/hr).  Vital signs will be measured prior to infusion 
and every 15 minutes for the first hour, then every 30 minutes for an additional hour, and then once 
an hour until the end of infusion. The window for vital signs will be per institutional standard of 
practice. 
  
 LENALIDOMIDE (Revlimid) 
Lenalidomide (REVLIMID®), a thalidomide analogue, is an immunomodulatory agent with anti-
angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1, 3-dihydro -2H-isoindol-2-yl) 
piperidine-2, 6-dione.  Lenalidomide has been studied extensively in myeloma and it is approved  
for use in newly diagnosed and in relapsed MM.  
 
Supply: REVLIMID® (lenalidomide) is available in 5, 10, 15 and 25 mg capsules for oral 
administration. Each capsule contains lenalidomide as the active ingredient and the following inactive 
ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, and magnesium 
stearate. The 5 mg capsule shell contains gelatin, titanium dioxide and black ink. The 10 mg capsule 
shell contains gelatin, FD&C blue #2, yellow iron oxide, titanium dioxide and black ink. 
 
Elimination: The metabolic profile of lenalidomide in humans has not been studied. In healthy 
volunteers, approximately two-thirds of lenalidomide is eliminated unchanged through urinary 
excretion. The process exceeds the glomerular filtration rate and therefore is partially or entirely 
active.  Half-life of elimination is approximately 3 hours.  
 
Pregnancy: Due to its structural similarities to thalidomide, a known human teratogen, lenalidomide 
is contraindicated in pregnant women and women capable of becoming pregnant. When there is no 
alternative, females of childbearing potential may be treated with lenalidomide provided adequate 
precautions are taken to avoid pregnancy.  Females must commit either to abstain continuously from 
heterosexual sexual intercourse or to use two methods of reliable birth control, including at least one 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
47 / 65 
highly effective method (e.g., IUD, hormonal contraception, tubal ligation, or partner’s vasectomy) and 
one additional effective method (e.g., latex condom, diaphragm, or cervical cap), beginning 4 weeks 
prior to initiating treatment with REVLIMID® (lenalidomide), during therapy with REVLIMID® 
(lenalidomide), during therapy delay, and continuing for 4 weeks following discontinuation of 
REVLIMID® (lenalidomide) therapy.  If hormonal or IUD contraception is medically contraindicated, 
two other effective or highly effective methods may be used. 
 
Deep Venous Thrombosis and Pulmonary Embolism: This drug has demonstrated a significantly 
increased risk of DVT and PE in patients with multiple myeloma who were treated with REVLIMID® 
(lenalidomide) combination therapy. Patients and physicians are advised to be observant for the signs 
and symptoms of thromboembolism. Patients should be instructed to seek medical care if they 
develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Prophylactic 
anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID® (lenalidomide) is 
required for patients enrolled in this current trial. 
 
10 PATIENT SAFETY 
 Monitoring of Adverse Events 
Significant adverse events should be identified and recorded.  Seriousness, expectedness, and 
causality will be assessed using the definitions that follow.  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for adverse event reporting. 
 Definitions of Adverse Events and Causality 
An Adverse Event (AE) is any untoward medical occurrence in a patient administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with the 
treatment.  For marketed products in the U.S., a Serious Adverse Event (SAE) is any untoward 
medical occurrence that at any dose:  
 
• Results in death (if the patient’s death is suspected as being a direct outcome of the adverse 
event) 
• Is life-threatening (the patient was at substantial risk of dying at the time of the adverse event 
or it is suspected that the use or continued use of the product would result in the patient’s 
death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization   
• Results in persistent or significant disability/incapacity 
• Results in a congenital anomaly/birth defect (i.e., exposure to a medical product prior to 
conception or during pregnancy resulted in an adverse outcome in a child) 
• Requires intervention to prevent permanent impairment or damage 
• Overdosage (regardless of adverse outcome) of any study medication.  An overdose is defined 
as the accidental or intentional ingestion of any dose of a product that is considered both 
excessive and medically important. 
• Pregnancy 
• Potential drug-induced liver injury(DILI): as defined by: 1:ALT or AST elevation > 3 times upper 
limit of normal (ULN)  AND 2: Total bilirubin > 2 times ULN, without initial findings of 
cholestasis (elevated serum alkaline phosphatase AND 3:   No other immediately apparent 
possible causes of AST/ALT elevation and hyperbilirubinemia, including, but not limited to, viral 
hepatitis, pre-existing chronic or acute liver disease, or the administration of other drug(s) 
known to be hepatotoxic. 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
48 / 65 
• Is an important medical event, defined as a medical event(s) that may not be immediately life 
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the patient or may require medical or surgical intervention 
to prevent one of the other serious outcomes listed in the definition above.  Examples of such 
events include, but are not limited to, intensive treatment in an emergency room or at home for 
allergic bronchospasm, or blood dyscrasias or convulsions that do not result in hospitalization.   
 
The SAE reporting period begins following the subject’s written consent to participate in the study 
through 100 days of discontinuation of dosing.   AEs should be followed to resolution or stabilization, 
and reported as SAEs if they become serious.  This also applies to patients experiencing AEs that 
cause interruption or discontinuation of investigational product, or those experiencing AEs that are 
present at the end of their participation in the study.  Such patients should receive post-treatment 
follow-up as appropriate.  If an ongoing AE changes in its severity or in its perceived relationship to 
study drug, a new AE entry for the event should be completed. 
 
Additionally, any serious adverse event considered by an investigator to be possibly, probably, or 
definitely related to the investigational product that is brought to the attention of the investigator at any 
time outside of the time period specified in the previous paragraph also must be reported immediately 
to the IRB (only as required per local policy) and Bristol-Myers Squibb (BMS) designated 
pharmacovigilance representative. 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above. These should also 
usually be considered serious. 
 
Note: The term "life-threatening" in the definition of "Serious Adverse Event" refers to an event in 
which the patient was at risk of death at the time of the event; it does not refer to an event that 
hypothetically might have caused death if it were more severe. 
 
An Unexpected Adverse Event is not listed in the current US Package Insert may be mentioned in 
the package insert, but differs from the event because of greater severity or specificity.  
 
Causality is a determination of whether there is a reasonable possibility that the drug may have 
caused or contributed to an adverse event. It includes assessing temporal relationships 
dechallenge/rechallenge information, association (or lack of association) with underlying diseases, 
and the presence (or absence) or a lack of one or more likely causes. 
 
The Investigator must attempt to determine if an adverse event is in some way related to the use of 
the study drug.  This relationship should be described as follows: 
 
Unlikely:  The event is clearly due to causes distinct from the use of the study drug, such 
as a documented pre-existing condition, the effect of a concomitant medication, a new 
condition which, based on the pathophysiology of the condition, and the pharmacology of 
the study drug, would be unlikely related to the use of the study drug. 
 
Possible: The event follows a reasonable temporal sequence from administration of the study drug 
or the event follows a known response pattern to the study drug BUT the event could have been 
produced by an intercurrent medical condition which, based on the pathophysiology of the condition, 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
49 / 65 
and the pharmacology of the study drug, would be unlikely related to the use of the study drug or the 
event could be the effect of a concomitant medication 
 
Probable: The event follows a reasonable temporal sequence from administration of the study drug 
and the event follows a known response pattern to the study drug AND the event cannot have been 
reasonably explained by an intercurrent medical condition or the event cannot be the effect of a 
concomitant medication 
Definite:The event follows a reasonable temporal sequence from administration of the study drug, 
the event follows a known response pattern to the study drug and based on the known pharmacology 
of the study drug, the event is clearly related to the effect of the study drug 
 
Unknown:  Based on the evidence available, causality cannot be ascribed 
    
 Serious Adverse Events 
 
When the principal investigator has determined that a Serious Adverse Event has occurred, the 
principal investigator is responsible for providing all Serious Adverse Events to BMS within 24 hours 
of this determination and to the IRB as per local policy.  This applies to initial and follow-up 
information. 
 
Follow-up Reports: 
 
• The Investigator should take all appropriate measures to ensure the safety of the patients, 
notably he/she should follow up the outcome of any Serious Adverse Event and complete 
follow-up forms as necessary.  The patient must be followed up until recovery, stabilization or 
return to baseline. This may mean that follow-up will continue after the patient has completed 
the trial and that additional investigations may be necessary.  
• Any reportable Serious Adverse Events brought to the attention of the Investigator at any time 
after cessation of the trial and considered by him/her to be reasonably associated with 
medication administered during the period should also be submitted to the IRB (as required 
per local policy) and to BMS (worldwide.safety@BMC.com; Fax: 609-818-3804). 
• As with the initial submission to the IRB, the principal investigator is also responsible for 
providing all follow-ups of Serious Adverse Events to the IRB (as required per local policy) and 
to BMS, using CIOMs or Medwatch form FDA 3500AA.  
 
10.3.1 Subsite/External Participating Site SAE Reporting Requirement. 
 
NOTE: External participating sites are not permitted to report directly to the OSU IRB or FDA.  
All external site SAEs are to be reported to the OSU Principal Investigator and Multi-Center 
Trial Program (MCTP).  The MCTP will facilitate submission of external site SAEs to the OSU 
IRB and FDA. 
 
All serious adverse events (SAEs) and other adverse events must be recorded on case report forms. 
In addition, all SAEs must be reported to the OSU Principal Investigator and MCTP within 24 hours of 
knowledge of the event using the FDA MedWatch 3500A mandatory reporting form and the “SAE 
Submission Form” cover sheet (refer to the Supplemental Forms Document). 
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
50 / 65 
Copies of de-identified source documentation pertaining to the SAE must be submitted to OSU. If a 
patient is permanently withdrawn from the study because of a SAE, this information must be included 
in the initial or follow-up SAE report form. 
 
All SAEs must be submitted to the local IRB per local IRB and institutional policy. 
 
Upon request of additional data or information that is deemed necessary must be reported to OSU as 
soon as possible but no later than 5 calendar days. 
 
 Reporting of Adverse Event Information Following Study Completion  
Collection of safety information following the end of investigational product administration is important 
in assisting in the identification of possible delayed toxicities or withdrawal effects.  All SAEs must be 
collected following the subject’s written consent to participate in the study through 100 days of 
discontinuation of dosing and must be reported to BMS Worldwide Safety. 
  
 
 Pregnancy Statement and Use in Nursing Women 
All women of childbearing potential MUST have a negative pregnancy test as required by the 
RevAssist program.  If the pregnancy test is positive, the patient must not receive any investigational 
product and must not be enrolled in the study. 
If, following initiation of the investigational product, it is subsequently discovered that a study subject 
is pregnant or may have been pregnant at the time of investigational product exposure, including 
during at least 6 half lives after product administration, the investigational product will be permanently 
discontinued in an appropriate manner (eg, dose tapering if necessary for subject safety).  
The investigator must immediately notify Worldwide Safety @BMS of this event via the Pregnancy 
Surveillance Form in accordance with SAE reporting procedures.  Follow-up information regarding the 
course of the pregnancy, including perinatal and neonatal outcome and, where applicable, offspring 
information must be reported on the Pregnancy Surveillance Form [provided upon request from BMS] 
any pregnancy that occurs in a female partner of a male study participant should be reported to BMS. 
Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
 
Definition of Childbearing Potential: For the purposes of this study, a female of childbearing 
potential is a sexually mature female who: 1) has not undergone a hysterectomy (the surgical removal 
of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been 
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time during 
the preceding 24 consecutive months). 
 
Thalidomide, an analog of lenalidomide causes fetal harm and birth defects when administered to a 
pregnant woman.  There are, however no adequate and well-controlled studies of lenalidomide in 
pregnant women.  In New Zealand white rabbits at 10 and 20 mg/kg/day, lenalidomide was 
maternally toxic (reduced body weight gain and feed consumption; at 20 mg/kg/day, weight loss and 
one abortion). Developmental toxicity at 10 and 20 mg/kg/day included reduced fetal body weights 
and increased post implantation losses and fetal variations (morbidity/purple-discolored skin, 
undeveloped intermediate lung lobe, irregular nasal-frontal suture, and delayed metacarpal 
ossification)45. The maternal and developmental no observed adverse effect levels (NOAELs) was 
3mg/kg/day. 
 
If the drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the 
patient should be apprised of the potential hazard to the fetus. 
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
51 / 65 
During the course of the trial, all patients of childbearing potential should be instructed to contact the 
treating physician immediately if they suspect they might have conceived a child.  In addition, a missed 
or late menstrual period should be reported to the treating physician.  If a female patient or the treating 
physician suspects that the female patient may be pregnant prior to administration of study drugs, the 
study drugs must be withheld until the results of a pregnancy test are available. If pregnancy is 
confirmed the patient must not receive study medications and must be withdrawn from the study.  
Throughout the entire pregnancy, additional contact should be made with the patient, and in some 
cases with the healthcare provider, to identify spontaneous abortions and elective terminations, as well 
as any medical reasons for elective termination. In addition, the study investigator should include 
perinatal and neonatal outcome. Infants should be followed for a minimum of 4 weeks. 
 
If a male patient is suspected of having fathered a child while on study drugs, the pregnant female 
partner must be notified and counseled regarding the risk to the fetus. In addition, the treating physician 
must follow the course of the pregnancy, including prenatal and neonatal outcome. Infants should be 
followed for a minimum of eight weeks. 
 
Upon live-birth delivery, the minimum information that should be collected includes date of birth, 
length of pregnancy, sex of infant, major and minor anomalies identified at birth. Outcomes can be 
obtained via mailed questionnaires, maternal interviews, medical record abstraction, or a 
combination of these methods. All serious adverse event reports relating to the pregnancy, including 
spontaneous abortion, elective abortion and congenital anomalies, should be forwarded to the FDA 
& BMS. (See Safety reporting section). 
 
It is not known whether lenalidomide or nivolumab is excreted in human milk. Because many drugs 
are excreted in human milk and because of the potential for serious adverse reactions in nursing 
infants from lenalidomide, a decision should be made whether to discontinue nursing or discontinue 
the drug, taking into account the importance of the drug to the mother.   
 
 Data Safety Monitoring Plan 
The data and safety monitoring plan will involve the continuous evaluation of safety, data quality and 
data timeliness. Investigators will conduct continuous review of data and patient safety at their regular 
Disease Group meetings (at least monthly) and the discussion will be documented in minutes. For 
each dose level, the Principal Investigator, study coordinator, and statistician, in consultation with 
treating physicians as appropriate will review all toxicities at a given dose level to inform the model for 
dose level adjustments.  The Principal Investigator of the trial will review toxicities and responses of 
the trial where applicable at these disease center meetings and determine if the risk/benefit ratio of 
the trial changes. Frequency and severity of adverse events will be reviewed by the Principal 
Investigator and compared to what is known about the agent/device from other sources; including 
published literature, scientific meetings and discussions with sponsors, to determine if the trial should 
be terminated before completion. Serious adverse events will be reviewed by the OSUCCC Data and 
Safety Monitoring Committee (DSMC). The Principal Investigator will also submit progress reports 
that will be reviewed by the committee per the DSMC plan. All reportable SAEs will be reported to the 
IRB of record as per the policies of the IRB. 
 
Mandatory safety and trial review teleconferences will be scheduled and moderated by the Multi-
Center Trial Program (MCTP). All sites involved in the study are expected to have a representative 
present for every call to review and discuss patients on study and other applicable agenda items. 
Meeting minutes will be used to document each teleconference. The minutes will be stored in the 
MCTP protocol files. Teleconferences must minimally be held monthly and may be held more 
frequently, as needed. For studies closed to accrual with patients expected to remain on long-term 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
52 / 65 
treatment and/or follow-up, teleconferences may be extended to occur every two months or quarterly. 
Decreasing frequency of teleconferences requires OSU PI and MCTP approval. 
 
 Data Submission 
The study will be managed per the Multi-Center Trial Program (MCTP) policies. Subsite data must be 
submitted to the MCTP as outlined in the protocol-specific monitoring plan. The protocol-specific 
monitoring plan will be provided by the MCTP to external participating sites prior to site activation. 
Data will be submitted using case report forms and the Data Submission Form cover sheet (refer to 
Supplemental Forms Document) supplied by the MCTP. Access to the OSU OnCore database may 
be provided to external participating sites for direct electronic data entry. All data submitted must be 
accompanied by supporting source documents, where applicable and as outlined in the protocol-
specific monitoring plan. 
 
 Auditing 
As the study sponsor, The Ohio State University Comprehensive Cancer Center (OSUCCC) will audit 
each site as per OSU policies. Audits will be performed by the OSUCCC Clinical Research Audit 
Team. For sites with an auditing mechanism in place that are able to share documentation of their 
auditing standards and processes followed, an agreement may be requested for the site to perform 
local auditing and provide formal audit reports to the OSUCCC Multi-Center Trial Program (MCTP) 
and the Quality Assurance Oversight Committee. 
 
 Study Termination 
 
The investigator may discontinue the trial at any time.  Reasons for early trial discontinuation may 
include, but are not limited to, unacceptable toxicity of study treatment, a request to discontinue the 
trial from a regulatory authority or an IRB, or poor enrollment.  
 
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
53 / 65 
11 REFERENCES 
 
1. 
Cook G, Campbell JD. Immune regulation in multiple myeloma: the host-tumour conflict. Blood 
Rev. 1999;13(3):151-162. 
2. 
Mozaffari F, Hansson L, Kiaii S, et al. Signalling molecules and cytokine production in T cells 
of multiple myeloma-increased abnormalities with advancing stage. Br J Haematol. 2004;124(3):315-
324. 
3. 
Frassanito MA, Cusmai A, Dammacco F. Deregulated cytokine network and defective Th1 
immune response in multiple myeloma. Clin Exp Immunol. 2001;125(2):190-197. 
4. 
Ratta M, Fagnoni F, Curti A, et al. Dendritic cells are functionally defective in multiple 
myeloma: the role of interleukin-6. Blood. 2002;100(1):230-237. 
5. 
Chauhan D, Singh AV, Brahmandam M, et al. Functional interaction of plasmacytoid dendritic 
cells with multiple myeloma cells: a therapeutic target. Cancer Cell. 2009;16(4):309-323. 
6. 
Beyer M, Kochanek M, Giese T, et al. In vivo peripheral expansion of naive CD4+CD25high 
FoxP3+ regulatory T cells in patients with multiple myeloma. Blood. 2006;107(10):3940-3949. 
7. 
Nielsen H, Nielsen HJ, Tvede N, et al. Immune dysfunction in multiple myeloma. Reduced 
natural killer cell activity and increased levels of soluble interleukin-2 receptors. APMIS. 
1991;99(4):340-346. 
8. 
Pilarski LM, Andrews EJ, Mant MJ, Ruether BA. Humoral immune deficiency in multiple 
myeloma patients due to compromised B-cell function. J Clin Immunol. 1986;6(6):491-501. 
9. 
Spisek R, Kukreja A, Chen LC, et al. Frequent and specific immunity to the embryonal stem 
cell-associated antigen SOX2 in patients with monoclonal gammopathy. J Exp Med. 2007;204(4):831-
840. 
10. 
Carbone E, Neri P, Mesuraca M, et al. HLA class I, NKG2D, and natural cytotoxicity receptors 
regulate multiple myeloma cell recognition by natural killer cells. Blood. 2005;105(1):251-258. 
11. 
Nucci M, Anaissie E. Infections in patients with multiple myeloma in the era of high-dose 
therapy and novel agents. Clin Infect Dis. 2009;49(8):1211-1225. 
12. 
Osterborg A, Nilsson B, Bjorkholm M, Holm G, Mellstedt H. Natural killer cell activity in 
monoclonal gammopathies: relation to disease activity. Eur J Haematol. 1990;45(3):153-157. 
13. 
Gonzalez M, San Miguel JF, Gascon A, et al. Increased expression of natural-killer-associated 
and activation antigens in multiple myeloma. Am J Hematol. 1992;39(2):84-89. 
14. 
Garcia-Sanz R, Gonzalez M, Orfao A, et al. Analysis of natural killer-associated antigens in 
peripheral blood and bone marrow of multiple myeloma patients and prognostic implications. Br J 
Haematol. 1996;93(1):81-88. 
15. 
Davies FE, Raje N, Hideshima T, et al. Thalidomide and immunomodulatory derivatives 
augment natural killer cell cytotoxicity in multiple myeloma. Blood. 2001;98(1):210-216. 
16. 
Shi J, Tricot GJ, Garg TK, et al. Bortezomib down-regulates the cell-surface expression of HLA 
class I and enhances natural killer cell-mediated lysis of myeloma. Blood. 2008;111(3):1309-1317. 
17. 
Frassanito MA, Silvestris F, Cafforio P, Silvestris N, Dammacco F. IgG M-components in active 
myeloma patients induce a down-regulation of natural killer cell activity. Int J Clin Lab Res. 
1997;27(1):48-54. 
18. 
Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide 
therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 
2006;108(10):3458-3464. 
19. 
Richardson P, Jagannath S, Hussein M, et al. Safety and efficacy of single-agent lenalidomide 
in patients with relapsed and refractory multiple myeloma. Blood. 2009;114(4):772-778. 
20. 
Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed 
multiple myeloma in North America. N Engl J Med. 2007;357(21):2133-2142. 
21. 
Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or 
refractory multiple myeloma. N Engl J Med. 2007;357(21):2123-2132. 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
54 / 65 
22. 
Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone 
versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple 
myeloma: an open-label randomised controlled trial. Lancet Oncol. 2009;11(1):29-37. 
23. 
Guo L, Zhang H, Chen B. Nivolumab as Programmed Death-1 (PD-1) Inhibitor for Targeted 
Immunotherapy in Tumor. J Cancer. 2017;8(3):410-416. 
24. 
Gettinger SN, Horn L, Gandhi L, et al. Overall Survival and Long-Term Safety of Nivolumab 
(Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated 
Advanced Non-Small-Cell Lung Cancer. J Clin Oncol. 2015;33(18):2004-2012. 
25. 
Rizvi NA, Mazieres J, Planchard D, et al. Activity and safety of nivolumab, an anti-PD-1 
immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung 
cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 2015;16(3):257-265. 
26. 
Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti-programmed death-
1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic 
correlates. J Clin Oncol. 2010;28(19):3167-3175. 
27. 
Brahmer JR, Hammers H, Lipson EJ. Nivolumab: targeting PD-1 to bolster antitumor immunity. 
Future Oncol. 2015;11(9):1307-1326. 
28. 
Voena C, Chiarle R. Advances in cancer immunology and cancer immunotherapy. Discov 
Med. 2016;21(114):125-133. 
29. 
Kazandjian D, Suzman DL, Blumenthal G, et al. FDA Approval Summary: Nivolumab for the 
Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based 
Chemotherapy. Oncologist. 2016;21(5):634-642. 
30. 
Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or 
refractory Hodgkin's lymphoma. N Engl J Med. 2015;372(4):311-319. 
31. 
Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in Patients With Relapsed or Refractory 
Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol. 2016;34(23):2698-
2704. 
32. 
Schafer PH, Gandhi AK, Loveland MA, et al. Enhancement of cytokine production and AP-1 
transcriptional activity in T cells by thalidomide-related immunomodulatory drugs. J Pharmacol Exp 
Ther. 2003;305(3):1222-1232. 
33. 
Hayashi T, Hideshima T, Akiyama M, et al. Molecular mechanisms whereby 
immunomodulatory drugs activate natural killer cells: clinical application. Br J Haematol. 
2005;128(2):192-203. 
34. 
Zhu D, Corral LG, Fleming YW, Stein B. Immunomodulatory drugs Revlimid (lenalidomide) and 
CC-4047 induce apoptosis of both hematological and solid tumor cells through NK cell activation. 
Cancer Immunol Immunother. 2008;57(12):1849-1859. 
35. 
Gorgun G, Samur MK, Cowens KB, et al. Lenalidomide Enhances Immune Checkpoint 
Blockade-Induced Immune Response in Multiple Myeloma. Clin Cancer Res. 2015;21(20):4607-4618. 
36. 
Funt SA, Page DB, Cattry D, et al. The Long PD-1 Receptor Binding Kinetics of Nivolumab 
May Increase Efficacy of Subsequent Therapy in Relapsed and Refractory Multiple Myeloma 
Patients. Blood. 2015;126(23):3057-3057. 
37. 
Efebera YA, Rosko AE, Hofmeister C, et al. First Interim Results of a Phase I/II Study of 
Lenalidomide in Combination with Anti-PD-1 Monoclonal Antibody MDV9300 (CT-011) in Patients 
with Relapsed/Refractory Multiple Myeloma. Blood. 2015;126(23):1838-1838. 
38. 
Palumbo A, Mateos MV, San Miguel J, et al. Pembrolizumab in combination with lenalidomide 
and low-dose dexamethasone in newly diagnosed and treatment-naive multiple myeloma (MM): 
randomized, phase 3 KEYNOTE-185 study. Annals of Oncology. 2016;27. 
39. 
Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide plus high-dose dexamethasone 
versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple 
myeloma: an open-label randomised controlled trial. Lancet Oncol;11(1):29-37. 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
55 / 65 
40. 
Wang M, Dimopoulos MA, Chen C, et al. Lenalidomide plus dexamethasone is more effective 
than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of 
prior thalidomide exposure. Blood. 2008;112(12):4445-4451. 
41. 
Stadtmauer EA, Weber DM, Niesvizky R, et al. Lenalidomide in combination with 
dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or 
refractory multiple myeloma. Eur J Haematol. 2009;82(6):426-432. 
42. 
Gandhi AK, Kang J, Capone L, et al. Dexamethasone synergizes with lenalidomide to inhibit 
multiple myeloma tumor growth, but reduces lenalidomide-induced immunomodulation of T and NK 
cell function. Curr Cancer Drug Targets;10(2):155-167. 
43. 
Sargent DJ, Chan V, Goldberg RM. A three-outcome design for phase II clinical trials. Control 
Clin Trials. 2001;22(2):117-125. 
44. 
Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 
2010;127(4):759-767. 
45. 
Christian MS, Laskin OL, Sharper V, Hoberman A, Stirling DI, Latriano L. Evaluation of the 
developmental toxicity of lenalidomide in rabbits. Birth Defects Res B Dev Reprod Toxicol. 
2007;80(3):188-207. 
46. 
Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple 
myeloma. Leukemia. 2006;20(9):1467-1473. 
 
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
56 / 65 
12 Appendix: ECOG/KPS Scale 
 
 
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. 
Mor V, Laliberte L, Morris JN, Wiemann M.  The Karnofsky Performance Status Scale:  an examination of its 
reliability and validity in a research setting.  Cancer 1984;53:2002-2007. 
 
 
 
 
 
 
 
 
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
57 / 65 
13 Appendix. IMWG Response Criteria 
Serum and urine M-protein estimates will be performed every 4 weeks; except for assessment of CR, 
patients with measurable disease restricted to the SPEP (or UPEP) will need to be followed only by 
SPEP (or UPEP).  Responses will be assessed according to the criteria of the International Myeloma 
Working Group 46, and characterized as follows: 
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
58 / 65 
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
59 / 65 
14  Appendix. NYHA Cardiac Disease 
 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence 
of cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased. 
Objective evidence of 
severe cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, Brown & Co; 1994:253-256. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
60 / 65 
15 Appendix.  FACT/GOG-Neurotoxicity 
By circling one (1) number per line, please indicate how true each statement has been for you during the 
past 7 days. 
 
 
ADDITIONAL CONCERNS 
Not 
at all 
A little 
bit 
Some- 
what 
Quite 
a bit 
Very 
much 
I have numbness or tingling in my hands……… 
0 
1 
2 
3 
4 
I have numbness or tingling in my feet………… 
0 
1 
2 
3 
4 
I feel discomfort in my hands…………………. 
0 
1 
2 
3 
4 
I feel discomfort in my feet…………………… 
0 
1 
2 
3 
4 
I have joint pain or muscle cramps…………… 
0 
1 
2 
3 
4 
I feel weak all over…………………………… 
0 
1 
2 
3 
4 
I have trouble hearing………………………… 
0 
1 
2 
3 
4 
I get a ringing or buzzing in my ears………… 
0 
1 
2 
3 
4 
I have trouble buttoning buttons……………… 
0 
1 
2 
3 
4 
I have trouble feeling the shape of small objects 
when they are in my hand……………………… 
0 
1 
2 
3 
4 
I have trouble walking………………………… 
0 
1 
2 
3 
4 
 
Sources:  Cella DF, Tulsky DS, Gray G, Sarafian B, Lloyd S, Linn E, et al.  The functional assessment of cancer therapy 
(FACT) scale:  development and validation of the general measure.  J Clin Oncol 1993;11(3):570-79. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
61 / 65 
16 Appendix.  Ethical and regulatory 
 Ethical Principles 
The study should be conducted according to the principles outlined by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments; the International Conference on 
Harmonization Guidelines for Good Clinical Practice; and FDA regulations regarding the conduct of 
clinical trials and the protection of human subjects.  
 
 Protocol Compliance and Protocol Revisions 
The study must be conducted as described in this approved protocol.  All revisions to the protocol 
must be provided to BMS.  The investigator should not implement any deviation or change to the 
protocol without prior review and documented approval/favorable opinion from the IRB of an 
Amendment, except where necessary to eliminate an immediate hazard(s) to study patients.  
Documentation of approval signed by the chairperson or designee of the IRB(s) must be sent to BMS.  
If the revision is an administrative letter, the investigator(s) must inform the IRB. 
 
 Informed consent, Data Safety and Monitoring 
It is the responsibility of the investigator to obtain written informed consent from a patient or a 
patient’s legal representative before any study related procedures are performed.  The Investigator 
will provide an informed consent in compliance with ICH GCP and U.S. FDA guidelines (21 CFR 50).  
The informed consent document must clearly describe the potential risks and benefits of the trial, and 
each prospective participant must be given adequate time to discuss the trial with the Investigator or 
site staff and to decide whether or not to participate.  The informed consent must be approved by the 
IRB prior to being presented to a potential patient. One copy of the patient's signed, dated and 
witnessed written consent will be kept in the patient’s medical record and one copy will be given to 
the patient or the patient’s legal representative. 
 
Investigator responsibilities are set out in the ICH guideline for Good Clinical Practice (GCP) and in the 
US Code of Federal Regulations. Investigators must enter study data into a secure data collection 
system that will be accessible to only parties involved in the trial.  The Investigator will permit study-
related monitoring visits and audits by BMS or its representatives, IRB, providing direct access to the 
facilities where the study took place, to source documents, and to all other study documents. 
 
 
 Institutional Review Board (IRB) Approval 
The Investigator must obtain the approval of the protocol, the informed consent document and any 
other material used to inform the patient about the nature of the trial from the local IRB in the form of 
a written letter.  On the approval letter, which must be signed by the chairperson of the IRB or the 
chairperson’s designee, the following items should be clearly stated:  trial title, protocol number and 
version, study-related documents (protocol, informed consent material, advertisement when 
applicable), IRB review date, and IRB decision.  The trial should not start until a copy of this written 
approval has been received by the Investigator. 
 
If the investigator is a member of the IRB, the Investigator may participate in any discussion of the 
study, but may not participate in the final vote deciding whether to approve the study.  
 
Annually, or more often if stipulated by the IRB, and at the completion or termination of the study, the 
Investigator will report the progress of the trial to the IRB and BMS. (see contact information in 
section “Serious Adverse Events”) 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
62 / 65 
 
 Additional Responsibilities of the Investigator 
 
The investigator(s) agrees to perform the study in accordance with ICH Good Clinical Practice and 
FDA regulations.  The Investigator is required to ensure compliance with respect to the investigational 
drug schedule, visit schedule and procedures required by the protocol.  
 
The investigator should be able to recruit the required number of suitable patients and should have 
sufficient time to properly conduct and complete the trial.  The Investigator should have available an 
adequate number of qualified staff and adequate facilities for the duration of the trial, and should 
ensure that all persons assisting with the trial are adequately informed about the protocol, the 
protocol-defined procedures, protocol therapy and trial related duties and functions.. 
 
The Investigator should be responsible for all trial-related medical decisions.  During and following a 
patient’s participation in a trial, the investigator should ensure that adequate medical care is provided 
to a patient for any adverse events related to the trial.   
 
 Use and Completion of Case Report Forms (CRFs) 
It is the responsibility of the Investigator to monitor the preparation and accurate use of CRFs to 
record all observations and other data pertinent to the clinical investigation.  All CRFs should be 
completed in their entirety to ensure accurate interpretation of data.   
 
Should a correction be made, the information to be modified must not be overwritten. The corrected 
information will be transcribed next to the previous value, initialed and dated by the authorized 
person. 
 
 Confidentiality 
It is the responsibility of the investigator to ensure that the confidentiality of all patients participating in 
the trial and all of their medical information is maintained.  Case report forms must never contain the 
name of a trial patient.  All case report forms and any identifying information must be kept in a secure 
location with access limited to the study staff directly participating in the trial.  Personal medical 
information may be reviewed by a representative of BMS, of the IRB, or of regulatory authorities in 
the course of auditing the trial.  Every reasonable effort will be made to maintain such information as 
confidential. 
 
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
63 / 65 
17 Appendix.  REV-ASSIST GUIDELINES 
As of 11-Sep-2008, 
 
 
 
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
64 / 65 
 
 
 
 
 
 
 
 


OSU-17160 Protocol Amd 2 - 29 Nov 2017 
65 / 65 
18 Appendix: Instructions for sample collection, storage and shipment  
The total amount of whole blood withdrawn for the laboratory tests will depend on the visit number. 
Whole blood should be divided and processed as follows: 
 
 
ANY REMAINING SERUM THAT IS NOT USED IN ANY OF THE TESTS SHOULD BE 
DISCARDED AS REQUIRED BY THE CENTER'S RELEVANT POLICIES.