Phase I/II Study of Lenalidomide in Combination With Anti-PD-1 Monoclonal Antibody CT-011 in Patients With Relapsed/Refractory Multiple Myeloma
Phase: PHASE1
Conditions: Multiple Myeloma
Sponsor: Ohio State University Comprehensive Cancer Center

OSU-13128 - Amd 6 - 26Jan2016 
1 
OSU Study #:  
OSU-13128  
IRB Protocol #:  
2013C0180 
Version:  
 
Amd 6 - 01/26/2016 
IRB Approved:  
04/29/16 
 
 
Phase I/II Study of Lenalidomide in Combination with Monoclonal Antibody 
MDV9300 (CT-011) in Patients with Relapsed/Refractory Multiple Myeloma 
 
 
Clinical Lead (PI):    
 
Yvonne A. Efebera, M.D.  
                                            
 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 
 
Clinical Site PI:  
Dana Farber Cancer  
 
Nikhil Munshi, M.D 
Cancer Institute 
 
 
Email: Nikhil_Munshi@dfci.harvard.edu 
 
Study Sponsor: 
 
 
Yvonne Efebera, MD (Investigator-Sponsor) 
 
IND#  
 
 
 
120501 
 
Funding Entity: 
 
 
American Cancer Society 
 
Drug Supplied: 
 
 
MDV9300 by Medivation 
 
Subsite Coordinator: 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Initial:  
04Feb2014 
Amd 2: 
19Feb2014 
Amd 3: 
26Mar2014 
Amd 4: 
11Jun2014 
Amd 5: 
19Jun2015 
Amd 6: 
26Jan2016 
 
 
 
 
 
 
 

OSU-13128 - Amd 6 - 26Jan2016 
2 
PROTOCOL SYNOPSIS 
 
Study Title 
Phase I/II Study of Lenalidomide in Combination with Monoclonal Antibody 
MDV9300 (CT-011) in Patients with Relapsed/Refractory Multiple Myeloma 
Study ID 
OSU-13128 
Sponsor 
Yvonne Efebera, MD (Investigator Sponsor) 
IND# 
120501 
Funding 
Entity 
American Cancer Society 
Primary 
Objectives 
To determine the maximum tolerated dose (MTD), safety and efficacy of CT-011 in 
combination with lenalidomide (Revlimid) and assess efficacy in terms of overall 
response rate in patients with relapse/refractory multiple myeloma (MM)  
 
Primary 
Endpoint 
 To determine MTD of CT-011 in combination with lenalidomide in the phase 
I study.  The MTD of CT-011 combined with lenalidomide will be defined as 
the highest dose combination of CT-011 and lenalidomide at which ≤ 1of 6 
patients at that dose level has dose-limiting toxicity.        
 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)  
 To determine overall survival (OS) 
 To assess pharmacokinetics and pharmacodynamics of CT-011 in 
combination with lenalidomide 
 To assess CT-011 immunogenicity and 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 
For the phase I portion 
 
We will conduct a standard 3+3 design over 4 dose levels of 1.5, 3, 3, and 6 mg/kg 
of CT-011 given intravenously every 4 weeks and lenalidomide given at 15,15, 25, 
and 25 mg orally daily on days 1-21 of a 28-day cycle. 
 
CT-011 will be administered intravenously on day 3 of each 28 day cycle. The 
drug is diluted into a 250mL saline bag which in the FIRST infusion is administered 
in a step-wise manner: 50ml/hr for 30min; 100ml/hr for 30min; 150ml/hr for 30 min 
and 200ml/hr till the end (another ~30min) for an approximate time of 2hrs.  If no 
infusion related AEs occurs the first time, subsequent administrations are at 
200mL/hr which will deliver the drug over approximately 1:15hrs. All patients will 
receive pre-medication (Tylenol 650mg or Ibuprofen 800mg or related medication), 
and an antihistamine (phenergan 25mg or equivalent) before CT-011 infusion. 
 
Patients will be assessed for response at the end of each cycle according to the 
IMWG response criteria.  
 

OSU-13128 - Amd 6 - 26Jan2016 
3 
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 non-hematologic 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.  However, the DLT will count 
towards establishment of maximally tolerated dose (MTD).   A cohort will be 
expanded if 1 of 3 pts experiences a DLT.  If 2 of 6 pts on a cohort experience a 
DLT, then MTD will be determined as the dose level immediately below that in 
which 2 of 6 pts experience a DLT.  The Phase II portion of the trial will commence 
upon completion of the Phase I portion.  In the event that a MTD is not 
established, safety and tolerability data collected in the Phase I portion of the 
study will guide decisions on dosing of CT-011 in the phase II trial. 
 
The maximum tolerated dose level (MTD) combination is defined as the dose level 
at which no more than one of six patients experiences a DLT as defined above. 
Any dose level that has two or more DLTs reported is considered to exceed the 
MTD and not be a tolerable dose level. Dose escalation will be determined based 
on the occurrence of DLTs observed in the first cycle of therapy. For the purposes 
of dose determination, DLTs will be counted by patient, i.e., a patient who 
experiences more than one DLT will be counted only once. 
 
Discontinuation of treatment due to disease progression will not constitute a DLT. 
In the phase I portion of this trial, if a patient goes off treatment before completing 
cycle one for reasons other than toxicity or DLT, they will be replaced at that dose 
level to fully evaluate the tolerability of this regimen at that dose level.  
 
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 CT-
011 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 

OSU-13128 - Amd 6 - 26Jan2016 
4 
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. 
 
For the Phase II portion 
Upon completion of the cohorts in phase I, the phase II portion of the study will 
commence utilizing the planned target doses (or MTDs determined) with CT-011 in 
combination with lenalidomide and dexamethasone 
 
During the phase II portion of this trial, we will not evaluate patients for DLTs as 
was done in the phase I portion; however, we will use the DLT criteria to identify 
potential toxicity and tolerability concerns occurring at any cycle to initiate further 
evaluation to ensure safety of patients. 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 
Dosing cohorts for the phase I study: We will conduct a standard 3+3 design over 
4 dose levels of 1.5, 3, 3, and 6 mg/kg of CT-011 given intravenously every 4 
weeks (28 days) on day 3, and lenalidomide given at 15, 15, 25, and 25 mg orally 
daily on days 1-21 of a 28-day cycle. The study drug CT-011 and lenalidomide can 
move independently of one another as described in the Table below. 
Dexamethasone 40 mg orally weekly may be added if only stable disease after 3 
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. 
 
A minimum of 3 patients to a cohort with at least one week break between cohorts. 
 
 
CT-011- mg/kg 
day 3  
Cohort -1 
1.5 
Cohort -2 
1.5 
Cohort 1 
1.5 
Cohort 2 
3 
Cohort 3 
3 
Cohort 4 
6 
 
 
 
 
 
  
 
 
 
 
 
If a DLT occurs in 2 or more patients during the first cycle, we will consider this 
 
Lenalidomide- mg 
Days 1-21 
Cohort -1 
10 
Cohort -2 
5 
Cohort 1 
15 
Cohort 2 
15 
Cohort 3 
25 
Cohort 4 
25 

OSU-13128 - Amd 6 - 26Jan2016 
5 
dose level to exceed the MTD and therefore be deemed intolerable for this patient 
population. If a DLT occurs in 1 of 3 patients during this time, an additional 3 
patients will be enrolled and evaluated for DLT before dose escalation can 
proceed. If no other patient in the cohort has a DLT, escalation to the next cohort 
may proceed 1 week later from the last included patient on the current cohort. If a 
second patient in a cohort has a DLT, MTD determination will then be conducted 
by one of the following schemes: 
 
 If ≥ 2 of 3 patients in cohort 1 exhibit a DLT at the dose of 1.5 mg/kg CT-
011 in combination with lenalidomide 15 mg, 3 more patients will be 
enrolled at a de-escalated dose level cohort. This de-escalation cohort 
(Cohort -1) will use the same dose of CT-011 (1.5 mg/kg) in combination 
with 10 mg lenalidomide. If no further DLTs are observed, we will consider 
dose escalation of the CT-011 with this lower dose of lenalidomide such 
that the dose escalation of CT-011 to 3 mg/kg with lenalidomide 10 mg will 
proceed in the next cohort. However, if ≥2 patients experience DLT with 
CT-011 1.5 mg/kg and lenalidomide 10 mg, then we will further de-escalate 
lenalidomide to 5 mg and enroll 3 more patients on CT-011 1.5 mg/kg 
combined with lenalidomide 5 mg.  The same criteria for MTD will be used 
for these de-escalation dose level cohorts. 
 
 If ≥ 2 patients in cohort 2 exhibit a DLT at the dose of 3 mg/kg CT-011 in 
combination with lenalidomide 15 mg, we will explore tolerability of an 
intermediate dose level of lenalidomide, where 3 patients will be enrolled 
and treated with 3 mg/kg of CT-011 in combination with 10 mg 
lenalidomide. The dose escalation of CT-011 to 6 mg/kg with lenalidomide 
10 mg will proceed in the next cohort if no more than one DLT is observed 
in the 3 mg/kg CT-011+10mg lenalidomide cohort. 
 
 If ≥ 2 patients in cohort 3 exhibit a DLT at the dose of 3 mg/kg CT-011 in 
combination with lenalidomide 25 mg, 3 more patients will be enrolled at the 
3 mg dose of CT-011 in combination with 15 mg lenalidomide. If there is < 1 
DLT with CT011 3mg/kg and lenalidomide 15 mg, this will be defined as the 
MTD.  If there are 2 or more DLT, then 3 additional patients will be enrolled 
at the CT-011 3mg/kg and lenalidomide 10 mg, which will become the MTD. 
 
 If ≥ 2 patients in cohort 4 exhibit a DLT at the dose of 6 mg/kg CT-011 in 
combination with lenalidomide 25 mg, 3 more patients will be enrolled at the 
6 mg dose of CT-011 in combination with 15 mg lenalidomide. If there is < 1 
DLT with CT011 6mg/kg and lenalidomide 15 mg, this will be defined as the 
MTD.  If there are 2 or more DLT, then 3 additional patients will be enrolled 
at the CT-011 6mg/kg and lenalidomide 10 mg, which will become the MTD. 
 
 
Once the MTD has been established or determined, an additional 18 subjects will 
be treated at the MTD in the phase II. 
Planned 
Sample size 
For the phase I portion:  a minimum of 12 and a maximum of 30 patients will be 
recruited. 
For the phase II portion: a maximum of 23 patients will be recruited 

OSU-13128 - Amd 6 - 26Jan2016 
6 
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 12-24 months. 
 
Eligibility 
Inclusion criteria 
 
 Patients must be at least 18 years of age with evidence of relapse or refractory 
disease 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) 
o Measurable biopsy proven plasmacytoma (should be measured 
within 28 days of registration to study) 
 Patients must have had at least 2 prior lines of therapy. 
 Patients must not have had progression of disease on lenalidomide 25 mg.  
Stable disease on lenalidomide is permitted. 
 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 90 days 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 90 days afterwards. 
o Female patients of child bearing potential must agree to comply with the 
fertility and pregnancy test requirements dictated by the Rev-Assist 

OSU-13128 - Amd 6 - 26Jan2016 
7 
program. 
 
Exclusion Criteria 
 
 Patients with peripheral neuropathy > CTCAE grade 2 
 Patients receiving concurrent corticosteroids other than for physiologic 
maintenance treatment. Patients should otherwise discontinue corticosteroids 
prior to registration to study. 
 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 prior to 
registration 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 registration to 
study 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-13128 - Amd 6 - 26Jan2016 
8 
Contents 
BACKGROUND AND RATIONALE .................................................................. 11 
1.1. 
Multiple Myeloma ................................................................................................ 11 
1.2. 
Natural Killer cells and MM ................................................................................. 11 
1.3. 
Lenalidomide (Revlimid) ..................................................................................... 11 
1.3.1 
Clinical Experience in Relapsed Multiple Myeloma .......................................................... 11 
1.4 
MDV9300 (CT-011) ............................................................................................ 13 
1.4.1 
CT-011 preclinical studies ................................................................................................. 13 
1.4.2 
CT-011 Clinical Studies .................................................................................................... 13 
1.4.3 
Toxicity of CT-011 ............................................................................................................. 14 
1.4.4 
CT-011 and lenalidomide in multiple myeloma ................................................................. 18 
1.5 
Study rationale .................................................................................................... 18 
2 
STUDY OVERVIEW AND OBJECTIVE .................................................... 18 
2.1 
Study Overview .................................................................................................. 18 
2.2 
Primary Objective ............................................................................................... 19 
2.3 
Primary Endpoints .............................................................................................. 19 
2.4 
Secondary Endpoints ......................................................................................... 19 
2.5 
Safety Parameters .............................................................................................. 19 
3 
ELIGIBILITY CRITERIA ........................................................................... 19 
3.1 
Inclusion Criteria ................................................................................................. 19 
3.2 
Exclusion Criteria ................................................................................................ 20 
3.3 
Inclusion of Women and Minorities ..................................................................... 21 
4 
STUDY DESIGN AND DURATION........................................................... 21 
4.1 
Study Design ...................................................................................................... 21 
4.2 
Definition of Dose Limiting Toxicity ..................................................................... 21 
4.3 
Dose Escalation/De-escalation ........................................................................... 22 
4.4 
Duration of Treatment ......................................................................................... 23 
4.5 
Study Accrual ..................................................................................................... 24 
4.6 
Duration of Study Period .................................................................................... 24 
5 
TREATMENT PLAN AND PROCEDURES .............................................. 24 
5.1 
CT-011 ............................................................................................................... 24 
5.1.1 Schedule ............................................................................................................ 24 
5.1.2 
Premedication ................................................................................................................... 25 
5.1.3 
Route and Method of Administration ................................................................................. 25 
5.1.4 
CT-011 Infusional monitoring ............................................................................................ 26 
5.1.5 
CT-011 Dose Adjustments ................................................................................................ 26 
5.2 
Lenalidomide  (RevlimidTM) ................................................................................. 26 
5.2.1 
Lenalidomide Administration and Schedule ...................................................................... 26 
5.2.2 
Lenalidomide dose levels .................................................................................................. 27 
5.3 
Dexamethasone ................................................................................................. 27 
5.3.1 
Table 5.1 Adverse events and Dose Adjustment of drugs ............................................... 28 
5.3.2 
Lenalidomide dose levels .................................................................................................. 29 
5.4 
Dexamethasone ................................................................................................. 29 
5.5 
Supportive Care .................................................................................................. 29 
5.5.1 
Thromboprophylaxis.......................................................................................................... 30 
5.5.2 
Growth factors ................................................................................................................... 30 
5.6 
Requirements at the beginning of each cycle ..................................................... 30 
5.7 
Patient Withdrawal .............................................................................................. 30 
5.8 
Schedule of Tests and Observations .................................................................. 31 
5.8.1 
Screening .......................................................................................................................... 31 

OSU-13128 - Amd 6 - 26Jan2016 
9 
5.8.2 
Evaluation during treatment .............................................................................................. 31 
5.8.3 
Post-treatment Follow-up .................................................................................................. 31 
5.8.4 
Sample collection for immunologic correlative studies ..................................................... 32 
5.8.5 
Schedule for correlative studies ........................................................................................ 32 
5.8.6 
Schedule of Eventsa .......................................................................................................... 33 
6.0 
STATISTICAL CONSIDERATIONS ......................................................... 35 
6.1 
Overview of study design ................................................................................... 35 
6.2 
Safety Endpoints ................................................................................................ 37 
6.3 
Clinical outcome definitions ................................................................................ 37 
6.4 
Prior and concomitant treatment ......................................................................... 37 
6.5 
Prohibited treatments ......................................................................................... 38 
7.0 
REGISTRATION PROCEDURES ............................................................. 38 
7.1 
Registration Guidelines ...................................................................................... 38 
7.2 
Assignment of Study Numbers ........................................................................... 38 
7.3 
Study Records .................................................................................................... 38 
7.4 
Selection Procedures ......................................................................................... 38 
7.5 
Subsite Patient Registration ............................................................................... 38 
8.0 
Correlative studies ................................................................................. 39 
8.1 
PK and correlative laboratory investigations ....................................................... 40 
8.2 
T-cell specific correlative science ....................................................................... 40 
8.3 
NK-cell specific correlative science .................................................................... 41 
8.4 
CD14(+) monocyte specific, correlative science ................................................. 41 
9.0 
Investigational drugs .............................................................................. 41 
9.1 
CT-011 ............................................................................................................... 41 
9.2 
LENALIDOMIDE (Revlimid) ............................................................................. 42 
10.0 PATIENT SAFETY ................................................................................... 43 
10.1 Monitoring of Adverse Events ............................................................................. 43 
10.2 Definitions of Adverse Events and Causality ...................................................... 43 
10.3 Subsite SAE Reporting Requirements ................................................................ 45 
10.4 Serious Adverse Events ..................................................................................... 45 
10.5 Reporting of Adverse Event Information Following Study Completion ................ 46 
10.6 Pregnancy Statement and Use in Nursing Women ............................................ 46 
10.7 Patient Withdrawal and Study Termination ......................................................... 47 
11.0 REFERENCES ......................................................................................... 49 
Appendix A: ECOG/KPS Scale ........................................................................ 52 
Appendix B: IMWG Response Criteria ........................................................... 53 
Appendix C: NYHA Cardiac Disease .............................................................. 55 
Appendix D:  FACT/GOG-Neurotoxicity ......................................................... 56 
Appendix E:  Ethical and regulatory ............................................................... 57 
Ethical Principles ........................................................................................................... 57 
Protocol Compliance and Protocol Revisions ................................................................ 57 
Informed consent, Data Safety and Monitoring ............................................................. 57 
Institutional Review Board (IRB) Approval .................................................................... 58 
Additional Responsibilities of the Investigator ............................................................... 58 
Use and Completion of Case Report Forms (CRFs) ..................................................... 59 

OSU-13128 - Amd 6 - 26Jan2016 
10
Confidentiality ................................................................................................................ 59 
Appendix F:  REV-ASSIST GUIDELINES ........................................................ 60 
Appendix G: Instructions for sample collection, storage and shipment ..... 62 
 

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11
BACKGROUND AND RATIONALE  
1.1. 
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.    
 
1.2. 
Natural Killer cells and MM 
Natural Killer cells (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 MM13-15.  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 effect16, 17.   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-component6,7,18.  
 
1.3. 
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 

OSU-13128 - Amd 6 - 26Jan2016 
12
grade 3/4 myelosuppression in patients receiving 15 mg twice daily as compared to those receiving 
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 dexamethasone32. 
 
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 therapies33.  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 response33.  
 
Two phase III trials comparing lenalidomide + dexamethasone to single agent dexamethasone in 
patients with relapsed and/or refractory multiple myeloma were published34,35.  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 
 
Table 1-2 
DVT & PE Risks in Phase III Trials of Relapse refractory MM  

OSU-13128 - Amd 6 - 26Jan2016 
13
Weber et al 
Dimopoulos et al 
Lenalidomide 
+ 
Dexamethasone 
Dexamethasone 
Alone 
Lenalidomide 
+ 
Dexamathasone 
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 therapy36. Subsequently most therapies involving dexamethasone, uses low-
dose. 
 
1.4 
MDV9300 (CT-011)   
MDV9300 (Medivation, Inc., previously CT-AcTibody or BAT) is a novel IgG1 humanized monoclonal 
antibody (mAb) that modulates the immune system, with previously demonstrated anti-tumor efficacy 
in experimental models of both solid and liquid tumors25,29,30,37-39.  
 
   
1.4.1 CT-011 Preclinical Studies 
 
The efficacy of CT-011 and its murine version mCT-011 (formerly BAT) was studied in experimental 
tumor models of leukemia, lymphoma, melanoma, lung, colon, fibrosarcoma, and breast cancers37, 39, 
41, 43-46. Treatment with the antibody resulted in an immune response against murine and human 
tumors, and inhibited tumor growth, extended the survival of tumor-bearing mice, and generated 
tumor-specific protection against tumor re-challenge. Specifically for BCL1 leukemia/lymphoma 
model, mCT-011 treatment resulted in the reduction of peripheral blasts and blood leukocytosis and 
in the enhancement of survival of tumor-bearing mice43. CT-011 was shown to best operate when 
administered 10-14 days post tumor inoculation, suggesting it may be relevant for the treatment of 
active disease. The activity of the antibody was suggested to be associated also with processes of 
lymphopoiesis as the administration of mCT-011 to athymic mice and to athymic mice engrafted with 
human colon carcinoma resulted in induced lymphopoiesis exhibited in the increase in the number of 
CD3 CD4 and CD8 T cells as well of CD56 positive NK cells47. In MM, CT-011 was shown to enhance 
ex-vivo T cell responses to autologous dendritic/myeloma fusion vaccine for multiple myeloma48.  CT-
011 also enhanced human NK-cell function against autologous primary MM cells through effects on 
NK-cell trafficking, immune complex formation with MM cells, and cytotoxicity specifically toward MM 
tumor cells but not normal cells12. CT-011 alone or the combination with  lenalidomide was shown to 
statistically significantly increase cytotoxicity against MM tumor cell targets when compared to control 
(p=0.02)49.     
 
1.4.2 CT-011 Clinical Studies 
 
A Phase 1, open-label, dose-escalation study was conducted in 17 hematological malignancy 
patients50: eight acute myeloid leukemia (AML) patients, four non-Hodgkin’s lymphoma (NHL) 

OSU-13128 - Amd 6 - 26Jan2016 
14
patients, three chronic lymphocytic leukemia (CLL) patients, one Hodgkin’s disease (HD) patient, and 
one multiple myeloma (MM) patient. The purpose of the study was to evaluate the safety, 
pharmacokinetics, clinical response, and maximum tolerated dose (MTD) of CT-011 (0.2, 0.6, 1.5, 
3.0, and 6.0 mg/kg). Most patients had failed several lines of conventional chemotherapy and 
radiotherapy as well as allogeneic (n=6) or autologous (n=3) stem cell transplantation prior to their 
enrollment to the study. Eleven of the patients were females and six were males, with an average age 
of 61 (20–77) years. Sixteen were Caucasian and one Middle-Eastern. In this study, CT-011 was 
found to have an acceptable safety profile at all dose levels, and was overall well tolerated with no 
observed serious/unexpected treatment-related adverse events and no observed infusion-related 
responses. The most common adverse event was diarrhea, which was detected in one low-dose 
patient (0.2 mg/kg) and one patient treated at the 3 mg/kg dose level. No single dose MTD could be 
established in this study. Apparent clinical responses were observed in six of the patients 12 months 
after treatment with CT-011: one complete remission (NHL - follicular lymphoma), four stable disease 
(HD, 2 CLL, and MM), and one minimal response (AML: platelet-transfusion-independency for 11 
months post treatment). Transient elevations in the percentage of peripheral blood CD4+ 
lymphocytes were observed at 24 hours post CT-011 treatment in 15 of the patients.  
 
A phase II study of CT-011 in combination with rituximab in patients with relapsed follicular lymphoma 
has been completed.  CT-011 given to patients with diffuse large B-Cell lymphoma following 
autologous stem cell transplant showed increases in specific CD4+ effector/memory T-lymphocytes51. 
The study has been completed and results and analysis of progression free survival are forthcoming. 
 
The pharmacokinetics of CT-011 was found to be proportionally correlated with the dose with a 
median t1/2 ranging between 270 hrs. and 410 hrs. No gender-related or disease-related differences 
in the pharmacokinetics of CT-011 were found. The median t1/2 for the six patients evaluated for 
apparent beneficial clinical responses was higher than that of the rest of the patients.  
 
1.4.3 Toxicity of CT-011 
 
Adverse Events Reported during Phase 1 Human Study 
Adverse Events 
Number of patients 
Relationship to treatment 
Diarrhea1 
2 
none 
Rash2  
1 
none 
Pain 
1 
none 
Back pain 
1 
none 
Shortness of breath 
1 
none 
Weakness 
1 
possible 
Flushing 
1 
possible 
Blurred vision 
1 
none 
Pressure wound 
1 
none 
Urine infection 
1 
none 
1. One of the patients had diarrhea at the time of enrollment 
2. The patient was enrolled with rash 
 
Adverse Events reported in the study in DLBCL patients after transplant:   
Data presented as number of patients with a given AE (number of events are shown in parentheses).  
Events noted ONLY as Grade 1-2, are shown at ≥10% of total number of events.   
Event 
Number of patients (Number of events) 
Severity Grade 
 
All grades 
1 
2 
3 
4 
5 

OSU-13128 - Amd 6 - 26Jan2016 
15
Event 
Number of patients (Number of events) 
Severity Grade 
 
All grades 
1 
2 
3 
4 
5 
Any AE 
69(613) 
65(392) 
49(145) 
30(60) 
9(14) 
1a (1) 
Neutropenia 
19(25) 
3(3) 
7(7) 
9(10) 
5(5) 
- 
Fatigue 
18(21) 
16(19) 
2(2) 
- 
- 
- 
Upper respiratory tract infection 
14(15) 
9(10) 
5(5) 
- 
- 
- 
Diarrhea 
12(19) 
10(14) 
4(5) 
- 
- 
- 
Cough 
12(14) 
11(13) 
1(1) 
- 
- 
- 
Thrombocytopenia 
10(15) 
5(6) 
- 
4(5) 
2(4) 
- 
Hyperglycemia 
9(12) 
8(10) 
2 (2) 
- 
- 
- 
Leukopenia 
9(12) 
6(8) 
3 (3) 
1(1) 
- 
- 
Pyrexia 
9(11) 
3(3) 
4(6) 
2(2) 
- 
- 
Anemia 
7(8) 
2(3) 
2(2) 
3(3) 
- 
- 
Neurtophil count decreased 
7(7) 
1(1) 
3(3) 
3(3) 
- 
- 
Hypotension 
7(9) 
3(5) 
3(3) 
1(1) 
- 
- 
APTT prolonged 
6(7) 
3(4) 
2(2) 
1(1) 
- 
- 
Headache 
6(8) 
5(7) 
- 
1(1) 
- 
- 
Herpes zoster 
5(5) 
1(1) 
3(3) 
1(1) 
- 
1(1)a 
Lymphopenia 
5(5) 
1(1)  
3(3) 
1(1) 
- 
- 
Platelet count decreased 
5(5) 
4(4) 
- 
1(1) 
- 
- 
Vomiting 
4(6) 
2(2) 
2(2) 
1(2) 
- 
- 
Urinary tract infection  
4(4) 
1(1) 
2(2) 
1(1) 
- 
- 
Renal failure 
3(3) 
1(1) 
- 
2(2) 
- 
- 
Hypertension 
3(3) 
- 
2(2) 
1(1) 
- 
- 
DVT 
3(3) 
1(1) 
1(1) 
1(1) 
- 
- 
Pain 
3(3) 
2(2) 
- 
1(1) 
- 
- 
Fall 
3(3) 
1(1) 
1(1) 
1(1) 
- 
- 
Lobar pneumonia 
2(2) 
1(1) 
- 
1(1) 
- 
- 
Hypophosphatemia 
2(3) 
- 
2(2) 
1(1) 
- 
- 
Bone pain 
2(2) 
- 
1(1) 
1(1) 
- 
- 
Head injury 
1(1) 
- 
- 
- 
1(1) 
- 
Accident 
1(1) 
- 
- 
- 
1(1) 
- 
Myelodysplastic syndrome 
1(1) 
- 
- 
- 
1(1)b 
- 
Intracranial hemorrhage 
1(1) 
- 
- 
- 
1(1) 
- 
Subarachnoid hemorrhage 
1(1) 
- 
- 
- 
1(1) 
- 
Pneumothorax 
1(1) 
- 
- 
- 
1(1) 
- 
Cardiac arrest 
1(1) 
- 
- 
1(1) 
- 
- 
Duodenal ulcer 
1(1) 
- 
- 
1(1) 
- 
- 
GI hemorrhage 
1(1) 
- 
- 
1(1) 
- 
- 
General physical health decline 
1(1) 
- 
- 
1(1) 
- 
- 
Clostridium difficile colitis 
1(1) 
- 
- 
1(1) 
- 
- 
Vascular injury 
1(1) 
- 
- 
1(1) 
- 
- 
Pelvic fracture 
1(1) 
- 
- 
1(1) 
- 
- 
Hyperhidrosis 
1(1) 
- 
- 
1(1) 
- 
- 
Cholecystectomy 
1(1) 
- 
- 
1(1) 
- 
- 
Blood Phosphorus decreased 
1(1) 
- 
- 
1(1) 
- 
- 
Glioma 
1(1) 
- 
- 
1(1) 
- 
- 
Tachypnea 
1(1) 
- 
- 
1(1) 
- 
- 
COPD 
1(1) 
- 
- 
1(1) 
- 
- 
ARDS 
1(1) 
- 
- 
1(1) 
- 
- 

OSU-13128 - Amd 6 - 26Jan2016 
16
Event 
Number of patients (Number of events) 
Severity Grade 
 
All grades 
1 
2 
3 
4 
5 
Facial bone fracture 
1(1) 
- 
- 
1(1) 
- 
- 
Myositis 
1(1) 
- 
- 
1(1) 
- 
- 
Rhabdomyolysis 
1(1) 
- 
- 
1(1) 
- 
- 
Hemoglobin decreased  
9(9) 
6(6) 
3(3) 
- 
- 
- 
Nausea 
8(9) 
7(8) 
1(1) 
- 
- 
- 
Sinusitis 
6(9) 
2(2) 
4(7) 
- 
- 
- 
Insomnia 
7(7) 
7(7) 
- 
- 
- 
- 
Rash 
6(7) 
6(7) 
- 
- 
- 
- 
aOne patient developed fatal disseminated zoster infection during the follow-up period 10 months after last dose of 
pidilizumab. This was considered unrelated to study drug. 
bOne patient with pre-existing leukopenia and thrombocytopenia developed myelodysplasia 13 months following the last 
dose of pidilizumab.  This was considered unrelated to study drug. 
 
Adverse events reported in the study in patient with follicular lymphoma observed in at least 3 
patients regardless of attribution 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infusion related Events: 
Infusion related actions were not reported as such in study in patients with DLBCL following 
autologous stem cell transplantation. However, there were several adverse events that were noted on 
the days when CT-011 was administered that were regarded as possibly or probably related to CT-
011 by the investigators. These included the following: 
 
Adverse 
event  
Grade 
Number 
of 
patients 
Action taken 
Hypotension 
1 (3 subjects) 
2 (1 subject) 
4 
None (2 subjects)  
Dosing temporary interrupted (2 subjects) 
Fatigue  
1 
3 
None 
Adverse Event 
Number of Patients (Percentage of Patients) 
Severity Grade 
All 
1 
2 
3/4/5 
Fatigue 
15 (50%) 
13 (43%) 
2 (7%) 
0 
Anemia 
14 (47%) 
14 (47%) 
0 
0 
Leukopenia 
11 (37%) 
11 (37%) 
0 
0 
Thrombocytopenia 
10 (34%) 
8 (27%) 
2 (7%) 
0 
Respiratory Infection 
6 (20%) 
1 (3%) 
5 (17%) 
0 
Neutropenia 
6 (20%) 
5 (17%) 
1 (3%) 
0 
Dyspnea 
6 (20%) 
6 (20%) 
0 
0 
Pain 
5 (17%) 
3 (10%) 
2 (7%) 
0 
Nausea 
5 (17%) 
5 (17%) 
0 
0 
Edema 
4 (13%) 
3 (10%) 
1 (3%) 
0 
Sweating 
4 (13%) 
4 (13%) 
0 
0 
Neuropathy 
4 (13%) 
4 (13%) 
0 
0 
Cough 
4 (13%) 
4 (13%) 
0 
0 
Hypotension 
3 (10%) 
2 (7%) 
1 (3%) 
0 
Pruritus 
3 (10%) 
3 (10%) 
0 
0 
Diarrhea 
3 (10%) 
3 (10%) 
0 
0 
Anorexia 
3 (10%) 
3 (10%) 
0 
0 

OSU-13128 - Amd 6 - 26Jan2016 
17
Adverse 
event  
Grade 
Number 
of 
patients 
Action taken 
Pain 
1 
2 
None 
Nausea 
1 
2 
None 
Arthralgia 
1 
1 
None 
Cough 
1 
1 
None 
Drowsiness 
1 
1 
None 
Facial 
flushing 
1 
1 
None 
Hot flashes 
1 
1 
None 
Hypoxia 
2 
1 
None 
Pruritius 
1 
1 
None 
 
Two infusion reactions have been reported in study in patients with colorectal cancer, both at the 
FOLFOX plus CT-011 arm. In one patient “infusion related reaction/hypersensitivity” was noted after 4 
dosages of CT-011 (approximately 3 months from study start) that was assessed by the investigator 
to be a grade 2 oxaliplatin related toxicity (unrelated to CT-011) manifested by shortness of breath 
and flushing. Further treatment in the study was discontinued. The second patient experienced an 
“infusion allergic reaction” after 4 dosages of CT-011 (approximately 3 months from study start) that 
was assessed by the investigator to be a grade 1 5FU and oxaliplatin related toxicity (unrelated to 
CT-011). In addition, there has been one case of Grade 2 hypersensitivity possibly related to CT-011 
that occurred on the day of CT-011 infusion in the study but not defined as an infusion related. Two 
additional hypersensitivity events (Grade 1 and 3) had occurred previously in the same patient on 
days other than those of CT-011 administration and also defined as possibly related to CT-011.   
 
Eight subjects that participated in a study in patients with metastatic melanoma experienced infusion 
reactions manifested in the following symptoms:  
Adverse event  
Grade 
Number 
of 
patients1 
Dose 
(mg/kg) 
Action taken 
Urticaria 
3 (1 subject) 
1 (1 subject) 
2 
6.0 
Patient with Grade 1 event: 
Dose interrupted; 
Patient with Grade 3 event: 
Dose interrupted, 
concomitant medication 
given and dose reduced to 
1.5mg/kg. 
Hypotension 
2 
1 
6.0 
Dose interrupted 
Hypertension 
2 
2 
6.0 
Dose interrupted 
Rigors 
2 
1 
6.0 
Dose interrupted (event 
accompanying 
hypertension) 
Facial flushing 
1 
1 
6.0 
None 
Injection site 
reaction 
1 
1 
6.0 
None 
Burning at iv 
site 
1 
1 
1.5 
None 

OSU-13128 - Amd 6 - 26Jan2016 
18
(1) Hypertension and rigors occurred in the same patient 
Autoimmune Toxicity 
Three serious adverse events with potentially immunological etiology have been noted in a study in 
patients with metastatic melanoma and include Grade 3 arthritis, Grade 3 pneumonitis and Grade 4 
hepatitis.  
 
 
1.4.4 CT-011 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 drug16, 52.   Numbers of both T cells and NK cells are increased in patients receiving IMID 
therapy53.   NK cell killing is also enhanced including antibody-dependent cellular cytotoxicity (ADCC) 
and natural NK cell cytotoxicity53, 54. These events correlate with clinical responses to IMID therapy in 
patients53.  In our study, CT-011 alone, and with lenalidomide, exerts effects on the NK cell 
cytoskeleton and increased migration of NK cells towards MM targets mediated via the CXCR4 / 
stromal-derived factor-1α (SDF-1α) pathway.  Pretreatment of NK cells with CT-011 with or without 
lenalidomide enhanced immune complex formation between NK cells and MM tumor targets and also 
augmented NK cell activation and cytotoxicity against MM, as well.  The combination of CT-011 and 
lenalidomide synergistically enhanced NK cell interferon-gamma production against RPMI-8226, a 
lenalidomide-resistant multiple myeloma cell line, and enhanced NK cell target acquisition of primary 
multiple myeloma tumor cells.    
 
1.5 
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 alone34,35.  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 toxicity36. The response to the combination was shown 
even in patients with prior thalidomide use55, however, response is better if used earlier than later56.  
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 dexamethasone33. 
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.  
 
We sought to determine the response in relapse/refractory multiple myeloma patients using CT-011 in 
combination with lenalidomide.  Because decreased NK cell activity and enhancement may be seen 
with steroids57 (although less so at low doses), patients will receive CT-011 plus lenalidomide with an 
option to add low-dose dexamethasone after 3 cycles if stable disease. 
 
 
2 
STUDY OVERVIEW AND OBJECTIVE 
2.1 
Study Overview 
This is a single-arm, open label, phase I/II study of CT-011 in combination with lenalidomide in adult 
(age 18 years and older) patients with relapsed MM.  A 4-cohort, dose-escalation, phase I portion will 

OSU-13128 - Amd 6 - 26Jan2016 
19
be completed with the primary endpoint to determine safety and tolerability, seeking maximally 
tolerated doses (MTDs) of each agent in combination in a standard 3+3 design over 4 dose levels of 
1.5, 3, 3, and 6 mg/kg of CT-011 given intravenously every 4 weeks (every 28 days), and 
lenalidomide given at 15, 15, 25, and 25 mg orally daily on days 1-21 of a 28-day cycle.  A minimum 
of 12 and a maximum of 30 patients will be recruited for the phase I portion of the study. Upon 
identification of the MTD for the dose level combination of CT-011 and lenalidomide, the phase II 
portion of the study will commence accruing an additional 23 patients to assess 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, 
pharmacokinetic and pharmacodynamics data, immunomonitoring of lymphocyte subsets, including T 
and NK cell subsets, and ex vivo immune functional assays. For both phases, Dexamethasone 40 mg 
orally weekly may be added if only stable disease after 3 cycles. Dexamethasone can be reduced to 
20 mg based on tolerability or if patient is 70 years or older. 
 
2.2 
Primary Objective 
To determine the maximum tolerated dose (MTD), safety and efficacy of CT-011 in combination with 
lenalidomide (Revlimid) and assess efficacy in terms of overall response rate in patients with 
relapse/refractory multiple myeloma (MM)  
 
2.3 
Primary Endpoints 
 To determine MTD of CT-011 in combination with lenalidomide in the phase I study.  The MTD 
of CT-011 combined with lenalidomide will be defined as the highest dose combination of CT-
011 and lenalidomide at which ≤ 1of 6 patients at that dose level has dose-limiting toxicity.        
 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 
 
2.4 
Secondary Endpoints 
 To determine time to progression (TTP).  
 To determine overall survival (OS). 
 To assess pharmacokinetics and pharmacodynamics of CT-011 in combination with 
lenalidomide. 
 To assess CT-011 immunogenicity and correlative biologic studies to assess 
immunomonitoring of lymphocytes subsets including T and NK cell, and ex-vivo assessment of 
immune functional activities. 
 
2.5 
Safety Parameters 
Infusion related and treatment emergent toxicities per NCI CTCAE v.4 
 
3 ELIGIBILITY CRITERIA 
3.1 
Inclusion Criteria 
 
 Patients must be at least 18 years of age with evidence of relapse or refractory disease 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) 

OSU-13128 - Amd 6 - 26Jan2016 
20
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 
registration to study) 
 Patients must have had at least 2 prior line of therapy. 
 Patients must not have had progression of disease on lenalidomide 25 mg.  Stable disease on 
lenalidomide is permitted. 
 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 within 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 90 days after study therapy discontinuation. 
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 continuing through 90 days 
after study therapy discontinuation. 
o Female patients of child bearing potential must agree to comply with the fertility and pregnancy 
test requirements dictated by the Rev-Assist program.\ 
 
3.2 
Exclusion Criteria 
 
 Patients with peripheral neuropathy > CTCAE grade 2 
 Patients receiving concurrent corticosteroids for reason(s) other than for physiologic maintenance 
treatment. Patients should otherwise discontinue corticosteroids prior to registration to study. 
 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%. 

OSU-13128 - Amd 6 - 26Jan2016 
21
 Patients who have received targeted or investigational agents prior to registration 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 registration to study 
      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. 
 
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for the study. 
 
4 STUDY DESIGN AND DURATION 
4.1 
Study Design 
This is a non-randomized open-label phase I/II study for patients with relapsed and refractory multiple 
myeloma. For the phase I part, we will conduct a standard 3+3 design over 4 main dose levels 
cohorts evaluating 1.5, 3, 3, and 6 mg/kg of CT-011 given intravenously every 4 weeks (every 28 
days) on day 3, and lenalidomide given at 15, 15, 25, and 25 mg orally daily on days 1-21 of a 28-day 
cycle, to determine the maximum tolerated dose. The phase II will commence once the MTD is 
determined, and this dose level combination for CT-011 and lenalidomide will be used for the phase II 
portion of this trial. Patients will be assessed for response at the end of cycle 4 or sooner if necessary 
according to the IMWG response criteria.  
 
4.2 
Definition of Dose Limiting Toxicity  
For the phase I portion, patients will be monitored for safety by assessing toxicities as graded by the 
NCI CTCAE v4.0. The maximum tolerated dose (MTD) or 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 non-hematologic 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  

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22
 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 
 
 
4.3 
Dose Escalation/De-escalation 
 
If a DLT occurs in 2 or more patients on a dose level during the first cycle, the MTD will be exceeded 
and we will consider this dose level to be intolerable. If a DLT occurs in 1 of 3 patients during this 
time, an additional 3 patients will be enrolled at that dose level cohort and evaluated for DLT before 
dose escalation can proceed. If no other patient in the cohort has a DLT, escalation to the next cohort 
may proceed 1 week later from the last included patient on the current cohort. If a second patient in a 
cohort has a DLT, MTD determination will then be conducted by one of the following schemes: 
 
 If ≥ 2 of 3 patients in cohort 1 exhibit a DLT at the dose of 1.5 mg/kg CT-011 in combination 
with lenalidomide 15 mg, 3 more patients will be enrolled at a de-escalated dose level cohort. 
This de-escalation cohort (Cohort -1) will use the same dose of CT-011 (1.5 mg/kg) in 
combination with 10 mg lenalidomide. If no further DLTs are observed, we will consider dose 
escalation of the CT-011 with this lower dose of lenalidomide such that the dose escalation of 
CT-011 to 3 mg/kg with lenalidomide 10 mg will proceed in the next cohort. However, if ≥2 
patients experience DLT with CT-011 1.5 mg/kg and lenalidomide 10 mg, then we will further 
de-escalate lenalidomide to 5 mg and enroll 3 more patients on CT-011 1.5 mg/kg combined 
with lenalidomide 5 mg.  The same criteria for MTD will be used for these de-escalation dose 
level cohorts. 
 
 If ≥ 2 patients in cohort 2 exhibit a DLT at the dose of 3 mg/kg CT-011 in combination with 
lenalidomide 15 mg, we will explore tolerability of an intermediate dose level of lenalidomide, 
where 3 patients will be enrolled and treated with 3 mg/kg of CT-011 in combination with 10 
mg lenalidomide. The dose escalation of CT-011 to 6 mg/kg with lenalidomide 10 mg will 
proceed in the next cohort if no more than one DLT is observed in the 3 mg/kg CT-011+10mg 
lenalidomide cohort. 
 
 If ≥ 2 patients in cohort 3 exhibit a DLT at the dose of 3 mg/kg CT-011 in combination with 
lenalidomide 25 mg, 3 more patients will be enrolled at the 3 mg dose of CT-011 in 
combination with 15 mg lenalidomide. If there is < 1 DLT with CT011 3mg/kg and lenalidomide 
15 mg, this will be defined as the MTD.  If there are 2 or more DLT, then 3 additional patients 
will be enrolled at the CT-011 3mg/kg and lenalidomide 10 mg, which will become the MTD. 
 
 If ≥ 2 patients in cohort 4 exhibit a DLT at the dose of 6 mg/kg CT-011 in combination with 
lenalidomide 25 mg, 3 more patients will be enrolled at the 6 mg dose of CT-011 in 
combination with 15 mg lenalidomide. If there is < 1 DLT with CT011 6mg/kg and lenalidomide 
15 mg, this will be defined as the MTD.  If there are 2 or more DLT, then 3 additional patients 
will be enrolled at the CT-011 6mg/kg and lenalidomide 10 mg, which will become the MTD 
 
 
To determine dose escalation, we will focus on the number of patients who experience dose limiting 
toxicity; i.e. a patient who experiences more than one DLT will be counted only once. 
 
Discontinuation of treatment due to disease progression will not constitute a DLT. 
 

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23
In the Phase 1 portion of the study, subjects who withdraw or prematurely discontinue treatment 
before completing the first treatment cycle for reasons other than toxicity and DLT will be replaced. 
 
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 CT-011, lenalidomide and dexamethasone(if initiated after cycle 1-2) 
will continue for a minimum of 8 additional cycles or until withdrawal.   
 
For the Phase II portion 
Upon determination of the MTD in the phase I portion of this trial, the phase II portion of the study will 
commence enrollment at the MTD determined in the phase I portion with CT-011 in combination with 
lenalidomide. In the event that a MTD is not established, safety and tolerability data collected in the 
Phase I portion of the study will guide decisions on dosing of CT-011 in the phase II trial. 
Dexamethasone 40 mg orally weekly may be added if only stable disease after 3 cycles according to 
the IMWG criteria (section13). Dexamethasone can be reduced to 20 mg based on tolerability or if 
patient is 70 years or older. 
 
During the phase II portion of this trial, we will not evaluate patients for DLTs as was done in the 
phase I portion; however, we will use the DLT criteria to identify potential toxicity and tolerability 
concerns occurring at any cycle to initiate further evaluation to ensure safety of patients. An 
independent Data and Safety Monitoring Committee will continue oversight of this trial. See Appendix 
E for details. 
 
 
4.4 
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 
 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. Otherwise patient can continue 
treatment until one of the above endpoints is reached. 
 
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. 
 
 

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24
4.5 
Study Accrual  
For the phase I portion, a minimum of 12 and a maximum of 30 patients will be recruited.  
Once the MTD has been established, an additional 23 subjects will be treated at the MTD in the 
phase II. 
 
4.6 
Duration of Study Period 
The total study enrollment period is expected to be up to 24 months. 
 
 
5 TREATMENT PLAN AND PROCEDURES 
For the Phase I portion, this is a standard 3+3 design over 4 dose levels of 1.5, 3, 3, and 6 mg/kg of 
CT-011 given intravenously every 4 weeks (every 28 days) on day 3, and lenalidomide given at 15, 
15, 25, and 25 mg orally daily on days 1-21 of a 28-day cycle. The study drug CT-011 and 
lenalidomide can be escalated or de-escalated independently of one another as described in the 
Table below. Twelve to 30 patients will be recruited in the phase I portion of the trial.  The phase II 
portion will utilize the 6 patients treated at the MTD in the phase I portion and an additional 23 
patients will be accrued. Dexamethasone 40 mg orally weekly may be added if only stable disease 
after 3 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. 
 
 
5.1 
CT-011 
5.1.1 Schedule 
 
Table 5-1: Treatment Regimen During Phase I Study: 28 day Cycle 
 
 
CT-011- mg/kg 
day 3  
Cohort -1 
1.5 
Cohort -2 
1.5 
Cohort 1 
1.5 
Cohort 2 
3 
Cohort 3 
3 
Cohort 4 
6 
 
 
 
Lenalidomide- mg 
Days 1-21 
Cohort -1 
10 
Cohort -2 
5 
Cohort 1 
15 
Cohort 2 
15 
Cohort 3 
25 
Cohort 4 
25 
 
 

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25
CT-011 is an investigational agent supplied by Medivation, Inc., It is supplied for this protocol for 
clinical trial use only and it is not commercially available. 
 
5.1.2 Premedication 
All patients will receive pain relief medication (Tylenol 650mg or Ibuprofen 800mg or related 
medication), and an antihistamine (H1 blocker; 25-50mg diphenhydramine hydrochloride 
administered I.V.).  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 CT-
011 dose, chlorpheniramine administered at 10mg I.V 20-50 minutes prior to CT-011 dose, oral 
chlorpheniramine taken 2 hours prior to CT-011 dose or oral diphenhydramine taken 2 hours prior to 
CT-011 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. 
 
5.1.3 Route and Method of Administration 
CT-011 will be administered intravenously on day 3 of a 28 day cycle.  
CT-011 is to be administered intravenously using a peripheral line or a central device if such has 
been inserted. Patients will be dosed on a mg/kg basis. 
 
The first time CT-011 is to be administered intravenously at a dose of 1.5/3.0/6.0mg/kg delivered over 
approximately 2 hours as follows: 
1. Initial rate of infusion is 50 mL/hr for 30 minutes; If no symptoms related to infusion appear:  
2. Increased rate to 100 mL/hr; for 30 minutes; If no symptoms appear:  
3. Increased rate to 150 mL/hr for 30 minutes; If no symptoms appear:  
4. Increase rate to 200 mL/hr for 30 minutes;  
 
In the event that Grade 3 or higher infusion-related toxicity occurs during infusion, administration of 
CT-011 should be stopped immediately. Administration of CT-011 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.   
 
If no drug related or infusion related adverse events occur during the first administration, further CT-
011 administrations could be delivered over approximately 1:15 hours at a rate of 200mL/hr. 
Subsequent administrations should be made as scheduled in the absence of Grade 3 or higher 
adverse events or disease progression.  
 
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 CT-011, the IV infusion line must be flushed with 0.9% sodium 
chloride. The following are two recommended methods for flushing the CT-011 IV infusion line: 
 
1) When the CT-011 infusion is complete, add an additional 50mL of 0.9% sodium chloride for 

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26
injection to the CT-01 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 CT-011 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. 
 
5.1.4 CT-011 Infusional monitoring 
The potential risks that may be related to the administration of monoclonal antibodies in general, 
adverse events that were possibly related to CT-011 administration in the Phase 1 study, and a few 
theoretical risks for CT-011 included infusion-related effects.  Infusion related effects have not been 
observed in the Phase I clinical study with CT-011.  
 
Vital signs (temperature, blood pressure, pulse rate, respiratory rate) and ECG will be closely 
monitored prior to, during, and after 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. 
 
5.1.5 CT-011 Dose Adjustments 
The phase I study showed that CT-011 was well tolerated with no treatment related toxicity at all dose 
level50.  Specifically no hematologic toxicity was seen.  No dose adjustments or modifications will be 
made with CT-011 except If DLT was seen with CT-011 at 3 mg/kg in combination with lenalidomide 
5 mg, then CT-011 will be reduced to 1.5 mg/kg with lenalidomide 5 mg, which will be the DLT. If 
adverse events occur that require holding CT-011, the dose will remain the same once treatment 
resumes. If CT-011 is held for more than 4 weeks, then patient will be taken off study. 
 
5.2 
Lenalidomide  (RevlimidTM) 
 
5.2.1 Lenalidomide Administration and Schedule 
Lenalidomide will be given orally. Schedule as shown in table 5.1 
The first dose level starts at 15 mg days 1-21 of a 28 day cycle. 
If a dose is missed or vomited up, the dose will not be made up.  
 
Beginning by day 1 of cycle #2 and on day 1 of every cycle thereafter, while all six conditions below 
have been met, patients will be evaluated for lenalidomide dose escalation.  
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 
 Not yet reached the maximum daily dose of 25 mg of lenalidomide 
 Are willing to undergo dose escalation of lenalidomide. 
 Serum Creatinine maintained at ≤ 2mg/dL as in initial eligibility 
 

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27
Then the patient’s dose for lenalidomide will be increased by 5 mg per cycle for days 1-21 of a 28 day 
cycle. If any of the criteria are not met, then no lenalidomide dose escalations will occur during this 
cycle. 
 
5.2.2 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 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. 
 
5.3 
Dexamethasone 
Dexamethasone 40 mg orally weekly (days 1,8,15, 22) may be added if only stable disease after 3 
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. 
 
 

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28
 
5.3.1 Table 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 dexamethsone). 
Rash 
Lenalidomide  
If grade 3 or greater, hold lenalidomideuntil 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 
 
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. 
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. 

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29
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 
 
5.3.2 Lenalidomide dose levels 
Toxicities are to be assessed according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE), Version 4.0.  Dose modifications or delays will be done based on the toxicity experienced 
during a cycle of therapy.  
 
5.4 
Dexamethasone 
Dexamethasone 40 mg orally weekly (days 1,8,15, 22) may be added if only stable disease after 3 
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. 
 
 
5.5 
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. 
All patients will receive prophylaxis with either an H-2 blocker or proton pump inhibitor while on study 
medications. 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. 
 
 

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30
5.5.1  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.   
 
 
 
5.5.2 Growth factors 
Prophylactic use of growth factors is not recommended. 
 
5.6 
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 by 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. 
 
5.7 
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: 
 
 Patients who participate in another investigational drug trial 
 Patients’ non-compliance with the protocol that can negatively affect the treatment effect 
 Patients who express a desire to withdraw from the study (the patient has the right to withdraw 
for any reason without prejudice) 
 Evidence of progressive disease would require withdrawal of the patient from the study. 
 Any other reasons deemed by the principal investigator and treating physician. 
 Patients who must discontinue use of either CT-011 or lenalidomide 
 

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31
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 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.  
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 up.  
 
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. 
 
5.8 
Schedule of Tests and Observations  
5.8.1 Screening  
 
Medical history & clinical examination, ECOG/WHO PS, vital signs, concomitant medications,  date of 
diagnosis, previous treatment, and appropriate assessment of inclusion and exclusion criteria will be 
performed within 4 weeks prior to starting protocol-based therapy.  
 
5.8.2 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  
 
5.8.3 Post-treatment Follow-up  
 
After the end of study treatment (whatever the reason for discontinuation), the patient will be followed 
for 6 months. Adverse events will be followed for at least 30 days, during which time all procedures 
for the reporting of SAEs will be followed.  
a. 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. Follow up data should be 
submitted at 1 month after protocol therapy discontinuation and then every 3 months until 
progression or death, whichever occurs first. 
 

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32
 
5.8.4 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.   
 
5.8.5 Schedule for correlative studies 
 
Laboratory correlative studies will be obtained at screening, days 3, 4, 6, 10 and 17 of cycle 1, days 3 
of subsequent 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-13128 - Amd 6 - 26Jan2016 
33
5.8.6 Schedule of Eventsa  
 
Investigations 
Screening 
C1D3 
C1D4 
C1D6 
C1D10 
C1D17 
C2D3 
C3D3 
C5D3 
CxD3 
End 
of Txb 
Follow 
Upp 
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 
X 
 
 
 
 
 
 
 
 
 
 
Toxicity evaluation 
X 
X 
 
 
 
 
X 
X 
 
X 
X 
X 
CBC / differential / plateletse 
X 
X 
 
 
 
 
X 
X 
X 
Xf 
X 
 
PTT, INR, TSHe 
X 
 
 
 
 
 
 
 
 
 
 
 
BMP, glucose, magnesiume 
X 
X 
 
 
 
 
X 
X 
 
X 
 
 
LFTs 
X 
X 
 
 
 
 
X 
X 
 
X 
 
 
Beta 2 microglobuling 
X 
 
 
 
 
 
 
X 
 
 
X 
 
12-lead ECGh 
X 
 
 
 
 
 
 
X 
 
 
 
 
Serum monoclonal protein 
assessmentsi 
X 
Xi 
 
 
 
 
Xi 
Xi 
 
Xi 
Xi 
 
24hr urine for creatinine 
clearance 
X 
 
 
 
 
 
 
 
 
 
 
 
24hr urine monoclonal protein 
and immunofixationj 
X 
Xj 
 
 
 
 
Xj 
Xj 
 
Xj 
Xj 
 
BM biopsy, unilateralk    
X 
 
 
 
 
 
 
 
Xk 
 
Xk  
 
CT-011 Given 
 
X 
 
 
 
 
X 
X 
X 
X 
 
 
Prescribe lenalidomide via 
RevAssistl 
X 
 
 
 
 
 
 
     
 
 
 
 
T-cell, NK-cell, and CD14 
Correlative studiesm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

OSU-13128 - Amd 6 - 26Jan2016 
34
CT-011 PKn 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
ADA (immunogenicity)o 
X 
 
 
 
 
 
 
 
 
 
 
 
a. With the exception of PK samples, all othertime points 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. Lenalidomide and dexamethasone will start on day 1 of each cycle.  Patients 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 serum ß-HCG) will also be ordered at this time. Patients 
must have a negative ß-HCG result prior to starting lenalidomide on day 1 of each cycle.        
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. CBC/d/p should also be checked on day 17 of a cycle where lenalidomide’s dose has been escalated.  
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 electropheresis & immunofixation, immunoglobulin levels, serum free light chain assay) will be 
performed on day 3 of each cycle (when patients come in for CT-011 infusion)  as well as off study.   
j. 
24hr urine monoclonal protein assessment (Urine protein electropheresis & 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. T-cell, NK-cell, and CD14 correlates will be collected prior to CT-011 dosing on C1D3, C1D4, C1D6, C1D10, C1D17 and then on Day 3 of all 
subsequent cycles. T-cell correlates only will also be collected at 1, 3, and 6 months after discontinuation of protocol therapy.  
n. Samples for CT-011 PK determination will be collected  in cycle 1 prior to CT-011 infusion, immediately at the end of the infusion, 1 hour after end of 
infusion, approximately 24(C1D4), 72(C1D6), 168 (C1D10)) & 336 (C1D17)) hrs– and just prior to next (cycle 2) infusion. Off-study correlates should be 
obtained at the time the patient is removed from protocol for any reason. 
o. We will assess for immunogenicity at baseline and monthly starting 1 month after dose level 3 (3 mg/kg) is started. This will be done within 30 minutes of 
CT-011 infusion. This will be done by Medivation Inc. (see Appendix G) 
p. Adverse events 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. Follow up data should be submitted at 1 month after protocol therapy discontinuation and then every 3 months until 
progression or death, whichever occurs first.   
 

OSU-13128 - Amd v26Jan2016 
35  
6.0      STATISTICAL CONSIDERATIONS 
6.1 Overview of study design 
 
This is a phase I/II clinical trial designed to first determine the MTD of the combination of CT-011 + 
lenalidomide in relapsed/refractory MM patients and then to assess the associated efficacy of this 
regimen in this patient population through evaluation of the overall response rate. The phase I portion 
follows the standard cohorts-of-3 phase I clinical trial design, and the phase II portion will utilize a 
one-stage three outcome phase II design (Sargent et al, 2001).  
 
6.1.1 Phase I portion 
 
In the phase I portion, we will assess the MTD using a standard cohorts-of-3 phase I trial design, 
where the MTD is defined as the dose level at which no more than one of 6 patients experiences a 
dose-limiting toxicity (DLT). The dose escalation rules follow the standard design, where cohorts of 3 
are accrued to a dose level and evaluated for DLT before making a decision to dose escalate or not. 
If in the first 3 patients on a dose level there are no DLTs observed, the next cohort of 3 can be 
accrued to the next dose level. If one DLT of the first 3 patients at a dose level experiences DLT, then 
3 additional patients will be accrued to that dose level to ensure it is tolerable and does not exceed 
the MTD. Any dose that has two or more patients with DLTs has exceeded the MTD and is deemed 
to have unacceptable toxicity. If the first dose level proves to have unacceptable toxicity (i.e. 2+ 
DLTs), then 3-6 patients will be accrued to the de-escalation dose level (dose level -1). For this 
portion of the trial, we expect a minimum of 12 patients (worst case scenario of 2+ DLTs on dose 
level cohorts 1, -1, and -2) and a maximum of 30 patients (e.g. 6 at each of the 4 dose levels and an 
intermediate dose level). Adverse events and toxicities will be summarized using the NCI CTCAE 
version 4 and based on severity and perceived attribution to study treatment; these outcomes will be 
assessed and tabulated by dose level.  
 
 
6.1.2 Phase II portion 
 
Previous studies of lenalidomide alone in a similarly defined relapsed/refractory MM patient 
population has shown an overall response rate of 25%, which also included the addition of 
dexamethasone after 2 cycles to non-responding stable disease patients. We will consider this 
regimen promising if the true overall response rate is 50% or greater when lenalidomide is combined 
upfront with CT-011. Therefore, we will test the null hypothesis that the true overall response rate 
(ORR) is at most 25% (reflecting a combination regimen ORR that would not be of interest) versus 
our alternative hypothesis that the true ORR in patients treated with this combination regimen is at 
least 50%.  
 
Decision Rule: The largest response rate where this treatment regimen would be considered 
ineffective in this population is 25%, and the smallest response rate that would warrant subsequent 
studies with this proposed regimen in this patient population is 50%. The following Three-Outcome 
phase II study design is a modification of the standard one-stage phase II design and uses a 
maximum of 29 evaluable patients to test the null hypothesis that the true response rate is at most 
25%. Since we will include the 6 patients treated at the MTD from the phase I portion of the trial, this 
will require accruing an additional 23 evaluable patients for this phase of the study. Based on this 
study design, there are three possible outcomes: 
 

OSU-13128 - Amd v26Jan2016 
36  
 “Not promising”: This regimen will be classified as not promising with respect to the response 
rate in this patient population if at most 9 patients have any response after 4 cycles of therapy 
out of the total 29 evaluable patients.  
 “Promising”: This regimen will be classified as promising with respect to increasing the 
response rate in this patient population if at least 12 patients have an observed response to 
treatment after 4 cycles of therapy out of the total 29 evaluable patients. Subsequent larger 
confirmatory studies may be warranted.  
 “Inconclusive”: The results of this study will be classified as inconclusive with respect to this 
regimen demonstrating an improved response rate if only 10 or 11 of the 29 total evaluable 
patients have a response after 4 cycles of therapy. In this case, other factors such as 
progression-free survival, toxicity, and correlative outcomes will be used in addition to the 
response data to make the final determination as to whether or not this treatment is considered 
promising and worthy of further study in this patient population.  
 
In this type of three-outcome phase II design with an uncertainty region, the associated errors are not 
the same as in the standard phase II study designs. In this study, the type I and type II error rates are 
constrained at 4% and 3%, respectively; The other parameters included in this type of design are eta 
(the probability of determining that a regimen is not worth pursuing further when it truly is not 
effective) and pi (the probability of determining that a regimen is promising when it truly is). Under this 
design, eta=0.83 and pi=0.87.  
 
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 CT-
011. In particular, we will evaluate biological and cellular markers in patients treated with CT-011, 
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 CT-011 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 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 

OSU-13128 - Amd v26Jan2016 
37  
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. 
 
6.2 
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. 
 
6.3 
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. 
 
6.4 
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-13128 - Amd v26Jan2016 
38  
6.5 
Prohibited treatments 
The use of concomitant chemotherapy, 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 4 weeks prior to first dose administration. Concomitant radiotherapy during treatment 
for palliation of pain may be permissible with prior approval of study PI.  Radiotherapy should be 
directed to a localized area (involved field radiotherapy) and cannot exceed 25Gy. Radiotherapy to 
more than one localized area at a time is not allowed.   Participation in any clinical study involving any 
medications or treatments, whether approved or investigational, is prohibited. 
 
7.0 
REGISTRATION PROCEDURES 
7.1 
Registration Guidelines 
Eligible patients will be entered on study centrally at The Ohio State University. OSU patients will be 
registered by the OSU Clinical Research Coordinator/Specialist. Subsite patients will be registered by 
the OSU Subsite Coordinator. 
 
Following registration, patients should begin protocol treatment within 72 hours. Issues that would 
cause treatment delays should be discussed with the Principal Investigator. If a patient does not 
receive protocol therapy following registration, the patient’s registration may be canceled, pending 
approval by the Principal Investigator who will determine whether the patient will be replaced. 
Patients that do not receive any protocol therapy will not be evaluable for toxicity or response 
 
7.2 
Assignment of Study Numbers 
Each patient enrolled in the study will be registered in the OSU database. Each patient enrolled will 
be assigned a sequential study identifier by the study team. 
 
7.3 
Study Records 
Study data will be collected in standardized case report forms (CRF). The investigator or designate 
will record all patient information, including patient identification, disease stage, previous treatment, 
as well as information concerning drug administration, results of laboratory tests, toxicity and efficacy 
data.  
 
A specific form will be used for recording and reporting serious adverse events as defined in section 
10. 
 
7.4 
Selection Procedures 
All eligible patients must be registered. This must be done before the start of treatment.  On receipt of 
all the necessary baseline information, a clinical research coordinator will assess whether the patient 
is eligible or not.  
 
7.5 
Subsite Patient Registration 
Subsite patients will have eligibility verified and will be centrally registered at The Ohio State 
University by the OSU Subsite Coordinator. Subsites should call or email the OSU Subsite 
Coordinator to verify enrollment availability prior to consenting patients. 

OSU-13128 - Amd v26Jan2016 
39  
 
Following registration, patients should begin protocol treatment within 72 hours. Issues that may 
cause treatment delays should be discussed with the OSU Principal Investigator and OSU Subsite 
Coordinator as soon as possible. The OSU Subsite Coordinator must be notified immediately if a 
patient does not receive protocol therapy. 
 
Only patients deemed eligible by the subsite research team should be submitted for eligibility 
verification and registration by the OSU Subsite Coordinator.  
 
To request subsite patient registration, the documents below must be completed by the subsite 
research team and faxed to the OSU Subsite Coordinator. The OSU secure email system may be 
used. Contact the OSU Subsite Coordinator for more information. 
 
Required documents for registration (refer to Supplemental Forms Document): 
 
 
Enrollment Form 
 
Signed Eligibility Checklis 
 
Source documents verifying every inclusion & exclusion criteria 
 
Required screening items as listed in the Protocol Calendar. Screening tests must be within 
the specified window. 
 
Signed informed consent document (and HIPAA form, if separate) 
 
Documentation of consent process 
 
Emails and other signed and dated documents used as source documentation 
 
The OSU Subsite Coordinator will confirm receipt of the registration documents with the subsite 
contact listed on the Enrollment Form (refer to Supplemental Forms Document). If confirmation is not 
received within 2 hours, it is strongly recommended that the subsite call the OSU Subsite Coordinator 
to confirm registration documents were received. 
 
Registration requests will be processed as soon as possible and no later than 1 business day after 
receipt of the registration documents, pending there is no additional information needed to complete 
eligibility verification. Registration will occur upon OSU confirmation that the patient meets eligibility 
criteria. 
 
The Subsite Coordinator will securely email the subsite contact listed on the Enrollment Form (refer to 
Supplemental Forms Document) with the registration confirmation and the patient’s assigned study 
number. 
 
 
8.0 
Correlative studies 
The focus of our correlative studies will be to study the immunogenicity of CT-011 through peripheral 
blood studies in the following general areas: 
 
  To assess pharmacokinetics (PK) and pharmacodynamics of CT-011 in combination with 
lenalidomide. 
 To assess CT-011 immunogenicity and correlative biologic studies to assess immunomonitoring of 
lymphocytes subsets including T and NK cells and ex-vivo assessment of immune functional 
activities.  
 

OSU-13128 - Amd v26Jan2016 
40  
8.1 
PK and correlative laboratory investigations 
Samples for CT-011 PK determination will be collected with cycle 1 prior to CT-011 infusion, 
immediately at the end of the infusion, 1 hour after end of infusion, approximately 24(C1D4), 
72(C1D6), 168 (C1D10) & 336 (C1D17) hrs– and just prior to cycle 2 CT-011 administration. CT-
011 blood levels will be assessed with a specific ELISA technique previously validated and 
derived concentrations will be used to calculate PK parameters.  We will compare these results 
with PK data obtained in the single agent phase I study previously completed to assess for any 
effects of co-administration of len on CT-011 PK.   
We will also assess for immunogenicity at baseline and monthly starting 1 month after dose level 
3 (3 mg/kg) is started. This will be done by Medivation Inc. (see Appendix G) 
 
We will also 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).   
 
8.2 
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- 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-
effect of therapy on levels of circulating tumor reactive T cells will be determined by quantifying IFN-
expressing CD4(+) and CD8(+) T cells.  The impact of CT-011 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 CT-011 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.   
 
 

OSU-13128 - Amd v26Jan2016 
41  
8.3 
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.  Preliminary data from another group suggest that CT-011 upregulates activation 
markers on NK cells in an in vitro system.58  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 CT-011 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 CT-011 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.59  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 one cycle of treatment and assess PD-L1 expression by flow 
cytometry.   
 
8.4 
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 CT-011 after each cycle of therapy.  We will specifically study the induction of these 
antigens on CD14(+) cells as a consequence of CT-011 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.   
 
9.0 
Investigational drugs 
9.1 
CT-011 
CT-011 (humanized monoclonal antibody) for parenteral administration is supplied as a 20 mg/mL 
clear solution in phosphate buffer saline and is preservative-free. The drug product is packaged in 
depyrogenated clear 6-mL glass vials (type 1 neutral glass) sealed with Tefloncoated gray chlorobutyl 
rubber stoppers and sealed with aluminum seals. Each vial consists of 5.25 mL of approximately 20 
mg/mL CT-011. 
 
Label Of The Drug:  The container label and the immediate outer carton label of the marketed 
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: The vials of CT-011 MUST be kept frozen as per US Pharmacopoeia, 
between -13ºF to 5ºF until use. Prior to planned infusion, the CT-011 drug product vial(s) must be 
thawed at room temperature for approximately 1 hour. Once thawed, the drug product should be 
diluted immediately into an infusion bag and administered to the patient as soon as possible. It is 
important to note that the thawed vials of CT-011 drug product can be held refrigerated at 2ºC to 8ºC 
(35ºF to 46ºF) for no longer than 7 days, though it is advised to use the thawed drug product 
immediately. The thawed drug product vials must not be frozen again. The infusion bag containing 

OSU-13128 - Amd v26Jan2016 
42  
CT-011 can be stored at room temperature for no longer than 2 hours prior to the initiation of infusion, 
though it is advised to administer drug product immediately. CT-011 vials or infusion bags that are not 
stored as described above (e.g. at longer periods of time or at higher temperatures) must not be used 
and must be discarded according to the Center’s policy for handling of unused drugs and only after 
drug accountability monitoring has been performed. 
 
Preparation of CT-011 For Administration: The solution will be prepared by a pharmacist, the 
Investigator, or a study nurse. Appropriate aseptic techniques should be used. Prior to infusion the 
vial(s) must be thawed at room temperature for approximately 1 hour; the vial(s) should be swirled 
gently to make sure that the solution is clear, colorless, and transparent. DO NOT SHAKE! Effort 
must be made so that once thawed; the drug will be diluted immediately into an infusion bag and 
administered to the patient as soon as possible (see Section 8.3 for drug product storage conditions). 
Each vial contains approximately 20 mg/mL CT-011. While most lots will be provided at this 
concentration, note that current specifications allow for a concentration range of 19mg/ml to 21mg/ml. 
Determine the total amount of CT-011 required based on the drug handling sheet provided keeping in 
mind that maximal total dose allowed is 600mg per patient  
 
The appropriate amount of CT-011 solution should be withdrawn from the vial(s) and added to an 
infusion bag containing 250 mL of 0.9% sodium chloride solution, USP. The bag will be identified with 
the patient number. The bag should then be gently inverted to mix the solution in order to avoid 
foaming. Parenteral solutions should be inspected visually for particulates and discoloration prior to 
administration. Once the infusion is prepared, it should be administered immediately. 
 
 Method of Administration:  CT-011 will be administered intravenously on day 3 of each 28 day 
cycle. The drug is diluted into a 250mL saline bag which in the FIRST infusion is administered in a 
step-wise manner: 50ml/hr for 30min; 100ml/hr for 30min; 150ml/hr for 30 min and 200ml/hr till the 
end (another ~30min) for an approximate time of 2hrs.  If no infusion related AEs occurs the first time, 
subsequent administrations are at 200mL/hr which will deliver the drug over approximately 1:15hrs.  
 In the event that Grade 3 or higher toxicity occurs during infusion, administration of CT-011 should 
be stopped immediately. Administration of CT-011 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. 
  
9.2 
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.  

OSU-13128 - Amd v26Jan2016 
43  
 
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 
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. 
 
10.0 PATIENT SAFETY 
10.1 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. 
10.2 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 

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44  
 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 once study drug treatment is initiated to within 30 days following 
cessation of treatment.  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 within 24 
hrs of the site becoming aware of the event to the IRB and ProductLife Ltd using the forms provided 
by Medivation Inc. for this purpose. 
 
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-13128 - Amd v26Jan2016 
45  
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 
    
10.3 Subsite SAE Reporting Requirements 
NOTE: Subsite institutions are NOT permitted to report directly to the FDA or The Ohio State 
University Office of Responsible Research Practices. All reports must be sent to the OSU 
Principal Investigator and Subsite Coordinator for submission to the FDA and ORRP. 
 
Subsites must report SAEs to their IRB of record as per their institutional and IRB policies. 
 
Subsites must report all SAEs to the lead Principal Investigator and the OSU Subsite Coordinator 
within 24 hours of knowledge of the event. SAEs are to be reported on MedWatch 3500A form and 
submitted with the SAE Submission Form (refer to Supplemental Forms Document). All SAEs and 
unanticipated problems involving risk to subjects or others will be reported by the OSU Subsite 
Coordinator following institutional and FDA guidelines.  In addition, all serious adverse events (SAEs) 
are reported by the OSU Subsite Coordinator to The Ohio State University Office of Responsible 
Research Practices, Medivation Inc. via ProductLife Ltd and to the Food and Drug Administration 
(FDA) if applicable and within the timeframes outlined in the below table. Subsite institutions are NOT 
permitted to directly report to The Ohio State University Office of Responsible Research Practices, 
Medivation Inc., ProductLife Ltd or FDA. All AE/SAEs will be reported to the DSMC at the quarterly 
DSMC review meetings; however, the investigator determines corrective action is necessary, and “ad 
hoc” DSMC meeting will be called. 
 
Fatal adverse events related to treatment which are unexpected must be reported within 24 
hours of the Investigators first awareness of the event to the OSU Principal Investigator, OSU 
Subsite Coordinator and Medivation Inc. via ProductLife Ltd. The OSU Subsite Coordinator 
will immediately report to The Ohio State University Office of Responsible Research Practices 
and the DSMC. Fatalities not related to the study drug/device must be reported within 5 days.  
 
10.4 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 ProductLife LTD by 
fax [0 800 022 4815] within 24 hrs of the site becoming aware of the event and to the IRB within 
respective required guidelines.  If fax is not available, the form may be scanned and emailed to 
safety@productlife-group.com.  This applies to initial and follow-up information. 
 

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46  
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 and to 
Medivation Inc via ProductLife Ltd. 
 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 and to Medivation Inc, 
designated pharmacovigilance representative, ProductLife Ltd, using the forms provided by 
Medivation Inc. for this purpose. 
 
10.5 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 which occur within 30 days of discontinuation of dosing or completion of the patient’s 
participation in the study if the last scheduled visit occurs at a later time.   
 
10.6 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. 
 
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 postimplantation losses and fetal variations (morbidity/purple-discolored skin, 
undeveloped intermediate lung lobe, irregular nasal-frontal suture, and delayed metacarpal 
ossification)60. 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. 
 
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 

OSU-13128 - Amd v26Jan2016 
47  
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 
& Medivation Inc. (See Safety reporting section). 
 
It is not known whether lenalidomide or CT-011 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.   
 
10.7 Patient Withdrawal and Study Termination 
A patient should be withdrawn from the trial treatment if, in the opinion of the investigator, it is 
medically necessary, or if it is the wish of the patient.  If a patient does not return for a scheduled visit, 
every effort should be made to contact the patient.  In any circumstance, every effort should be made 
to document patient outcome, if possible. 
 
Patients should be removed from therapy if any of the following occurs: 
 
 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. 
 Patient refusal to continue with therapy. 
 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. 
 Termination of the study. 
 
If a patient withdraws from protocol therapy, it should be clearly documented with additional notation 
of whether the patient has agreed to complete follow up as outlined in the protocol. Subsite 

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48  
institutions must notify the OSU Subsite Coordinator as soon as possible if the patient withdraws from 
protocol therapy and must provide the documentation of the reason and whether the patient will 
complete follow up. 
 
The reason and date of discontinuation are to be documented in the patient’s medical record and in 
the CRF.  
 
The investigator should complete all end of treatment procedures when a patient withdraws from 
treatment.  All patients who discontinue the trial secondary to an adverse event should be followed 
until resolution, stabilization or return to a baseline condition. 
 
Patients who fail to complete treatment for reasons other than adverse event or unacceptable toxicity 
may be replaced.  All patients who receive one dose of study treatment should be included in any 
safety analysis. 
 
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.  
 
 

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Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a 
humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer 
Res. 2008;14:3044-3051. 
51. 
Rotem-Yehudar R, Armand P, Devine S, et al. The Humanized Anti PD-1 Antibody, CT-011, Increases 
Specific CD4+ Effector/Memory and Memory T Lymphocytes in Patients with Diffuse Large B Cell 
Lymphoma (DLBCL) Following Autologous Stem Cell Transplantation (AuSCT). ASH Annual Meeting 
Abstracts. 2009;114:1216-. 
52. 
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;305:1222-1232. 
53. 
Hayashi T, Hideshima T, Akiyama M, et al. Molecular mechanisms whereby immunomodulatory drugs 
activate natural killer cells: clinical application. Br J Haematol. 2005;128:192-203. 
54. 
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;57:1849-1859. 
55. 
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;112:4445-4451. 
56. 
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;82:426-432. 
57. 
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;10:155-167. 
58. 
Chu F FM, Qin H, et. al. In vitro and in vivo effects of CT-011, a humanized anti-PD-1 monoclonal antibody, in 
combination with rituximab against human B-cell lymphomas. Blood. 2009;114. 
59. 
Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127:759-767. 
60. 
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;80:188-207. 
61. 
Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple 
myeloma. Leukemia. 2006;20:1467-1473. 
 
 
 

OSU-13128 - Amd v26Jan2016 
52  
Appendix A: 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-13128 - Amd v26Jan2016 
53  
 
Appendix B: 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 61, and characterized as follows: 
 

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55  
Appendix C: 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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56  
Appendix D:  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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix E:  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 Medivation Inc.  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 
Medivation Inc.  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 Medivation Inc. or its representatives, IRB, providing direct 
access to the facilities where the study took place, to source documents, and to all other study 
documents. 
The Investigator, or a designated member of the Investigator’s staff, must be available at some time 
during monitoring visits to review data and resolve any queries and to allow direct access to the 
subject’s records (e.g., medical records, office charts, hospital charts, and study related charts) for 
source data verification.  The data collection must be completed prior to each visit and be made 
available to the Medivation Inc. representative so that the accuracy and completeness may be 
checked. 
 
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 the minutes. 
The PI 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 PI and compared to what is known about the agent/device 

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58  
from other sources; including published literature, scientific meetings and discussions with the 
sponsors, to determine if the trial should be terminated before completion. Serious adverse events 
and responses will also be reviewed by the OSUCCC Data and Safety Monitoring Committee 
(DSMC). The PI will also submit a progress report quarterly that will be reviewed by the committee 
per the DSMC plan. All reportable Serious Adverse Events (SAE) will also be reported to the IRB of 
record as per the policies of the IRB. 
Subsite institutions are expected to perform internal data and safety monitory and must submit the 
findings to the OSU Subsite Coordinator. Likewise, the OSU Data and Safety Monitoring reports will 
be distributed to the subsite institutions participating in this study. 
 
Monthly safety and trial review teleconferences will be scheduled and moderated by the Multi-
Institution Program. All sites involved in the study are expected to have a representative present 
every month to review and discuss patients on study and other applicable agenda items. Meeting 
minutes will be used to document each monthly teleconference. The minutes will be stored in the 
Multi-Institution Program protocol files. 
 
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 Medivation Inc. (see contact information 
in section “Serious Adverse Events”) 
All subsite consents must be sent to the OSU Subsite Coordinator for review and approval prior to 
submission to the local IRB. In addition, all subsite IRB approval letters for amendments and annual 
renewals must be sent to the OSU Subsite Coordinator in a timely manner. 
 
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.. 
 

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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. 
All subsite data is to be submitted within 2 weeks of completion of each cycle of therapy. Refer to the 
Data Submission Form in the Supplemental Forms Document for submission information. 
 
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 Medivation Inc., 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. 
 
The investigator is required to retain, in a confidential manner, sufficient information on each 
participant (specifically, full name; current address; and social security number), so the participant 
may be contacted by the FDA or the Ohio State University, should the need arise. 

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60  
 
Appendix F:  REV-ASSIST GUIDELINES 
As of 11-Sep-2008, 
 
 
 
 

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62  
 
Appendix G: 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: 
 
A. Immunogenicity  
3.0mL of whole blood should be transferred to a tube without anticoagulant for the generation of 
serum for the performance of immunogenicity evaluation (serum will be generated as per the 
standard Center's procedure).  Approximately 1.5 mL serum will be collected per patient per sampling 
time and will be divided into separate test tubes that will be clearly labeled with the following 
information:  test type (IMM), patient study identification number, visit number, date and time of blood 
withdrawal. 
4 tubes, each containing 200 µL serum will be stored at -80°C pending shipment instructions by 
Medivation Inc. or a designated laboratory. A -20°C freezer could serve as an alternative in the event 
that the center does not have access to a -80°C freezer. In such an instance, shipment of of serum 
samples will be made within 30 days from date of serum collection.  
The kits containing tubes, packaging material, shipment forms will be provided by Medivation Inc. 
Each kit contains all the material that is needed to collect the samples for one visit. The packaging 
material and shipment forms will be provided by the courier company. 
 
B. Pharmacokinetics  
3.0 mL of whole blood should be transferred to a tube without anticoagulant for the generation of 
serum for the performance of immunogenicity evaluation (serum will be generated as per the 
standard Center's procedure).  Approximately 0.6 mL serum will be collected per patient per sampling 
time and will be divided into separate test tubes that will be clearly labeled with the following 
information:  test type (PK), patient study identification number, visit number, date and time of blood 
withdrawal. 
4 tubes, each containing 200 µL serum will be stored at -80°C pending shipment instructions by 
Medivation Inc. A -20°C freezer could serve as an alternative in the event that the center does not 
have access to a -80°C freezer. In such an instance, shipment of serum samples to the testing lab will 
be made within 30 days from date of serum collection.  
The kits containing tubes, packaging material, shipment forms will be provided by Medivation Inc. 
Each kit contains all the material that is needed to collect the samples for one visit. The packaging 
material and shipment forms will be provided by the courier company. 
 
ANY REMAINING SERUM THAT IS NOT USED IN ANY OF THE TESTS ABOVE SHOULD BE 
DISCARDED AS REQUIRED BY THE CENTER'S RELEVANT POLICIES.