Clinical trial NCT01441063
Conditions: Castleman Disease Multicentric Castleman Disease Giant Lymph Node Hyperplasia
Keywords: Kaposi Sarcoma Herpesvirus Human Immunodeficiency Virus Tocilizumab Multicentric Castleman Disease Interleukin-6 Castleman Disease Acquired Immunodeficiency Syndrome (AIDS) Human Herpesvirus-8
Sponsor: National Cancer Institute (NCI)
Start date: 2011-09-13; Completion date: 2020-10-05
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Kaposi's sarcoma-associated herpes virus (KSHV)-associated multicentric Castleman disease (KSHV-MCD) is caused by a herpes virus known as KSHV. This disease can also cause several other cancers, including Kaposi sarcoma. People with KSHV-MCD often have symptoms like fever, weight and muscle loss, and fluid in the legs or abdomen. Tocilizumab may be able to block the chemicals in the body that cause KSHV-MCD symptoms. Researchers want to test this drug and other anti-virus drugs to find the best combination of drugs to treat KSHV-MCD.

Objectives:

\- To test the effectiveness of tocilizumab with and without other anti-virus drugs for KSHV-MCD.

Eligibility:

\- People at least 18 years of age who have KSHV-MCD and have certain symptoms and blood abnormalities caused by their KSHV-MCD.

Design:

* Participants will be screened with a medical history and physical exam. They will also have blood tests, and a skin biopsy.
* Participants will have tocilizumab injections every 2 weeks for up to 12 weeks. They will provide daily blood samples for the first 3 days of treatment.
* After the sixth dose, participants will be monitored for 4 weeks to check for possible side effects.
* Those whose KSHV-MCD does not improve or worsens during the study may have tocilizumab combined with two other anti-virus drugs, zidovudine and valganciclovir. These drugs are pills that will be taken four times a day for 5 days out of every 2 weeks.
* Blood, urine, and saliva samples will be collected throughout the study.

Detailed description:
BACKGROUND:

* Kaposi sarcoma herpesvirus-associated multicentric Castleman disease (KSHVMCD) is a rare lymphoproliferative disorder that develops predominantly in human immunodeficiency deficiency virus (HIV) infected patients. Patients often have symptoms from interleukin-6 (IL-6), KSHV encoded viral IL-6 (vIL-6), and other cytokines
* Goals of therapy include rapid resolution symptoms and elimination of reservoirs of KSHV-infected plasmablasts.
* Tocilizumab is a humanized anti-IL-6 receptor (gp80) antibody with activity against MCD unrelated to KSHV (KSHV-negative MCD). While tocilizumab does not directly affect vIL-6 signaling or other KSHV driven pathologic processes, IL-6 overproduction plays a major role in symptoms in KSHV-MCD, and blocking IL-6 may be sufficient to treat this disorder by blocking autocrine and paracrine stimulation. Combination with zidovudine (AZT) and valganciclovir (VGC), agents that target KSHV replication, have virus-activated cytotoxic activity, and are active in KSHV-MCD may be useful and necessary in some patients.

OBJECTIVES:

* Primary objective: Estimate clinical benefit of tocilizumab 8mg/kg every 2 weeks for up to 12 weeks in patients with symptomatic KSHV-MCD using a modified KSHVMCD Clinical Benefit Response Criteria
* Secondary objectives:
* Estimate best clinical, biochemical, radiographic, and overall responses in patients with KSHV-MCD treated for up to 12 weeks with tocilizumab 8mg/kg every 2 weeks using the prior National Cancer Institute (NCI) KSHV-MCD Response Criteria.
* In patients with inadequate response to tocilizumab monotherapy: explore preliminarily the activity of tocilizumab 8mg/kg every 2 weeks, combined with AZT 600 mg orally q6 hours and VGC 900 mg orally q12 hours on days 1-5 of a 14-day cycle
* Evaluate safety and tolerability of tocilizumab alone and combined with AZT/VGC
* Evaluate the effect of tocilizumab on the pharmacokinetics of antiretroviral agents that are Cytochrome P450 3A4 (CYP3A4) substrates in patients with symptomatic KSHV-MCD
* Evaluate progression-free and overall survival of patients treated with tocilizumab and tocilizumab/AZT/VGC
* Evaluate of effect of tocilizumab on KS

Eligibility

* Pathologically confirmed KSHV-associated MCD
* Age greater than or equal to 18
* At least one clinical symptom and at least one laboratory attributable to KSHV-MCD
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
* No life- or organ-threatening manifestations of MCD
* Patients requiring therapy for rheumatoid arthritis will be excluded
* HIV-infected patients must agree to continue or start combination antiretroviral therapy

DESIGN:

* Open label, single center pilot study. Eligible patients receive tocilizumab 8 mg/kg every 2 weeks for up to 12 weeks. In addition, patients requiring treatment intensification also receive AZT 600 mg orally q6 hours and VGC 900 mg orally q12 hours on days 1-5 of a 14-day cycle.
* Sample size 17: two stage phase II design, alpha equals beta equals 0.10, ruling out \<20% KSHV-MCD Clinical Benefit Partial Response or better with tocilizumab and targeting a \>50% KSHV-MCD Clinical Benefit Partial Response or better requires 10 in the first stage. 0-2 of 10 major response: stop accrual, 3+/10: accrual to 17 total.
* Responses evaluated by KSHV-MCD Clinical Benefit Response Criteria and NCI KSHV-MCD criteria under prospective evaluation.
* Safety and tolerability evaluated using current Common Terminology Criteria for Adverse Events (CTCAE).

Arms: arm 1: Tocilizumab 8 mg/kg on Day 1 of a 14 day cycle a maximum of 6 cycles. If indicated, zidovudine (AZT) and valganciclovir (VGC) will be administered concurrently with tocilizumab, with day 1 of the cycle being the day tocilizumab is administered.
Interventions: intervention 1: Zidovudine intervention 2: Tocilizumab intervention 3: Valganciclovir (VGC)
Intervention descriptions: intervention 1: Zidovudine (AZT) 600 mg orally q6 hours (every 6 hours) intervention 2: Tocilizumab 8mg/kg every 2 weeks intervention 3: Valganciclovir (VGC) 900 mg orally q12 hours (every 12 hours) on days 1-5 of a 14-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title: Tocilizumab in KSHV-MCD 
Version Date: 05/30/2019 
 
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Abbreviated Title: Tocilizumab in KSHV-MCD 
CC Protocol #: 11-C-0233 F 
Version Date: 5/30/2019 
NCT Number: NCT01441063 
Pilot Study of Tocilizumab in Patients with Symptomatic Kaposi Sarcoma Herpesvirus 
(KSHV) - associated Multicentric Castleman Disease 
 
NCI Principal Investigator:    
Robert Yarchoan, M.D, A-F 
 
 
HAMB/CCR/NCI 
 
 
 
 
 
10 Center Drive, 6N-106 
 
 
 
 
 
Bethesda, MD 20892-1868 
 
 
 
 
 
240-760-6075 
 
 
 
 
 
robert.yarchoan@nih.gov   
 
 
Investigational agents: none 
Commercial Agents: Tocilizumab, Zidovudine and Valganciclovir  
 
 


Abbreviated Title: Tocilizumab in KSHV-MCD 
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PRÉCIS  
Background: 
x Kaposi sarcoma herpesvirus-associated multicentric Castleman disease (KSHV-MCD) is a 
rare lymphoproliferative disorder that develops predominantly in HIV-infected patients. 
Patients often have symptoms from interleukin-6 (IL-6)(1-4), KSHV-encoded viral IL-6 
(vIL-6)(3,5-8), and other cytokines 
x Goals of therapy include rapid resolution symptoms and elimination of reservoirs of KSHV-
infected plasmablasts.  
x Tocilizumab is a humanized anti-IL-6 receptor (gp80) antibody with activity against MCD 
unrelated to KSHV (KSHV-negative MCD)(9). While tocilizumab does not directly affect 
vIL-6 signaling or other KSHV driven pathologic processes, IL-6 overproduction plays a 
major role in symptoms in KSHV-MCD, and blocking IL-6 may be sufficient to treat this 
disorder by blocking autocrine and paracrine stimulation. Combination with zidovudine 
(AZT) and valganciclovir (VGC), agents that target KSHV replication, have virus-activated 
cytotoxic activity(10), and are active in KSHV-MCD(11) may be useful and necessary in 
some patients. 
 
Objective: 
x Primary objective: Estimate clinical benefit of tocilizumab 8mg/kg every 2 weeks for up to 
12 weeks in patients with symptomatic KSHV-MCD using a modified KSHV-MCD Clinical 
Benefit Response Criteria  
 
Eligibility 
x Pathologically confirmed KSHV-associated MCD 
x Age ≥ 18 
x At least one clinical symptom and at least one laboratory attributable to KSHV-MCD 
x ECOG performance status ≤ 2 
x No life- or organ-threatening manifestations of MCD 
x Patients requiring therapy for rheumatoid arthritis will be excluded 
x HIV-infected patients must agree to continue or start combination antiretroviral therapy 
 
Design: 
x Open label, single center pilot study. Eligible patients receive tocilizumab 8 mg/kg every 2 
weeks for up to 12 weeks. In addition, patients requiring treatment intensification also 
receive AZT 600 mg orally q6 hours and VGC 900 mg orally q12 hours on days 1-5 of a 14-
day cycle. 
x Sample size 17: two stage phase II design, D=E=0.10, ruling out <20% KSHV-MCD Clinical 
Benefit Partial Response or better with tocilizumab and targeting a >50% KSHV-MCD 
Clinical Benefit Partial Response or better requires 10 in the first stage. 0-2 of 10 major 
response: stop accrual, 3+/10: accrual to 17 total.   
x Responses evaluated by KSHV-MCD Clinical Benefit Response Criteria and NCI KSHV-
MCD criteria under prospective evaluation.   


Abbreviated Title: Tocilizumab in KSHV-MCD 
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x Safety and tolerability evaluated using current CTCAE. 
 


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TABLE OF CONTENTS 
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
1 
INTRODUCTION .................................................................................................................. 6 
1.1 
Study Objectives ............................................................................................................. 6 
1.2 
Background and Rationale .............................................................................................. 6 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ....................................................... 11 
2.1 
Eligibility Criteria ......................................................................................................... 11 
2.2 
Screening Evaluation .................................................................................................... 13 
2.3 
Registration Procedures ................................................................................................ 15 
2.4 
Baseline Evaluation ...................................................................................................... 15 
2.5 
On Study Assessments .................................................................................................. 18 
3 
STUDY IMPLEMENTATION ............................................................................................ 20 
3.1 
Study Design ................................................................................................................. 20 
3.2 
Drug Administration ..................................................................................................... 22 
3.3 
Dose Modifications ....................................................................................................... 22 
3.4 
Study Calendar .............................................................................................................. 25 
3.5 
Radiation Therapy Guidelines ...................................................................................... 26 
3.6 
Criteria for Removal from Protocol Therapy and Off Study Criteria ........................... 26 
4 
SUPPORTIVE CARE/CONCURRENT THERAPIES ........................................................ 27 
4.1 
General KS and HIV Related ........................................................................................ 27 
4.2 
Opportunistic infections ................................................................................................ 27 
4.3 
Anemia .......................................................................................................................... 27 
4.4 
Thrombocytopenia ........................................................................................................ 27 
4.5 
Febrile Neutropenia ...................................................................................................... 27 
4.6 
Concurrent Therapies .................................................................................................... 28 
5 
BIOSPECIMEN COLLECTION .......................................................................................... 29 
5.1 
Correlative Studies for Research/Pharmacokinetic Studies .......................................... 29 
5.2 
Sample Storage, Tracking and Disposition ................................................................... 30 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 34 
6.1 
Data Collection ............................................................................................................. 34 
6.2 
Response Criteria .......................................................................................................... 35 
6.3 
Toxicity Criteria ............................................................................................................ 44 
7 
NIH REPORTING REQUIREMENTS / DATA SAFETY MONITORING PLAN............ 45 
7.1 
Definitions..................................................................................................................... 45 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting - ................................... 45 
7.3 
NIH Required Data and Safety Monitoring Plan .......................................................... 45 
8 
STATISTICAL CONSIDERATIONS.................................................................................. 46 
8.1 
Racial/gender make-up ................................................................................................. 46 
8.2 
Age exclusion................................................................................................................ 46 
8.3 
Sample size considerations and Statistical Plan............................................................ 46 


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9 
HUMAN SUBJECTS PROTECTIONS ............................................................................... 48 
9.1 
Rationale For Subject Selection .................................................................................... 48 
9.2 
Participation of Children ............................................................................................... 49 
9.3 
Participation of Subjects Unable to Consent ................................................................ 49 
9.4 
Evaluation of Benefits and Risks/Discomforts ............................................................. 49 
9.5 
Risks/Benefits Analysis ................................................................................................ 50 
9.6 
Consent and Assent Process and Documentation ......................................................... 50 
10 PHARMACEUTICAL INFORMATION ............................................................................. 51 
10.1 
Tocilizumab .................................................................................................................. 51 
10.2 
Zidovudine (AZT) ......................................................................................................... 51 
10.3 
Valganciclovir / Ganciclovir ......................................................................................... 51 
11. 
REFERENCES ................................................................................................................. 53 
12. 
APPENDICES .................................................................................................................. 60 
12.1. Appendix 1: KSHV-MCD Clinical Benefit Response Criteria .................................... 60 
12.2. Appendix 2: KSHV-associated multicentric Castleman disease response criteria 
(Evaluated in 04-C-0275) ......................................................................................................... 61 
12.3. Appendix 3: MCD Response Assessment tools............................................................ 64 
12.4. Appendix 4: Modified ACTG Kaposi Sarcoma Response Worksheets ....................... 66 
12.5. Appendix 5: Performance Status Scales ....................................................................... 68 
 
 
 


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1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
 Primary Objective 
1.1.1.1 Estimate clinical benefit of tocilizumab 8mg/kg every 2 weeks for up to 12 weeks in 
patients with symptomatic KSHV-MCD using a modified KSHV-MCD Clinical Benefit 
Response Criteria (Appendix 1) 
 Secondary Objectives 
1.1.2.1 Evaluate best clinical, biochemical, radiographic, and overall response in patients with 
KSHV- associated MCD treated for up to 12 weeks with tocilizumab 8mg/kg every 2 
weeks using the prior NCI KSHV-MCD Response Criteria (Appendix 2). 
1.1.2.2 In patients with inadequate response to tocilizumab monotherapy: explore preliminarily 
the activity of tocilizumab 8mg/kg every 2 weeks, combined with zidovudine (AZT) 
600 mg orally q6 hours (every 6 hours) and valganciclovir (VGC) 900 mg orally q12 
hours (every 12 hours) on days 1-5 of a 14-day cycle. 
1.1.2.3 Evaluate safety and tolerability of tocilizumab alone and in combination with 
AZT/VGC in this patient population  
1.1.2.4 Evaluate the effect of tocilizumab on the pharmacokinetics of antiretroviral agents that 
are CYP3A4 substrates in patients with symptomatic KSHV-MCD 
1.1.2.5 Evaluate of effect of therapy on KS using modified ACTG response criteria 
1.1.2.6 Evaluate progression-free and overall survival with tocilizumab and 
tocilizumab/AZT/VGC. 
1.2 
BACKGROUND AND RATIONALE 
Kaposi sarcoma herpesvirus-associated multicentric Castleman disease (KSHV-MCD)(12) is a 
rare lymphoproliferative disorder characterized by severe inflammatory symptoms and a waxing 
and waning course that is eventually lethal if untreated.  It arises predominantly in HIV-infected 
patients.  There is no standard therapy. Goals of therapy include rapid resolution of interleukin-6 
(IL-6)(1-4) associated symptoms and elimination of reservoirs of pathogenic KSHV-infected 
cells. 
Rituximab has emerged as an effective agent in the treatment KSHV-MCD(1), but can be 
associated with a worsening of KS(13,14).  The pathophysiology of this deleterious effect is 
unknown, but may be due to the adverse effects of B-cell depletion(15-17) on antigen 
presentation or KSHV-specific antibodies(18,19).  The risk for additional rare but serious 
infectious complications persist beyond the actual dosing of rituximab(20,21).  The mechanism 
of action of rituximab in KSHV-MCD is unknown. The pathogenic cells of interest in KSHV-
MCD are KSHV-infected, vIL-6 expressing, O-restricted plasmablasts(22,23) predominantly in 
the mantle zones of lymph nodes.  The KSHV infected cells themselves are generally CD20 
negative(24,25); however, CD20 cells are frequently noted in KSHV uninfected lymphocytes 
within KSHV-MCD lymph node specimens(26) (personal observation, Uldrick, Pittaluga, 
Yarchoan, Figure 1), and it is likely that depletion of CD20 + cells with the use of rituximab 


Abbreviated Title: Tocilizumab in KSHV-MCD 
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results in diminution of autocrine and paracrine signaling in the tumor microenvironment from 
human IL-6 and other cytokines).(27-32) 
 
 
Figure 1. CD20 immunohistochemistry (brown), high power field of mantle zone of a 
lymph node in a patient with symptomatic KSHV-MCD.  No evidence of CD20+ KSHV 
infected cells noted, CD20 negative plasmablasts, circled in red.  Slide from S. Pittaluga. 
Like MCD in patients not infected with KSHV, inflammatory symptoms and laboratory 
abnormalities are associated with marked increases in IL-6(3,4). Unique to KSHV-MCD, a 
KSHV encoded viral homologue, vIL-6(3,6-8) can be detected in the serum of most patients and 
likely contributes to disease pathogenesis and symptoms.  Human IL-6 signal transduction 
requires IL-6 to first bind a co-receptor that may be either membrane bound or soluble, IL-6 
receptor (gp80).  The IL-6/gp80 complex can then bind gp130, leading to dimerization and 
intracellular signal transduction. Interestingly, vIL-6 can signal directly through gp130 without 
gp80(33-40). IL-6 dysregulation in KSHV-MCD(1,3,4,41) (11)is pronounced, and comparable to 
IL-6 dysregulation in other forms of Castleman disease; in 33 clinically defined MCD flares 
evaluated in the HAMB natural history study, IL-6 was elevated in 29 (88%), and the median IL-
6 during flares was 24.2 pg/mL (range 1.4-171.5; p=0.0034 compared with remission)(42). 
These IL-6 levels are comparable with those seen in non-KSHV associated MCD (34.8 +/- 34.5 
pg/mL)(9), and substantially higher than circulating IL-6 in healthy individuals (2.3 +/- 1.1 
pg/mL)(43). Both IL-6 and vIL-6 are believed to contribute to disease symptomatology.  Within 
sheets of plasmablasts arising in the setting of KSHV-associated MCD, most KSHV infected 
cells either moderately or strongly express the human IL-6 receptor (Figure 2F, below), and 
targeting pathologic IL-6 signaling through the use of a humanized monoclonal antibody for 
gp80 is a highly rational, B-cell sparing approach to the treatment of KSHV-MCD.  
 
 


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Figure 2. KSHV-positive plasmablasts in a lymphoproliferative lesion in a patient with 
KSHV-MCD. (A) high levels of cytoplasmic IgM (brown). (B). CD27 (brown), a marker for 
mature B cells, is expressed in 20% to 30% of KSHV-positive (blue) plasmablasts. (C) vIL-6 
(brown) is strongly expressed in 10% to 15% KSHV-positive (blue) plasmablasts; (D) hIL6-R 
(blue) is expressed in most KSHV-positive (brown) cells. From: Du M, et. al. Blood; 2001 
97(7);2130-36(23) 
Anti-IL-6 therapy has been evaluated and found to be effective in both mouse models of IL-6 
overproduction(44) as well as clinical studies in KSHV-uninfected patients with MCD(9,45,46).  
The best-studied anti-IL-6 therapy is tocilizumab, a humanized anti-IL-6 receptor (gp80) 
antibody, which inhibits signal transduction by both membrane bound gp80 and soluble 
gp80(47-49).  In a phase 2 study conducted in Japan, 26 patients with KSHV-negative MCD 
(and 2 patients with KSHV-MCD) received tocilizumab 8 mg/kg every other week for 16 weeks, 
followed by an open-label extension, which resulted in improvement in symptoms, adenopathy, 
and laboratory abnormalities in most patients. 75% of patients on corticosteroids at baseline were 
able to discontinue corticosteroids(9).  Tocilizumab resulted in rapid reduction in the IL-6-
dependent inflammatory markers, c-reactive protein and hepcidin(50), with a gradual 
improvement in anemia, hypoalbuminema, lymphadenopathy, and hepatosplenomegy(9).  These 
findings mirror the desired effects of KSHV-MCD therapy.  Tocilizumab is approved in Japan 
for the treatment of KSHV-negative MCD.  The two patients with KSHV-MCD were also 
reported to have responded , but no details were given.  Thus, while tocilizumab does not 
directly affect vIL-6 signaling or other KSHV driven processes that may be pathogenic in 
KSHV-MCD, blocking IL-6 alone may be sufficient to treat KSHV-MCD by blocking the 
symptoms induced by IL-6 excess as well as stopping a cycle of vIL-6 and human IL-6 autocrine 
and paracrine stimulation involving both KSHV infected and KSHV uninfected cells.  Also, as 
noted above, there is some indication from the Japanese trial that the 2 KSHV-MCD patients 
responded to tocilizumab.   
 
 
 
 
 


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However, it is also possible that the combination of tocilizumab with KSHV-directed therapy 
may be necessary, at least in some patients. The HIV and AIDS Malignancy Branch (HAMB) 
has been evaluating selectively targeting of KSHV-MCD plasmablasts based on their expression 
of KSHV lytic genes.(10) One KSHV lytic gene, ORF36, encodes a phosphotransferase that 
activates ganciclovir to a toxic triphosphate moiety, and another, ORF21, encodes a thymidine 
kinase that phosphorylates AZT.(10,51,52)  We previously showed that PEL cells in which 
KSHV was lytically activated produced increased amounts of triphosphate moieties of AZT and 
ganciclovir and that AZT and ganciclovir had synergistic toxicity, at doses attainable in patients, 
against these PEL lines with activated KSHV.(10) We hypothesized that the combination of AZT 
and ganciclovir would selectively target the KSHV-infected plasmablasts expressing in KSHV-
MCD and have utility in the treatment of symptomatic disease. The rationale for this regimen is 
to selectively target MCD-KSHV cells expressing KSHV lytic genes (ORF21 and ORF36) 
through their activation of AZT and ganciclovir to toxic moieties.  Importantly, while not all 
KSHV-infected MCD cells that express vIL-6 express other lytic genes, targeting lytically active 
KSHV-infected cells would also be expected to lead to decreases in the KSHV encoded vIL-6.  
Additionally, these drugs have other effects on the KSHV life cycle that may be clinical relevant. 
In particular, ganciclovir can inhibit KSHV replication,(53,54) and VGC, an orally available pro-
drug of ganciclovir alone has been reported to reduce the frequency of flares or induce a 
remission in 3 patients with KSHV-MCD.(55) Through its antiviral effect, ganciclovir can 
reduce KSHV spread to new cells, and this may contribute to its clinical activity in KSHV-MCD.  
However, for cells already infected with KSHV, ganciclovir blocks a relatively late step in the 
KSHV lytic cycle and thus would not be expected to suppress expression of vIL-6, an early lytic 
gene.(56,57)  Also, cidofovir, another antiviral drug with activity against KSHV, has not been 
found to have utility in KSHV-MCD,(58) suggesting that targeting anti-KSHV replicative 
activity alone is generally insufficient to yield anti-MCD activity.  
 
To explore this hypothesis, a pilot study of high-dose AZT and VGC, an orally available pro-
drug of ganciclovir, was conducted in the HAMB in patients with symptomatic KSHV-MCD.  In 
conducting this study, we also prospectively defined clinical, biochemical, and radiographic 
criteria to assess responses to KSHV-MCD, and piloted the use of these criteria in assessing the 
responses to therapy(11).  A summary of the results from this study is noted in Table 1.  
Evaluation of serum vIL-6 at baseline compared to time of best clinical response in this study 
suggested symptom improvements with AZT/VGC are associated with decreased vIL-6 levels 
(Figure 3), although our findings were not statistically significant, probably due to the relatively 
high cut-off of the assay for vIL-6 and a limited number of patients. This study provided 
evidence that a regimen of AZT combined with VGC has activity in the treatment of KSHV-
MCD.  Our findings support the paradigm that lytically active KSHV-infected cells and 
associated lytic viral proteins such as vIL-6 are important in disease pathophysiology, and that 
KSHV lytic genes can be used to selectively target the KSHV-infected plasmablasts in this rare 
lymphoproliferative disorder. Nonetheless, AZT/VGC has limitations, including hematotoxicity 
with chronic use, and generally slow or insufficient responses in the setting of severe IL-6 
associated inflammatory symptoms. Our findings suggest that addition of AZT/VGC would be a 
rationale addition in patients for whom tocilizumab alone was insufficient.   
 


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Table 1. Best response to treatment with AZT/VGC in 14 patients with symptomatic 
KSHV-MCD 
Response Category 
Best Response 
Number (%) 
Clinical Response 
Complete Response 
7 (50%) 
 
Symptom-Free Disease 
3 (21%) 
 
Partial Response 
2 (14%) 
 
Major Clinical Response* 
12 (86%) 
 
Stable Disease  
2 (14%) 
Biochemical Response 
Complete Response 
3 (21%) 
 
Partial Response 
4 (29%) 
 
Major Biochemical Response† 
7 (50%) 
 
Stable Disease 
6 (43%) 
 
Progressive Disease 
1(7%) 
Radiographic Response§ 
Complete Response 
4 (29%) 
 
Complete Response, unconfirmed 
1 (7%) 
 
Major Radiographic Response‡ 
5 (36%) 
 
Stable Disease 
8 (67%) 
Overall Response 
Complete Response 
3 (21%) 
 
Partial Response 
1 (7%) 
 
Stable Disease 
9 (64%) 
 
Progressive Disease  
1 (7%) 
Major Clinical Response = Complete Response + Symptom Free Disease + Partial Response. 
† Major Biochemical Response = Complete Response + Partial Response. 
‡  Major Radiographic Response = Complete Response + Complete Response unconfirmed + 
Partial Response. 
§ One patient was not evaluable radiographically.  
 
From: Uldrick TS, Yarchoan R, et. al. High-dose zidovudine plus valganciclovir for Kaposi 
sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated 
cytotoxic therapy. Blood 2011 Jun 30;117(26):6977-86. 
 


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Figure 3. Changes in viral IL-6 in patients with symptomatic KSHV-MCD from baseline to 
time of best clinical response. Wilcoxon matched-pair signed rank test (NS) * Clinical course 
confounded by development endocarditis (- - - -). 
The primary objective of this study is to determine the efficacy of tocilizumab in the treatment of 
KHSV-MCD.  This may lead to less toxic therapeutic options for patients with KSHV-MCD, and 
will improve our understanding of disease pathogenesis.  The study is designed to allow for the 
addition of KSHV targeted therapy with AZT/VGC should tocilizumab not provide adequate 
responses. Additionally, we will evaluate disease drug-drug interactions by evaluating the PK of 
several antiretroviral agents that are CYP3A4 substrates in patients with symptomatic KSHV-
MCD, and while on tocilizumab (See Section 5.1.2). 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT  
2.1 
ELIGIBILITY CRITERIA 
 Inclusion Criteria 
2.1.1.1 Pathologically confirmed KSHV-MCD 
2.1.1.2 Age ≥ 18 
2.1.1.3 At least one clinical symptom probably or definitely attributed to KSHV-MCD 
2.1.1.4 Intermittent or persistent fever for at least 1 week (>38qC) 
2.1.1.5 Fatigue (CTCAE Grade 2 or greater) 
2.1.1.6 Gastrointestinal symptoms [includes nausea and anorexia] (CTCAE Grade 1 or greater) 
2.1.1.7 Respiratory symptoms [includes cough and airway hyperreactivity] (CTCAE Grade 1 or 
greater) 
2.1.1.8 At least one laboratory abnormality probably or definitely attributed to KSHV-MCD 
2.1.1.9 Anemia (Hgb [men] </=12.5 gm/dL, Hgb [women] </= 11 gm/dL) 
2.1.1.10 Thrombocytopenia (</=130,000/mm3) 


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2.1.1.11 Hypoalbuminemia (<3.4 g/dL) 
2.1.1.12 Elevated C-reactive protein (CRP) (CRP > 3 mg/L)] probably or definitely attributable 
to KSHV-MCD 
2.1.1.13 No life- or organ-threatening manifestations of MCD 
2.1.1.14 ECOG performance status ≤ 2 
2.1.1.15 HIV-infected patients should be receiving or willing to initiate an effective combination 
antiretroviral therapy (cART) regimen 
2.1.1.16 Willingness to complete tuberculosis evaluation and start prophylactic anti-tuberculosis 
therapy as soon as is medically feasible if patients have a reactive tuberculin skin test 
and/or positive QuantiFERON-TB Gold test and have not completed an adequate course 
of prevented anti-tuberculosis therapy, following American Thoracic Society / Centers 
for Disease Control recommended guidelines: 
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5231a4.htm  and 
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5905a1.htm?s_cid=rr5905a1_e 
2.1.1.17 Ability to understand and willingness to give informed consent  
2.1.1.18 Women of child bearing potential must agree to use birth control for the duration of the 
study 
 Exclusion Criteria 
2.1.2.1 Uncontrolled bacterial, mycobacterial, or fungal infection 
2.1.2.2 Uncontrolled intercurrent illness including, symptomatic congestive heart failure, 
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that 
would limit compliance with study requirements or ability to receive therapy. 
2.1.2.3 Pregnant or lactating women 
2.1.2.4 Any abnormality that would be scored as NCI CTC Grade 3 toxicity that is unrelated to 
HIV, its treatment, or to MCD that would preclude protocol treatment. Exceptions 
include: 
2.1.2.4.1 Lymphopenia 
2.1.2.4.2 Direct manifestations of Kaposi sarcoma or MCD 
2.1.2.4.3 Direct manifestation of HIV (i.e. low CD4 count) 
2.1.2.4.4 Direct manifestation of HIV therapy (i.e. Hyperbilirubinemia associated with protease 
inhibitors) 
2.1.2.4.5 Asymptomatic hyperuricemia 
2.1.2.4.6 Hypophosphatemia 
2.1.2.4.7 Elevated CK attributed to exercise 
2.1.2.5 Past or present history of malignant tumors other than Kaposi sarcoma unless one of the 
following:  
2.1.2.5.1 Complete remission for t 1 year from completion of therapy 
2.1.2.5.2 Completely resected basal cell carcinoma 


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2.1.2.5.3 In situ squamous cell carcinoma of the cervix or anus  
2.1.2.6 Patients with concurrent Kaposi sarcoma requiring immediate cytotoxic chemotherapy  
2.1.2.7 History of tocilizumab therapy within prior 6 weeks 
2.1.2.8 History of rituximab or intravenous bevacizumab therapy within six weeks 
2.1.2.9 History of t2 allergic reaction or any grade anaphylactic reaction during prior 
administration of tocilizumab 
 Recruitment Strategies 
Recruitment of patients from outside NIH is facilitated by multiple ongoing trials at NIH. Many 
patients find about NIH trials from NIH websites, such as https://clinicaltrials.gov/ or NIH social 
media, or from other patients through social media. 
2.2 
SCREENING EVALUATION  
 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
x Email, written, in person or telephone communications with prospective subjects  
x Review of existing medical records to include H&P, laboratory studies, etc.  
x Review of existing MRI, x-ray, or CT images 
x Review of existing photographs or videos 
x Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes 
 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the subject has signed the consent for study 
# 01C0129 on which screening activities will be performed.  
2.2.2.1 Clinical Evaluation 
x 
Complete medical history and review of systems 
x 
Comprehensive physical examination  
x 
Tuberculosis Screening by Tuberculin Skin test and/or QuantiFERON TB Gold 
x 
Documentation of previously positive results do not need to be repeated.  If no history 
of positive tuberculosis screening test, potential subjects will undergo tuberculosis 
screening following CDC/ATS guidelines. 
x 
Tuberculin skin test. Patients with reactive tuberculin skin test (>5 mm induration 48-
72 hours after intradermal placement of 5 TU of purified protein derivative) will be 
evaluated by review of systems, induced sputum for AFB stain and culture for 
mycobacteria, and will have either a chest X-ray or CT-scan to evaluate for evidence 
of disease. (see http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5231a4.htm) 


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x 
QuantiFERON TB Gold. Call 301-496-4433 (Microbiology Specimen Processing) to 
order specimen tubes and coordinate specimen processing. Patients with positive 
results will be evaluated by:  
x 
Review of systems 
x 
Induced sputum for AFB stain and culture for mycobacteria 
x 
Either a chest X-ray or CT-scan to evaluate for evidence of disease.  
x 
Evaluation for Kaposi sarcoma, including documentation of extent of disease (See 
Sections, 3.4, 6.2, and 12.4). If clinically warranted, additional studies for visceral KS 
involvement, including but not limited to: fecal occult blood test, gastrointestinal 
endoscopy, bronchoscopy, and CT scans, will be performed, based on clinical 
evaluation of the patient.  
2.2.2.2 Pathology: assessment of tumor specimen(s) for histopathology reviewed by NCI-LP 
pathologists. 
x 
Hematoxylin and eosin stain 
x 
Presence of the KSHV latency associated nuclear antigen (LANA)  
x 
Immunohistochemical evaluation for vIL-6 (for specimens being evaluated for MCD, 
not required for samples being evaluated for concurrent KS) 
2.2.2.3 Clinical Laboratory Data 
x 
 Acute Care, Hepatic Panel, Mineral Panel, LDH. 
x 
C-reactive protein, high sensitivity 
x 
CBC, diff (automated lymphocyte count), reticulocyte count 
x 
Hepatitis B S Ag, Hepatitis B S Ab, Hepatitis B core Ab, patients with detectable 
Hepatitis B core Ab or surface antigen require HBV DNA Quantitative 
x 
Hepatitis C antibody, HCV RNA Quantitative PCR 
x 
Anti-Hepatitis A IgG  
x 
RPR 
x 
HIV Western blot (Any previous positive result) 
x 
HIV viral load if HIV seropositive by Western Blot 
x 
Urine E-hCG (women) 
x 
Fecal Occult Blood Test  
2.2.2.4 Imaging 
x 
Computerized tomography: neck, chest, abdomen, and pelvis  
x 
18Fluorodeoxyglucose – Positron Emission Tomography / Computerized tomography 
(18FDG-PET/CT)   
2.2.2.5 Screening for Co-enrollment in other Protocols  
x 
Patients may be co-enrolled in 04-C-0275 and/or 01-C-0038  


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x 
Screening studies listed may also be used to determine eligibility for other HAMB 
protocols 
2.3 
REGISTRATION PROCEDURES 
Each patient will be reviewed by the Principal Investigator or the Lead Associate Investigator.  
Once it has been determined that a patient qualifies, informed consent will be obtained from the 
patient.   
Consenting patients will generally be co-enrolled in 04-C-0275 and/or 01-C-0038. 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to:  NCI Central Registration Office ncicentralregistration-l@mail.nih.gov .  
After confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to 
advise them of the acceptance of the patient on the protocol prior to the release of any 
investigational agents.  Verification of Registration will be forwarded electronically via e-mail to 
the research team. A recorder is available during non-working hours.  
 
 Treatment Assignment Procedures 
Cohort 
Number Name 
Description 
1 
Cohort 1 
Patients with KSHV-associated MCD 
Arm 
Number Name 
Description 
1 
Arm 1 
Tocilizumab, Zidovudine and Valganciclovir 
Arm Assignment  
Patients in Cohort 1 will be directly assigned to Arm 1. 
2.4 
BASELINE EVALUATION 
See Section 3.4 for schedule of evaluations. 
 Clinical Evaluation 
2.4.1.1 Complete medical history 
2.4.1.2 Comprehensive physical examination  
2.4.1.3 Kaposi sarcoma assessment if applicable (See Sections 3.4 and 6.2) 
2.4.1.3.1 Documentation of Extent of Disease 


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Baseline whole body photographs will be obtained upon entry into the study.  At this 
time, 5 lesions (hereafter called marker lesions), representative of the patient’s 
disease and, if possible, located on separate areas of the body will be selected.  These 
marker lesions should be lesions that have never been treated with local therapies 
such as radiation therapy or intralesional injections.  Detailed photographs of these 
lesions will be obtained with a metric rule beside them.  The size, color and 
nodularity of these lesions will be recorded. Documentation will depend on the 
number of lesions. 
2.4.1.3.2 Patients with 50 or More KS Lesions 
For patients with 50 or more lesions at entry, between 1 and 3 representative areas 
will be selected at baseline and these will be used for each subsequent evaluation.  
Representative areas are sections of the body (e.g. the back, a leg, an arm, etc.), which 
contain at least 20 KS lesions.  The total number of lesions in these representative 
areas will be counted and a record made of whether they are flat or raised.  If, in the 
course of treatment, a single lesion breaks up into 2 or more smaller lesions (whose 
area does not extend beyond the boundary of the initial lesion), these lesions will still 
be counted as single lesions for the purpose of assessing total numbers in defining a 
response to therapy.  An attempt will be made to distribute the “marker” lesions 
between the representative areas and the rest of the body.   
2.4.1.3.3 Patients with fewer than 50 KS lesions 
For patients with less than 50 lesions at entry, the total number of lesions will be 
counted and a record made of whether they are flat or raised. 
2.4.1.3.4 Additional studies for visceral KS involvement 
Additional studies, including but not limited to, fecal occult blood test, 
gastrointestinal endoscopy, bronchoscopy, and CT scans, will be performed at 
baseline where clinically indicated, based on clinical evaluation of the patient.  
 Labs required for Evaluation of MCD Biochemical Response (Performed in Clinical 
Center Department of Laboratory Medicine) 
2.4.2.1 Acute Care, Hepatic Panel, Mineral Panel, LDH. 
2.4.2.2 Complete Blood Count with differential 
2.4.2.3 C-reactive protein 
2.4.2.4 Ferritin (not used in MCD response evaluation, but included as an additional marker of 
IL-6 excess) 
 Other clinical laboratories for safety and pharmacodynamic monitoring (Performed in 
Clinical Center Department of Laboratory Medicine, may use screening laboratory values 
if performed within 7 days of study enrollment) 
2.4.3.1 CPK, amylase, lipase 
2.4.3.2 Lipid panel 
2.4.3.3 Quantitative immunoglobulin levels, including IgE 


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2.4.3.4 Serum Free Light Chains  
2.4.3.5 Lymphocyte phenotype TBNK.  Simultaneous CBC and automated differential must be 
drawn. 
2.4.3.6 Urinalysis and urine microscopy, patients with ≥ 2+ proteinuria will be monitored with 
spot urine: creatinine ratio  
2.4.3.7 Urine E-hCG (women)  
 Other clinical laboratories (Performed in Clinical Center Department of Laboratory 
Medicine, may use screening laboratory values if performed within 14 days of study 
enrollment) 
2.4.4.1 Thyroid function tests (TSH, free T4) 
2.4.4.2 25-OH Vitamin D, 1,25(OH2) Vitamin D 
2.4.4.3 Iron Binding Capacity, Iron, Folate, B12 
2.4.4.4 Haptoglobin  
2.4.4.5 Type and crossmatch, direct anti-globulin test 
2.4.4.6 APTT, PT, fibrinogen, lupus anticoagulant 
2.4.4.7 Erythrocyte Sedimentation Rate (ESR) 
2.4.4.8 RPR  
 Viral Monitoring 
2.4.5.1 HIV, HBV DNA Quantitative and HCV RNA Quantitative viral load monitoring by 
PCR to be performed in patients with respective infections. (Performed in Clinical 
Center Blood Bank may use screening if performed within 7 days of enrollment) 
2.4.5.2 KSHV saliva and PBMC, to be performed in the Laboratory of Dr. Denise Whitby. 
Saliva is collected in 50 mL Polyprophylene Conical Tubes with scope mouthwash, 
blood is collected in 1 ACD tube (BV Vacutainer® Ref 364606 yellow top), each 
labeled with unique identifier, send via messenger to Leidos Biomedical, Inc. Building 
535, Room 428A, contact phone number 301-846-1714. 
 Imaging 
2.4.6.1 CT-scan: neck, chest, abdomen, and pelvis, may use results from screening CT if 
performed within 14 days of starting tocilizumab 
2.4.6.2 
18FDG-PET/CT (Baseline only), may use results from screening 18FDG-PET/CT if 
performed within 14 days of starting tocilizumab  
2.4.6.3 Research Labs (See Sections 3.4. and 5.1.) 
2.4.6.4 Two ACD tubes (BD Vacutainer® Ref 364606 yellow top) store for plasma and cells 
2.4.6.5 Two serum tubes (BD Vacutainer® Ref 367820 red top tubes) 
2.4.6.6 1 sodium heparin (BD Vacutainer® Ref 367878 green top tube) store for cells  
2.4.6.7 Urine IFE (BD Vacutainer® Ref 364980 yellow top)  


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2.5 
ON STUDY ASSESSMENTS  
See Section 3.4 for schedule of evaluations. 
 Clinical Evaluation 
2.5.1.1 Complete medical history 
2.5.1.2 Comprehensive physical examination  
2.5.1.3 Kaposi sarcoma assessment if applicable (See sections 3.4 and 6.2) 
2.5.1.3.1 Documentation of Extent of Disease 
Baseline whole body photographs will be obtained upon entry into the study.  At this 
time, 5 lesions (hereafter called marker lesions), representative of the patient’s 
disease and, if possible, located on separate areas of the body will be selected.  These 
marker lesions should be lesions that have never been treated with local therapies 
such as radiation therapy or intralesional injections.  Detailed photographs of these 
lesions will be obtained with a metric rule beside them.  The size, color and 
nodularity of these lesions will be recorded at baseline, week 7, and week 15(+/-7 
days).  Documentation will depend on the number of lesions. 
2.5.1.3.2 Patients with 50 or More KS Lesions 
For patients with 50 or more lesions at entry, between 1 and 3 representative areas 
will be selected at baseline and these will be used for each subsequent evaluation.  
Representative areas are sections of the body (e.g. the back, a leg, an arm, etc.), which 
contain at least 20 KS lesions.  The total number of lesions in these representative 
areas will be counted and a record made of whether they are flat or raised.  If, in the 
course of treatment, a single lesion breaks up into 2 or more smaller lesions (whose 
area does not extend beyond the boundary of the initial lesion), these lesions will still 
be counted as single lesions for the purpose of assessing total numbers in defining a 
response to therapy.  An attempt will be made to distribute the “marker” lesions 
between the representative areas and the rest of the body.   
2.5.1.3.3 Patients with fewer than 50 KS lesions 
For patients with less than 50 lesions at entry, the total number of lesions will be 
counted and a record made of whether they are flat or raised. 
2.5.1.3.4 Additional studies for visceral KS involvement 
Additional studies, including but not limited to, fecal occult blood test, 
gastrointestinal endoscopy, bronchoscopy, and CT scans, will be performed at entry 
where clinically indicated, based on clinical evaluation of the patient.  
 Labs required for Evaluation of MCD Biochemical Response (Performed in Clinical 
Center Department of Laboratory Medicine) 
2.5.2.1 Acute Care, Hepatic Panel, Mineral Panel, LDH. 
2.5.2.2 Complete Blood Count with differential 


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2.5.2.3 C-reactive protein 
2.5.2.4 Ferritin (not used in MCD response evaluation, but included as an additional marker of 
IL-6 excess) 
 Other clinical laboratories for safety and pharmacodynamic monitoring (Performed in 
Clinical Center Department of Laboratory Medicine, may use screening laboratory values 
if performed within 7 days of study enrollment) 
2.5.3.1 CPK, amylase, lipase 
2.5.3.2 Lipid panel 
2.5.3.3 Quantitative immunoglobulin levels, including IgE 
2.5.3.4 Serum Free Light Chains  
2.5.3.5 Lymphocyte phenotype TBNK.  Simultaneous CBC and automated differential must be 
drawn. 
2.5.3.6 Urinalysis and urine microscopy, patients with ≥ 2+ proteinuria will be monitored with 
spot urine: creatinine ratio  
2.5.3.7 Urine E-hCG (women)  
2.5.3.8 Correlative Research Laboratory Studies:  
2.5.3.9 Day 1 of each cycle 
2.5.3.10 Three ACD tubes (BD Vacutainer® Ref 364606 yellow top) store for plasma and cells 
2.5.3.11 Two serum tubes (BD Vacutainer® Ref 367820 red top tubes) store 
2.5.3.12 1 sodium heparin (BD Vacutainer® Ref 367878 green top tube) store for cells  
2.5.3.13 Urine IFE (BD Vacutainer® Ref 364980 yellow top)  
2.5.3.14 Pharmacokinetic Studies (Performed by the Clinical Pharmacology Program) 
2.5.3.15 Baseline: 10 mL Blood in EDTA (Purple top) for DMET™ SNP analysis, one time 
draw only in patients consenting to SNP analysis 
2.5.3.16 6mL in sodium heparin (green top tube) for PK 
2.5.3.17 Cycle 1 
2.5.3.18 Pre-tocilizumab 
2.5.3.19 15 minutes post tocilizumab 
2.5.3.20 24 hours post-tocilizumab 
2.5.3.21 48 hours post-tocilizumab.   
2.5.3.22 Cycles 2-6 
2.5.3.23 Pre-tocilizumab 
2.5.3.24 15 minutes post-tocilizumab only.  


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 Clinical laboratories evaluated at Baseline and Week 12 Evaluation only (Performed in 
Clinical Center Department of Laboratory Medicine, may use screening laboratory values 
if performed within 14 days of study enrollment) 
2.5.4.1 Thyroid function tests (TSH, free T4) 
2.5.4.2 25-OH Vitamin D, 1,25(OH2) Vitamin D 
2.5.4.3 Iron Binding Capacity, Iron, Folate, B12 
2.5.4.4 Haptoglobin  
2.5.4.5 Direct anti-globulin test 
2.5.4.6 APTT, PT, fibrinogen, lupus anticoagulant 
2.5.4.7 Erythrocyte Sedimentation Rate (ESR) 
2.5.4.8 RPR  
 Viral Monitoring 
2.5.5.1 HIV, HBV DNA Quantitative and HCV RNA Quantitative viral load monitoring by 
PCR to be performed in patients with respective infections at baseline. (Performed in 
Clinical Center Blood Bank may use screening laboratory values if performed within 7 
days of study enrollment) 
2.5.5.2 KSHV saliva and PBMC, to be performed in the Laboratory of Dr. Denise Whitby. 
Saliva is collected in 50 mL Polyprophylene Conical Tubes with scope mouthwash, 
blood is collected in 1 ACD tube (BV Vacutainer® Ref 364606 yellow top), each 
labeled with unique identifier, send via messenger to Leidos Biomedical, Inc.-Frederick 
Building 535, Room 428A, contact phone number 301-846-1714. 
 Imaging 
2.5.6.1 CT-scan: neck, chest, abdomen, and pelvis [Baseline, Cycle 4 Day 1, Cycle 6 Day 15 
(+/- 1 week)]  
2.5.6.2 
18FDG-PET/CT (Baseline only), may use results from screening 18FDG-PET/CT if 
performed within 14 days of starting tocilizumab 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
Open label, single center pilot study. 
 
 


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 Protocol Schema 
 
 
 Indications for addition of AZT/VGC  
Escalation of therapy will be applied to patients having inadequate response to tocilizumab 
monotherapy. All decisions are based on evaluation of response using NCI KSHV-MCD Clinical 
Benefit Response Criteria, Appendix 1.  Indication for addition of AZT and VGC will be based 
on the following criteria: 
Elevated CRP (> 3.0 mg/L)(59), and one of the following: 
3.1.2.1 MCD Clinical Benefit Response Criteria defined progressive disease from entry or best 


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response (as defined during Clinical Benefit evaluations performed at each visit using 
the 8 parameters in the Clinical Benefit Response Criteria) and no Off-Therapy Criteria 
(Section 3.6.1) 
3.1.2.2 Failure to attain improvement in any clinical or biochemical parameter probably or 
definitely attributed to KSHV-MCD, or presence of any grade 3 symptom probably or 
definitely attributed to KSHV-MCD, after week 4 (end of Cycle 2) 
3.1.2.3 Failure to achieve a MCD Clinical Benefit Response Criteria defined partial response or 
better by end of week 8 (end of Cycle 4)  
The addition of AZT/VGC will not change the total number of tocilizumab doses. 
3.2 
DRUG ADMINISTRATION 
 Tocilizumab Administration 
3.2.1.1 Tocilizumab 8 mg/kg, to be administered through a peripheral intravenous catheter over 
60 minutes 
3.2.1.2 Tocilizumab is administered on day 1 (+/- 2 days if schedule change required due to 
travel considerations or holidays) of a 14 day cycle  
3.2.1.3 Tocilizumab to be administered for a maximum of 6 cycles, unless subject meets off-
treatment criteria (Section 3.6.1) prior to cycle 6  
 High-dose AZT and VGC Administration 
If indicated (See Section 3.1.2.), AZT and VGC will be administered as follows, and 
continued through the final cycle of tocilizumab: 
3.2.2.1 AZT and VGC will be administered concurrently with tocilizumab, with day 1 of the 
cycle being the day tocilizumab is administered 
3.2.2.2 AZT 600 mg PO q6 hours, Days 1-5 of 14 day cycle  
3.2.2.3 VGC 900 mg PO q12 hours, Days 1-5 of 14 day cycle 
3.2.2.4 For inpatients not tolerating oral therapy, intravenous AZT 300 mg q6 hours and 
intravenous ganciclovir 5 mg/kg q12 hours may be substituted 
3.3 
DOSE MODIFICATIONS 
 Tocilizumab Monotherapy 
3.3.1.1 Liver Function Abnormalities.   
3.3.1.1.1 New Grade 2 AST and/or ALT (>3-5 U/L x upper limit of normal): hold tocilizumab 
until AST and ALT return to d Grade 1 (< 3 x upper limit of normal). If recurrent 
Grade 2 AST or ALT abnormalities attributed to tocilizumab (not baseline 
abnormalities), discontinue tocilizumab  
3.3.1.1.2 Grade 3 AST and/or ALT (>5 times upper limit of normal). Discontinue tocilizumab  
3.3.1.2 Neutropenia 


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3.3.1.2.1 If neutropenia probably or definitely attributed to MCD, discuss with PI or physician 
clinical AI; dose adjustment may not be indicated in this setting. 
3.3.1.2.2 For ANC < 0.5 K/uL not probably or definitely attributed to MCD, add filgrastim 300 
mcg for patients <75 kg, 480 mcg for patients >75 kg SUBCUTANEOUS daily, and 
titrate subsequent frequency to maintain ANC > 1.0 K/uL, hold tocilizumab until ANC 
> 1.0 K/uL  
3.3.1.3 Thrombocytopenia, is common in both HIV and KSHV-MCD, but has been observed 
occasionally in tocilizumab studies performed in patients with rheumatoid arthritis 
(<2%).  
3.3.1.3.1 Thrombocytopenia possibly, probably, or definitely attributable to KSHV-MCD 
requires no dose adjustment. 
3.3.1.3.2 For platelets < 50 K/uL probably, or definitely attributable to tocilizumab and unlikely 
related to MCD, hold tocilizumab until platelet count > 50 K/uL  
3.3.1.4 Infections 
3.3.1.4.1 Intercurrent uncontrolled Grade 3 infection; hold tocilizumab until d Grade 2. 
 Tocilizumab combined with AZT and VGC 
3.3.2.1 Intravenous administration 
3.3.2.1.1 Ganciclovir 5/mg/kg IV over 60 minutes q12 hours may be substituted for oral VGC 
3.3.2.1.2 Intravenous AZT 300 mg IV over 60 minutes q6 hours may be substituted for oral 
AZT.   
3.3.2.2 Liver Function Abnormalities.   
3.3.2.2.1 New Grade 2 AST and/or ALT (>3-5 U/L x upper limit of normal): hold tocilizumab, 
AZT and VGC until AST and ALT return to d Grade 1 (< 3 x upper limit of normal). 
If recurrent Grade 2 AST or ALT abnormalities attributed to tocilizumab (not baseline 
abnormalities), discontinue tocilizumab, AZT and VGC  
3.3.2.2.2 Grade 3 AST and/or ALT (>5 times upper limit of normal). Discontinue tocilizumab, 
AZT and VGC  
3.3.2.3 Neutropenia 
3.3.2.3.1 If neutropenia probably or definitely attributed to MCD, discuss with PI or physician 
clinical AI; dose adjustment may not be indicated in this setting. 
3.3.2.3.2 For ANC < 0.5 K/uL not probably or definitely attributed to MCD, add filgrastim 
300mcg for patients <75 kg, 480 mcg for patients >75 kg SUBCUTANEOUS daily, 
and titrate subsequent frequency to maintain ANC >1.0 K/uL. 
3.3.2.3.3 Hold study drugs for up to 14 days while administering filgrastim. 
3.3.2.3.4 Resume AZT and VGC at full dose once ANC >1.0 K/uL. 
3.3.2.4 Anemia  
3.3.2.4.1 Anemia possibly, probably, or definitely attributed to KSHV-MCD requires no dose 
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3.3.2.4.2 Grade 3 anemia probably or definitely attributed to AZT and VGC (or ganciclovir): 
hold AZT and VGC until hemoglobin > 10 g/dL (Grade 1). 
3.3.2.5 Thrombocytopenia, is common in both HIV and KSHV-MCD.  
3.3.2.5.1 Thrombocytopenia possibly, probably, or definitely attributed to KSHV-MCD 
requires no dose adjustment. 
3.3.2.5.2 For platelets < 50 K/uL probably, or definitely attributed to AZT combined with VGC 
and tocilizumab and unlikely related to MCD, hold study drugs until platelet count > 
50 K/uL 
3.3.2.6 Renal dysfunction 
3.3.2.6.1 AZT: for creatinine clearance < 15 mL/min, consider 50% dose reduction. 
3.3.2.6.2 VGC: adjust the dose for creatinine clearance <60 mL/min as follows (See Table 2): 
 
Table 2: Dose modification of VGC in patients with renal dysfunction 
Creatinine Clearance (mL/min) 
Dose 
40-59 
450 mg twice daily 
25-39 
450 mg once daily 
10-24 
450 mg every 2 days 
Hemodialysis 
Use IV ganciclovir, see Table 3 
 
3.3.2.6.3 Ganciclovir: adjust the dose for creatinine clearance <70 mL/min as follows: 
Table 3:  Dose modification of ganciclovir in patients with renal dysfunction 
Creatinine Clearance 
Dose (mg/kg) 
50-69 
2.5 every 12 hours 
25-49 
2.5 every 24 hours 
10-24 
1.25 every 24 hours 
<10 
1.25 three times weekly following 
dialysis 
 
 
 


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3.4 
STUDY CALENDAR 
Procedure 
Screening 
/Baseline 
Cycle 1 
Cycle 2-6 
Week 
12 
Off 
Study 
D1 
D2 
D3 
D1 
History and PE1 
X 
X 
 
 
X 
X 
X 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
Biopsies2 
X 
 
 
 
 
 
 
Tuberculosis Screen 
X 
 
 
 
 
 
 
Hepatitis Evaluation3 
X 
 
 
 
 
 
 
HIV Western blot  
X 
 
 
 
 
 
 
CT Neck/Chest/Abd/Pelvis4 
X 
 
 
 
X4 
X 
 
MCD Response Labs 5 
X 
X 
X 
X 
X 
X 
X 
Other Labs6 
X 
 
 
X 
X 
X 
 
Baseline/Week 12 Only7 
X 
 
 
 
 
X 
 
Viral Monitoring8 
X 
 
 
 
X8 
 
X 
Lymphocyte TBNK 
X 
 
 
X 
X 
X 
X 
PD Research Specimens9 
X 
 
 
X 
X 
X 
X 
PK Research Specimens10 
X 
X 
X 
X 
X 
X 
 
MCD Response Evaluation 
X 
 
 
 
X 
X 
X 
Photography /KS evaluation11 
X 
 
 
 
X11 
X 
 
Adverse Event Monitoring 
X 
 
NIH Advance Directives 
Form12 
X 
 
 
 
 
 
 
1.    Includes current medications, and ECOG performance status 
2.    Pathologic Evidence of KSHV-MCD.  Kaposi sarcoma biopsy if applicable. 
3.    Hepatitis B S Ag, Hepatitis B S Ab, Hepatitis B core Ab, patients with detectable Hepatitis B core Ab or surface 
antigen require HBV –DNA viral load (PCR), Hepatitis C antibody, HCV RNA-PCR, Anti Hepatitis A IgG  
4.    Baseline, Day 1 Cycle 4 (+/- 1 week), documentation of possible complete response, week 12 (+/- 1 week). 
5.    CBC with differential, Reticulocyte count, Acute Care, Hepatic Panel, Mineral Panel, LDH, C-reactive protein, 
ferritin (included as marker of IL-6 induced acute phase reactant) 
6.    Lipid panel, quantitative immunoglobulins, IgE, free light chains, CPK, amylase, lipase, urinalysis, urine 
microscopy, urine E-hcg (women only). Can use screening labs if performed within 7 days of study enrollment. 
7.    Iron Binding Capacity, Iron, Folate, B12, PT/PTT, haptoglobin, ESR, lupus anticoagulant, TFTs, 25-OH 
vitamin D, Urine IFE, RPR. Can use screening labs if performed within 14 days of study enrollment. 
8.    HIV, HBV, and HCV in patients with evidence of infection at baseline: Baseline, Day 1 Cycle 3, Day 1, Cycle 6 
(+/- one week), off study only.  More frequently if clinically indicated. 
9.   Three yellow top tubes, three red top tubes, one green top tube, urine, saliva. (See Sections 5.1.1, 5.2). On Day 3, 
Cycle 1: 2 yellow tops, 1 red top only.  
10. For all subjects: Cycle 1, Day 1: Pre-tocilizumab, 15 minutes post tocilizumab, 24 hours post-tocilizumab, 48 
hours post-tocilizumab.  Cycles 2-6, pre-tocilizumab and 15 minutes post-tocilizumab only. At each time point: 
6mL in sodium heparin (green top tube).  For patients consenting to DMET genotyping, 10 mL in EDTA at 
baseline. 
11.   If indicated, modified ACTG KS disease measurements, Day1 Cycle 1, Day 1 Cycle 4.  Photography at 
baseline, week 12 only.  Patients with clinically significant progression of KS should be documented with 
measurements and photography. 
12.  As indicated in Section 9.3, all subjects ≥ age 18 will be offered the opportunity to complete an NIH advance 
directives form. This should be done preferably at baseline but can be done at any time during the study as long 
as the capacity to do so is retained. The completion of the form is strongly recommended, but is not required.  
 
 


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3.5 
RADIATION THERAPY GUIDELINES 
Radiation therapy for Kaposi Sarcoma is contraindicated. 
3.6 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to documenting removal from study, effort must be made to have all subjects complete a 
safety visit approximately 4 weeks following the last dose of study therapy. 
 Criteria for removal from protocol therapy 
3.6.1.1 Completion of 12 weeks of therapy 
3.6.1.2 Clinical or Biochemical Progressive Disease (as compared to baseline at the point that 
AZT and VGC were added) on tocilizumab combined with AZT and VGC, as defined 
by NCI-MCD Response Criteria. 
3.6.1.3 ECOG performance status ≥ 3 
3.6.1.4 Life or organ threatening manifestations of KSHV-MCD including neurologic, hepatic, 
pulmonary, cardiovascular, or renal dysfunction equivalent to grade IV adverse event 
using CTCAE 4.0 probably or definitely attributed to KSHV-MCD that does not 
improve within 14 days of therapy (or sooner at PI discretion, see Section 3.6.1.9) 
3.6.1.5 Unacceptable toxicity at least possibly attributable to tocilizumab, AZT and/or VGC (≥ 
Grade 3), with exception of common abnormalities most likely due to HIV or KSHV-
MCD (See Section 7.2.3).  
3.6.1.6 Patient preference 
3.6.1.7 Institution of a non-protocol therapy for Kaposi sarcoma, or other malignancy (i.e. 
primary effusion lymphoma) diagnosed during the course of the protocol. 
3.6.1.8 Pregnancy 
3.6.1.9 Patients may be removed from protocol therapy, if in the opinion of the PI, the risk of 
continued therapy outweighs the potential benefit of continued participation or if patient 
non-adherence interferes with study objectives. 
 Off-Study Criteria 
3.6.2.1 Completion of tocilizumab or discontinuation of tocilizumab and completion of 4 week 
safety follow-up visit  
3.6.2.2 Patients who do not comply with follow-up visits will be taken off study 
3.6.2.3 Patients with persistent toxicity at least possibly attributed to tocilizumab at the off-
study visit will be monitored on study for up to 4 months after the end of therapy or 
until the toxicity returns to baseline, whichever occurs first, with frequency and duration 
of follow up based on medical need 
3.6.2.4 Subjects may be taken off study at the discretion of the Principal Investigator or Lead 
Associated Investigator 


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 Off Protocol Therapy and Off-Study Procedure 
Authorized staff must notify the Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Update Form from 
the website (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov. 
Additional treatment and/or long-term follow up of patients is possible through enrollment in 04-
C-0275. 
4 
SUPPORTIVE CARE/CONCURRENT THERAPIES 
4.1 
GENERAL KS AND HIV RELATED 
Supportive care medications may be administered as clinically indicated, or at the discretion of 
the Principal Investigator. Other specific cytotoxic or biologic therapies for KS or KSHV-MCD 
are prohibited, with the exception of short-term courses of corticosteroids. 
4.2 
OPPORTUNISTIC INFECTIONS 
Subjects who develop opportunistic infections, including but not limited to pneumocystis jiroveci 
pneumonia, mycobacterial diseases, cytomegalovirus (CMV), and fungal infections will be 
treated using standard regimens.  All opportunistic infections will be discussed with the Principal 
Investigator. Consultation with the Infectious Disease Service is mandatory for subjects 
diagnosed with mycobacterium tuberculosis. Prophylactic antibiotics are outlined in Section 4.6. 
4.3 
ANEMIA 
Anemia will be treated conservatively.  Transfusions will generally be avoided unless a subject 
develops symptomatic anemia.  At the discretion of the principal investigator, transfusion may be 
performed for hemoglobin < 10 g/dL in patients with a history of cardiovascular disease. 
Appropriate evaluation for etiology of the anemia should be initiated. 
4.4 
THROMBOCYTOPENIA 
Thrombocytopenia should be treated conservatively.  In the absence of bleeding or a planned 
invasive procedure, platelet transfusions should be given for a platelet count below 10 K/uL.  If 
invasive procedures are planned or the patient develops bleeding, platelet transfusions should be 
administered in accordance with standard of practice, usually maintaining a platelet count > 50 
K/uL.  
4.5 
FEBRILE NEUTROPENIA 
Patients who develop febrile neutropenia will be hospitalized and treated with intravenous 
antibiotics. See Sections 3.3.1.2 and 3.3.2.3 for Treatment Modifications and filgrastim use 
pertaining to neutropenia. 


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4.6 
CONCURRENT THERAPIES 
 Anti-retroviral Therapy 
Patients will receive antiretroviral therapy if it is indicated.  Combination therapy will be 
generally based on Department of Health and Human Services Guidelines for treatment of HIV 
infection, available at http://www.aidsinfo.nih.gov/guidelines/.  However, patients may have 
extenuating circumstances requiring deviation from these guidelines.  Whenever possible, 
changing antiretroviral therapy should be avoided unless needed for optimal patient care.  
Additionally, referring physicians may manage this component of patient care.  In some patients 
who are prescribed AZT as part of the treatment for KSHV-MCD, AZT may replace another 
non-nucleoside reverse transcriptase inhibitor for the duration of therapy as long as there is no 
evidence of HIV mutations conferring resistance to AZT.  
 Anti-emetics 
Patients prescribed high-dose AZT combined with VGC will receive an appropriate “as needed” 
anti-emetic, i.e. compazine 10 mg orally or IV every 6 hours prn.  Other anti-emetic medications 
may be considered, however, glucocorticoids should be avoided. 
 Glucocorticoids 
Glucocorticoids will not be initiated for patients on study unless indicated for a severe medical 
condition not attributed to KSHV-MCD.  For patients on glucocorticoids at the time of 
enrollment, they will be tapered as soon as medically feasible.  Patients on >20 mg of prednisone 
or equivalent for at least 3 weeks will be monitored clinically for adrenal insufficiency. 
 Pneumocystis jiroveci Prophylaxis 
All HIV-infected patients with history of PCP or with CD4 cells d 200/mm3 should receive 
Bactrim DS (sulfamethoxazole 800 mg + trimethoprim 160 mg) PO 3x/week.  Alternatives 
include but are not limited Bactrim DS (sulfamethoxazole 800 mg + trimethoprim 160 mg) PO 
daily, Dapsone 100 mg PO qd, and monthly aerosolized pentamidine 300 mg.  Additionally, 
given potential infectious risk of anti-IL-6 therapy, PCP prophylaxis is will be strongly 
considered during study duration in all HIV infected patients, regardless of CD4 count.  
 MAC Prophylaxis 
Consider for all HIV-infected patients with a historic CD4 nadir less than 75 cells/mm3, or for 
patients whose CD4 cells fall below this level while on study. Recommend azithromycin 1200 
mg orally once weekly, but other agents are acceptable. 
 Latent Tuberculosis Therapy 
Patients with reactive tuberculin skin test (>5 mm induration 48-72 hours after intradural 
placement of purified protein derivative) or positive QuantiFERON TB Gold will be evaluated 
by induced sputum culture for mycobacteria, and will have either a chest X-ray or CT-scan to 
evaluate for evidence of disease.  Those who have not completed an adequate course of 
preventative anti-tuberculosis therapy must complete tuberculosis evaluation and start 
prophylactic anti-tuberculosis therapy prior to enrollment, following American Thoracic Society/ 
Centers for Disease Control recommended guidelines: 
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5231a4.htm 


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Preferred regimen is isoniazid 300 mg orally daily for nine months. 10-25 mg of pyridoxine 
(vitamin B6) should be given orally with each isoniazid dose to reduce the risk of isoniazid-
induced peripheral neuropathy. 
 Hepatitis B Virus 
In patients with hepatitis B virus (HBV) and HIV, a number of HIV drugs (including but not 
limited to: tenofovir, emtricitabine, lamivudine) also are appropriate for HBV therapy and should 
be incorporated in anti-HIV regimens for HBV-co-infected patients.  For HIV negative patients, 
HBV suppression with an appropriate anti-viral agent will be used. 
 Prevention of Herpes Simplex Virus Reactivation 
Valacyclovir will be considered in patients with history of oral or genital HSV infections.  
Valacyclovir will not be co-administered with VGC. 
5 
BIOSPECIMEN COLLECTION  
5.1 
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES 
 Biospecimen Banking for Immunologic and Other Studies 
Specimens will be collected for several planned correlative studies. Samples will be stored and 
run in batches.  Planned assays include: viral-IL6 (performed in the laboratory of Dr. Robert 
Yarchoan), multiplex inflammatory cytokine assay (Cat.# K15008 and  Meso-Scale Discovery, 
Gaithersburg, MD), soluble gp80 ELISA (Cat# 850.510.096, Gen-Probe, Cedex, France), KSHV 
serology, blood viral load, and saliva viral load (to be performed in the Laboratory of Dr. Denise 
Whitby). For all these testing, specimens will be sent via messenger to the AIDS Monitoring 
Laboratory (AML), Leidos Biomedical, Inc. in the NCI-Frederick. Specific assays will be 
performed in batches. Biospecimens for storage (See Section 5.2) will be collected in the 
following tubes (See Section 3.4 for collection schedule): 
5.1.1.1 Three ACD tubes (BD Vacutainer® Ref 364606 yellow top) 
5.1.1.2 Two serum tubes (BD Vacutainer® Ref 367820 red top tubes) 
5.1.1.3 1 sodium heparin (BD Vacutainer® Ref 367878 green top tube) 
5.1.1.4 Urine IFE (BD Vacutainer® Ref 364980 yellow top  
5.1.1.5 Saliva, collected in 50 mL polypropylene conical tube (Beckton-Dickenson labware) 
with 2 mL scope mouth wash (swish and spit) 
 Pharmacokinetic studies  
5.1.2.1 Background on disease-drug-drug interactions 
In the NCI Natural History study of KHSV-MCD, we have observed anecdotally that patients 
with active disease sometimes poorly tolerate other medications, including antiretroviral therapy.  
One possible explanation for this observation is that CYP3A4(60) is down regulated by IL-
6(61,62) and the setting of IL-6 excess, and patients symptomatic KSHV-MCD may have higher 
circulating levels drugs do to alterations in metabolism(63).  Furthermore, alterations in protein 
concentrations of albumin (decreased) and alpha 1-acid glycoprotein(64)(increased) may also 
effect protein binding in the setting of uncontrolled KSHV-MCD. Tocilizumab may counter 


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these IL-6 effects, and lead to lower drug concentrations, as has been shown for simvastatin in 
the setting of the treatment of rheumatoid arthritis(65). 
We will analyze limited PK of commonly used antiretroviral agents (ritonovir, lopinovir, 
atazanavir, and efavirenz) that are metabolized by CYP450 for changes in their plasma exposure 
in response to tocilizumab. 
5.1.2.2 Sample Collection (to be performed by the Clinical Pharmacology Program) 
5.1.2.2.1 PK Studies 
Patient samples will be collected as follows (also, see sections 2.4.4. and 3.4): 
Cycle 1, Day 1: Pre-tocilizumab, 15 minutes post tocilizumab (i.e. 75 minutes after beginning 60 
minute infusion), 24 hours post-tocilizumab, 48 hours post-tocilizumab.  Cycles 2-6, pre-
tocilizumab and 15 minutes post tocilizumab only. At each time point: 6mL in sodium heparin 
(green top tube) will be collected, for PK analysis of antiretroviral agents and tocilizumab (66).  
Cumulative plasma exposure of tocilizumab will be evaluated for pharmacokinetic and 
pharmacodynamics correlations using clinical and surrogate endpoints in Objectives 1.1.2.4-
1.1.2.6.  
See Section 5.2.7 for specimen handling. 
5.1.2.2.2 Genotyping 
Genotyping of baseline samples for SNPs in drug-metabolism enzymes will be performed in the 
event of unexplained heterogeneity in the antiretroviral PK. Genomic DNA will be analyzed for 
polymorphisms in genes involved in drug metabolism and transport that have been linked to the 
clinical pharmacology of antiretrovirals. Genotyping will be performed using the Drug 
Metabolizing Enzymes and Transporters (DMET, Affymetrix) genotyping platform and results 
will be quality checked via direct sequencing. 
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  
Samples will not be sent outside NIH without IRB notification and an executed MTA. 
 Background 
It is understood that per the NCI policy regarding the Requirements for the Research Use of 
Stored Human Specimens and Data, prospective NIH Intramural IRB approval and continuing 
IRB oversight must be obtained for research involving identified or coded samples or data where 
investigators can identify the source. This policy applies to research protocols where the 
remaining research activities are limited to data analysis and to the subsequent research use of 
specimens or data previously collected under a now terminated protocol.   The following 
guidelines describe how these principles apply to this specific protocol.   
 AIDS Monitoring Laboratory 
Many samples on this study will be processed and stored in the AIDS Monitoring Laboratory 
(AML) run by Leidos Biomedical, Inc. in the NCI-Frederick facility located with Fort Detrick.  
The samples are stored under code, and the information linking these unique codes to the patients 
is kept on the AML database.  The laboratory informatics system conforms to NIH Information 
Technology Security Requirements and NIH Protection of Human Research Subjects Guidelines.  


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All laboratory staff is trained to adhere to NIH Information Technology Security Requirements 
and NIH Protection of Human Research Subjects Guidelines.  Computers used to access 
inventory systems require username and password for login. The laboratory database is housed in 
a secure, protected environment and backups are performed routinely.  Access to specimen 
information, clinical data, and stored specimens is limited to approved laboratory staff and the 
investigator in charge of the study (or individuals authorized by the investigator). 
 Specimen Withdrawal for Research Purposes 
The protocol team will inform the AML staff when tests are to be run with the specimens, and 
the samples used for testing will be tracked by the AML.  This information will in turn be shared 
with the protocol team.  The research nurse on the study will be in charge of tracking this 
information for the protocol team. 
 Specimens Sent to the Whitby Laboratory 
Some of the specimens are sent to the laboratory of Dr. Denise Whitby, also in Leidos 
Biomedical, Inc.  in the NCI-Frederick facility located with Fort Detrick.  The samples sent are 
coded by the protocol research team and have no patient identifiers.  They are logged in by Dr. 
Whitby’s laboratory and kept in a locked facility.  They are run in batch when enough specimens 
are collected. Records are kept when the specimens are used for analysis.  
Denise Whitby Ph.D. 
Leidos Biomedical, Inc.  
1050 Boyles St, Building 535, Room 428A 
Frederick, MD 
Contact phone number 301-846-1714 
 Specimens sent to the Yarchoan Laboratory 
A limited number of samples will be sent to Dr. Yarchoan’s laboratory from Leidos Biomedical, 
Inc.  These will usually be sent batched.  Occasional samples may be sent directly to the 
Yarchoan laboratory. This is a locked laboratory, and a log is kept of the specimens and when 
they are utilized.   
Robert Yarchoan, M.D. 
10 Center Drive, Room 5A-25 
Bethesda, MD 20892 
Phone Contact: 240-760-6075 
 Specimens sent to the Tosato Laboratory 
A limited number of samples will be sent to Dr. Tosato’s laboratory from Leidos Biomedical, 
Inc.  These will usually be sent batched.  Occasional samples may be sent directly to the Tosato 
laboratory.  They will be kept locked and a log will be kept of the specimens and when they are 
utilized. The samples sent are coded by the protocol research team and have no patient 
identifiers.  They will in general be run in batch when enough specimens are collected. 
Giovanna Tosato, M.D. 
Building 37, Room 4124 
37 Convent Drive 
Bethesda, MD 20892 


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240-760-6144 
 
 Specimens sent to the Figg Laboratory/ Blood Processing Core (BPC) 
5.2.7.1 Sample Collection  
PK samples will be collected in green top, sodium heparin tubes (6mL), and delivered on ice to 
Douglas Figg in the Blood Processing Core (BPC). Samples for genotyping of baseline SNPs in 
drug-metabolism enzymes (DMET) will be sent in 10mL EDTA purple top tubes.  
Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the 
Friday before is preferred). 
For sample pickup, page 102-11964. 
For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 
240-760-6190 (main clinical pharmacology lab number). 
For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov. 
All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and 
stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with 
access to LABrador limited to defined Figg lab personnel, who are issued individual user 
accounts. Installation of LABrador is limited to computers specified by Dr. Figg. These 
computers have a password restricted login screen. All Figg lab personnel with access to patient 
information annually complete the NIH online Protection of Human Subjects course. 
 
LABrador creates a unique barcode ID for every sample and sample box, which cannot be traced 
back to patients without LABrador access. The data recorded for each sample includes the 
patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, 
as well as box and freezer location. Patient demographics associated with the clinical center 
patient number are provided in the system. For each sample, there are notes associated with the 
processing method (delay in sample processing, storage conditions on the ward, etc.). 
 
5.2.7.2 Sample Storage and Destruction  
Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80C 
according to stability requirements. These freezers are located onsite in the BPC and offsite at 
NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are 
required to be accompanied by laboratory staff at all times. 
 
Access to stored clinical samples is restricted. Samples will be stored until requested by a 
researcher named on the protocol. All requests are monitored and tracked in LABrador. All 
researchers are required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol) and that any unused 
samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to 
ensure that the samples requested are being used in a manner consistent with IRB approval. 
 


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Following completion of this study, samples will remain in storage as detailed above. Access to 
these samples will only be granted following IRB approval of an additional protocol, granting 
the rights to use the material.  
 
If, at any time, a patient withdraws from the study and does not wish for their existing samples to 
be utilized, the individual must provide a written request. Following receipt of this request, the 
samples will be destroyed (or returned to the patient, if so requested). The PI will report any loss 
or unanticipated destruction of samples per Section 7.2.1. Any samples lost (in transit or by a 
researcher) or destroyed due to unknown sample integrity (i.e. broken freezer allows for 
extensive sample thawing, etc.) will also be reported as per Section 7.2.1. 
 
Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use of the 
LABrador. It is critical that the sample remains linked to patient information such as race, age, 
dates of diagnosis and death, and histological information about the tumor, in order to correlate 
genotype with these variables 
 Clinical Testing of Stored Specimens 
Clinical testing of all samples will be one in accordance to the protocol.  The protocol team will 
inform the AML staff when tests are to be run with the specimens, and the samples used for 
testing will be tracked by the AML.  This information will in turn be shared with the protocol 
team.  The research nurse on the study will be in charge of tracking this information for the 
protocol team. 
 Clinical Center Processing and Storage of Clinical Specimens 
Many routine samples and a sample of the biopsy specimens are sent to the Laboratory of 
Pathology (CCR), Department of Laboratory Medicine, and Department of Transfusion 
Medicine at the NIH Clinical Center.  These samples will be handled according to the procedures 
of these departments.  Results for clinical testing are generally available via the CRIS electronic 
medical record. 
 Co-enrollment on 01-C-0038 and/or 04-C-0275 
If patients have co-enrolled on study 01-C-0038 (Collection of Blood, Bone Marrow, Tumor, or 
Tissue Samples from Patients with HIV Infection, KSHV Infection, Viral-related Pre-Malignant 
Lesions, and/or Cancer), then the samples may also be tested under the specifications of that 
study.  Similarly, if patients have co-enrolled on other studies approved by the NIH Intramural 
IRB that call for maintaining and testing the samples, then they may be transferred to those 
studies. 
 Handling of Specimens at Study Termination 
At the termination of the protocol, if patients have co-enrolled on study 01-C-0038 (Collection of 
Blood, Bone Marrow, Tumor, or Tissue Samples from Patients with HIV Infection, KSHV 
Infection, Viral-related Pre-Malignant Lesions, and/or Cancer), then the samples will be 
transferred to that study unless the patients request that this not occur.  Also, if patients have co-
enrolled on other studies approved by the NIH Intramural IRB that call for maintaining the 


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samples, then they will be maintained on those protocols.  Otherwise, the unused samples will be 
destroyed. 
 Loss or Destruction of Samples 
The PI or LAI will report any loss or unanticipated destruction of the samples that meet 
expedited reporting requirements as per Section 7.2.1, and any new use of the samples, 
specimens, or data will require prospective IRB approval. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the first study intervention, Study Day 1, through the end of treatment. At 
follow up visits (beyond 28 days), only adverse events which are serious and related to the study 
intervention need to be recorded. 
Adverse events will be recorded in the database only if they occur during treatment or within 30 
days of coming off treatment, unless they are assessed as being at least possibly due to study 
drug administration.  
Any abnormal laboratory value that is specifically defined as a Grade 1 or higher Adverse Event 
in CTCAE version 4.0 will be recorded in the database as an AE. Abnormal laboratory values 
that fall into the “Investigations - Other, specify” category but are not otherwise graded will only 
be recorded if they are determined by the investigator to be clinically significant.  
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (e.g., an 
overnight stay to facilitate chemotherapy and or correlative studies) are not considered serious 
adverse events (SAEs). However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (e.g., undesirable effects of any administered 
treatment) must be documented and reported as SAEs. 
 Clinical Research Records 
Members of the HIV and AIDS Malignancy Branch clinical research team will collect data on 
study subjects according to the Schedule of Evaluations outlined in Section 3.4.  Complete 
records must be maintained on each patient including supplementary information obtained from 
outside laboratories, radiology reports, or physician’s records, as well as relevant copies of notes, 
reports and results from the CC – CRIS electronic medical record system. These records will 
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records will be stored in a secure office of one of the clinical investigators.  The primary source 
documentation will assure the following:  
6.1.1.1 The patient satisfied each eligibility criterion.  
6.1.1.2 Signed informed consent was obtained prior to registration and treatment.  
6.1.1.3 Treatment was given according to protocol or any protocol violations documented and 
justified.   
6.1.1.4 Toxicity and response were assessed according to protocol. 
6.1.1.5 Drug accountability records were kept on each patient.  
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in Section 7.2.1. 
 Correlative and Exploratory Studies Performed with non-Clinical Collaborators 
Coded identifiers will be used when collecting and storing samples or data collected in 
collaboration with non-clinical investigators. Management of coded identifiers for samples 
stored at AML is performed at AML (See Section 5.2.2.), and management of unique identifiers 
in the BPC is performed at the BPC (see Section 5.2.7.) Samples sent directly to other 
collaborators will be labeled with a unique identifier number and date.  The study coordinator 
will securely maintain a log of patients and unique identification codes in the regulatory 
binder/file, which is only accessible to clinical investigators. (See Section 5.2) 
 Survival Endpoints 
6.1.3.1 Patients may be followed on 04-C-0275 either during, or any point after completion of 
this study.  Data on survival endpoints related to KSHV-MCD disease progression, 
development additional KSHV associated malignancies, subsequent therapy and death 
may be collected, and used in evaluation of the long-term safety, tolerability, and 
efficacy of tocilizumab.    
6.1.3.2 Patients not enrolled in 04-C0275 will be censored for disease progression endpoints at 
the time the patient is taken off-study. Overall survival data may be obtained by phone 
from a study subject-designated physician or durable power of attorney, or from the 
Social Security Death Index. 
6.2 
RESPONSE CRITERIA 
In this protocol, the response criteria for the primary outcome will be the KSHV-MCD Clinical 
Benefit Criteria (Section 6.2.2)  The following sections outline the original criteria as defined in 
the KSHV-MCD Natural History Protocol 04-C-0275 (Section 6.2.1) that will continued to be 
used, the newer Clinical Benefit Criteria (6.2.2), as well as the modified AIDS Clinical Trial 
Group criteria used to grade Kaposi Sarcoma responses (6.2.3). Also see section 8 for planned 
evaluation of the NCI-KSHV-MCD Response Criteria and KSHV Clinical Benefit Criteria. 


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 NCI KSHV-MCD Response Criteria 
6.2.1.1 Background  
Response to therapy will be based on KSHV-MCD response criteria under prospective 
evaluation, outlined in Appendix 1: KSHV-MCD Clinical Benefit Response Criteriaand 
Appendix 2 . The following criteria were devised in 2004, and had a minor amendment in 2008 
prior to grading responses in any HAMB KSHV-MCD study. This response criteria has been 
used in the evaluation of 2 other therapeutic modalities (AZT combined with VGC and rituximab 
combined with liposomal doxorubicin) in the treatment of KSHV-MCD.  These response criteria 
assess responses in several categories that are believed to be associated with disease activity, so 
as to record this in a unified way.  We anticipate that the results obtained will continue to shed 
light on the benefits attained with therapy and also provide guidance to refine response criteria in 
subsequent trials in this disease.  
Response criteria will be evaluated in each of three categories, clinical, biochemical, and 
radiographic. Clinical and biochemical responses will be evaluated at each visit, and 
radiographic responses will be evaluated for all scheduled CT scans.  The baseline for response 
criteria evaluations will be based on the Day1 Cycle 1 evaluation for clinical and laboratory 
parameters for any given therapy, as well as baseline CT scans as defined in Section 3.4.  Any 
new clinical, laboratory, or radiologic abnormalities that are probably or definitely attributed to 
MCD and that occur between baseline and the end of the final cycle of a given therapy must also 
resolve in order to be considered a complete response. Only those abnormalities attributed as 
probably or definitely related to the disease will be included in the response assessment. 
Given the waxing and waning course of MCD, patients may have progression in a given category 
at the time of interval evaluations. However, if on clinical evaluation there is evidence of clinical 
benefit, even though there may be lack of formal response in one or more of the categories, 
consideration will be given to continued study of that treatment. 
Best response will be described for clinical, biochemical and radiographic categories for each 
subject.  Additionally, best overall response and end of therapy overall response will be assessed 
for any given treatment based on all three response categories (clinical, biochemical, 
radiographic), as defined in Section 6.2.1.2.4. 
6.2.1.2 Definition of Responses (Also, See Appendix 2: KSHV-associated multicentric 
Castleman disease response criteria (Evaluated in 04-C-0275)) 
6.2.1.2.1 Clinical Response 
6.2.1.2.1.1 Complete Response (CR) - full resolution of signs and symptoms attributable to 
MCD lasting at least 3-4 weeks (depending on therapeutic intervention) and 
normalization of all involved nodal areas.  
6.2.1.2.1.2 Symptom Free Disease (SFD)- full resolution of symptoms that are attributable to 
MCD not yet lasting at least 3-4 weeks (depending on therapeutic intervention)  
6.2.1.2.1.3 Partial Response (PR) – Symptoms attributed to MCD will be assigned a NCI CTC 
grade-equivalent.  Improvement in at least 50% of the MCD-attributed signs and 


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symptoms by at least 1 NCI CTC grade-equivalent with remaining signs and 
symptoms showing no disease-related NCI CTC grade-equivalent increase lasting at 
least lasting at least 3-4 weeks (depending on therapeutic intervention) will be scored 
a partial clinical response 
6.2.1.2.1.4 Stable disease (SD) – no change in signs and symptoms of MCD that meet criteria 
for PR, SFD, CR nor PD.  The assignment of SD will be further annotated by the 
categories: improved, mixed response, stable, or worsened.  These categories will be 
assigned based on changes from day 1 to the last day of any given cycle, as they are 
designed to describe short-term changes in clinical status. This subcategorization of 
SD will be used for exploratory analysis only, and will NOT be used in designating 
and reporting Best Response or End of Treatment Response. 
Improved (I): improvement in one or more symptoms or signs by t 1 grade with no new 
symptoms and no symptoms worsening by t 1 grade. 
Mixed Response (M): improvement in one or more symptoms or signs by t 1 grade in 
combination with new symptoms or one or more symptoms worsen by t 1 grade. 
Stable (S): no change in grade of any symptom. 
Worsened (W): No symptoms improve, and either new symptoms develop or one or more 
symptoms worsen by t 1 grade. 
6.2.1.2.1.5 Progressive disease (PD) – worsening of 2 or more signs and/or symptoms 
attributed to MCD by t 1 grade 
6.2.1.2.1.6 Major Clinical Response = Complete Response + Symptom Free Disease + Partial 
Response. 
6.2.1.2.2 Biochemical Response  
Five biochemical parameters are used in response assessment, hemoglobin, platelet 
count, C-reactive protein, sodium, and albumin. 
6.2.1.2.2.1 Complete response CR - normalization of all biochemical tests related to MCD 
lasting at least 3-4 weeks (depending on therapeutic intervention). 
6.2.1.2.2.2 Partial PR – 50% improvement in all biochemical tests related to MCD lasting at 
least 3-4 weeks (depending on therapeutic intervention). 
6.2.1.2.2.3 Stable disease SD – no significant change in biochemical parameters related to 
MCD that meet criteria for PR, CR or PD. The assignment of SD will be further 
annotated by the categories: improved, mixed response, stable, or worsened.  These 
categories will be assigned based on changes from day 1 to the last day of any given 
cycle, as they are designed to describe short-term changes in the laboratory 
parameters used in the evaluation of biochemical responses status.  Direction of 
laboratory changes do not need to change the CTC grade, but must be larger than 
that the intra-assay variability of the test.  The following minimum changes must be 
noted: Na - t 2mmol/L, albumin t0.2 g/dL, platelets t  platelets/uL5 K/uL, 


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hemoglobin t 0.2 g/dL, CRP t 0.5 mg/L.  This subcategorization of SD will be used 
for exploratory analysis only, and will NOT be used in designating and reporting 
Best Response or End of Treatment Response. 
6.2.1.2.2.4 Progressive disease (PD) – 25% worsening of at least 2 biochemical parameters 
related to MCD by t 1 grade, or clear deterioration of one parameter that has impact 
of physiologic or health status. 
6.2.1.2.2.5 Major Biochemical Response = Complete Response + Partial Response. 
6.2.1.2.3 Radiographic Response 
The optimal imaging modality for monitoring MCD and evaluating radiographic response 
has not been defined. KSHV-MCD is a lymphoproliferative disease marked by multifocal 
lymphadenopathy. Diffuse splenomegaly is an additional common finding.  Radiographic 
response criteria in this protocol have been modeled on the radiographic response criteria 
for malignant lymphoma studies as published by the International Working 
Group(67,68). Special attention has been given to splenic findings given the previously 
described natural history of MCD.  CT scans will be used to define response criteria.  
PET scans will be explored as an imaging modality within the protocol, but are not used 
for defining radiographic response.  As outlined in Revised Response Criteria published 
by the International Working Group, lymph node evaluation will based on serial 
evaluation of up to SIX dominant pathologic lymph nodes.  Any lymph node >1.5 cm at 
follow-up evaluation will also be evaluated if a subject otherwise potentially meets 
criteria for CR or CRu radiographic response, even if it was not identified as one of the 
original six dominant pathologic lymph nodes.  
Given the prominence of splenomegaly, a separate response will be noted for lymph 
nodes and for the spleen.  Unlike the International Working Group lymphoma criteria, 
which generally focus on nodules within the spleen, MCD response criteria in this 
protocol will focus on overall spleen size.  In order to obtain an overall complete 
radiographic response, both spleen and lymph nodes must meet criteria as defined below. 
As an additional modification, pleural effusions must resolve in order to obtain a 
complete response. Although unconfirmed complete response (CRu) has been removed 
from the 2007 revision of radiographic response criteria for malignant lymphoma, we 
have maintained a modified version of CRu that is potentially clinically meaningful in 
MCD.  
 
The following responses are based on CT scan of neck, chest, abdomen and pelvis to 
evaluate sites of disease. 
6.2.1.2.3.1 Complete response (CR) - All lymph nodes and nodal masses must have regressed 
to normal size (d 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm 
before therapy) for at least one month. For the SIX target lesions, involved nodes 
that were 1.1 to 1.5 cm in their greatest transverse diameter before treatment must 
have decreased to d 1 cm in their greatest transverse after treatment or by more than 
75% in the sum of the products of the greatest diameters (SPD). The spleen, if 
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must have regressed <12 cm and must not be palpable on physical examination. Any 
macroscopic nodules in any organs detectable on imaging techniques should no 
longer be present. All pleural effusions must have resolved. 
6.2.1.2.3.2 Complete response unconfirmed (CRu) - Any residual lymph node mass > 1.5 cm 
in greatest transverse diameter that has regressed by > 75% in sum of the products of 
the greatest diameters and does not change over one year of observation and/or 
residual splenomegaly >12 cm in longest dimension, but that has regressed by 75% 
and does not change over one year.   In organs involved by disease, any residual 
lesions that have decreased by > 75% in sum of the products of the greatest 
diameters or are < 1 cm, are consistent with scar, and stable over the last two 
treatments will be considered to fulfill criteria for CR.   
6.2.1.2.3.3 Partial response (PR) - For lymph nodes: 50% or greater decrease in the sum of the 
products of the longest perpendicular diameters (SPD) of the six dominant lymph 
nodes lasting for a period of at least one month. No increase in size of other nodes, 
For spleen: a 50% decrease in longest dimension of spleen [decrease >  (baseline 
length – 12 cm) / 2]  No new lesions, including pleural effusions, may appear. 
6.2.1.2.3.4 Stable disease (SD) - tumor measurements not meeting the criteria of CR, PR, or 
PD. 
6.2.1.2.3.5 Progressive disease (PD) - For lymph nodes, an increase of 25% or more in the sum 
of the products of the longest perpendicular diameters of all measured lesions 
compared to the smallest previous measurements during a given therapy. For spleen, 
an increase of greater than 25% in the longest dimension of the spleen compared to 
the smallest previous measurement during a given therapy., or the appearance of any 
new lesion(s), including pleural effusions, will be considered progressive disease. 
6.2.1.2.3.6 Major Radiographic Response = Complete Response + Complete Response 
unconfirmed + Partial Response. 
6.2.1.2.4 Overall Response 
Overall response will be determined based on responses in clinical, biochemical, and 
radiographic response criteria.  Overall responses are defined as the highest response 
below. 
6.2.1.2.4.1 Complete response (CR)  = Complete response in all categories 
6.2.1.2.4.2 Partial response (PR)  = Partial response or better in all categories 
6.2.1.2.4.3 Stable disease (SD)  = Stable disease or better in all categories 
6.2.1.2.4.4 Progressive disease (PD) = Progressive disease in any one category 
 


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 KSHV-MCD Clinical Benefit Response Criteria  
6.2.2.1 Background 
In the literature, there are no established criteria for responses in MCD (including KSHV-MCD) 
and no uniformity among various articles.  Some studies report results in only in general terms of 
resolution of symptoms and fever(14) or a composite of symptoms, fever, and an elevated C-
reactive protein.(13) We developed and have tested the use of a set of NCI KSHV-MCD 
response criteria in our current ongoing studies (especially 04-C-0275), which are more rigorous, 
and included more biochemical and radiographic endpoints.  Within 04-C-0275, we have gained 
experience with these criteria with two treatment modalities: AZT/VGC and rituximab combined 
with liposomal doxorubicin. While we found these criteria to be useful and to provide a complete 
picture, they have the disadvantage of being rather cumbersome.  Also, the radiographic 
responses usually lagged behind the other responses.  Based on experience within a total of 28 
patients in this Natural History protocol, our sense was that the evaluation of therapy would 
benefit from a combined primary response criteria that included the most important clinical 
(symptomatic) criteria and the most important laboratory criteria.  From discussions with other 
investigators working on MCD in the United States and Europe, it appears that these other 
groups are moving in a similar direction. 
With this experience, we have developed KSHV-MCD Clinical Benefit Response Criteria as a 
more streamlined tool for assessment of patients receiving therapy for KSHV-MCD.  These 
criteria do not depend on radiographic findings.  As such, it allows for same-day assessment of 
clinical benefit utilizing common symptoms and clinical laboratories. To evaluate clinical benefit 
in patients with KSHV-MCD receiving therapy, clinical and laboratory responses are assessed in 
aggregate, and compared to baseline. These criteria allow for assessment of patients who may be 
deriving meaningful clinical benefit from therapy, but have not necessarily achieved an overall 
complete response by the original NCI KSHV-MCD response criteria.  In an effort to harmonize 
response criteria across researchers in the field, we hope to propose these criteria for use across 
KSHV-MCD studies, and will compare it our prior methodology (see Section 8.3.2.2). We plan 
to simultaneously assess the patients using the original NCI KSHV-MCD Response Criteria to 
gather information on the two criteria.  Ultimately, our sense is that responses in the disease will 
involve tracking Clinical Benefit response Criteria and Radiographic responses separately. 
In brief, assessment of KSHV-MCD Clinical Benefit Response is made on evaluation of eight 
indicator abnormalities (four symptom groups and four laboratory parameters) that are most 
closely associated with disease activity. 
6.2.2.2 KSHV-MCD Clinical Benefit Response Criteria 
Indicator Abnormalities Assessed in Responses  
Symptoms 
Laboratory Abnormalities 
Fever (includes chills and rigors) 
Elevated C-reactive protein 
Fatigue (includes lethargy) 
Thrombocytopenia 
Gastrointestinal (includes nausea and 
anorexia) 
Anemia 
Respiratory (includes airway 
hyperreactivity and cough) 
Hypoalbuminemia 


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For the purposes of response assessment, clinical symptoms attributed to MCD will be assigned 
an NCI-CTCAE grade equivalent, with response assessment based on changes in grade severity 
or symptom resolution. 
Increases in hemoglobin in patients who have received a transfusion do not count towards PR or 
CR for 3 weeks, and increases in albumin or platelet count in patients who have received a 
transfusion do not count towards PR or CR for 7 days. 
6.2.2.3 Complete Response (CR): 
Full resolution of all clinical symptoms and laboratory abnormalities (whether or not these are 
indicator abnormalities) probably or definitely attributable to MCD, lasting at least 3 weeks.  
6.2.2.4 Partial Response (PR):  
PR is assessed based on the eight indicator abnormalities above. At least 50% of the 
abnormalities probably or definitely attributed to KSHV-MCD must improve by the minimum 
amounts specified below to attain PR. 
Only abnormalities present in a specific patient at baseline may count toward the achievement of 
a PR (e.g. if six of indicator abnormalities are present at baseline, at least three must meet the 
specified criteria to be considered a PR). 
Improvement in symptoms require at least 1 CTCAE grade equivalent improvement. For 
symptom groups (e.g. gastrointestinal and respiratory), where multiple symptoms within the 
group are present at least half of those attributable to KSHV-MCD must improve by at least 1 
CTCAE grade equivalent to consider the group as a whole to be improved. 
Improvement in for each laboratory parameters requires either normalization of the lab value or 
else the following: 
6.2.2.4.1 C-reactive protein reduction to ≤50% of baseline 
6.2.2.4.2 Hemoglobin increment 2g/dL not explained by transfusion 
6.2.2.4.3 Platelet increment ≥50 K/uL not explained by transfusion 
6.2.2.4.4 Albumin increment ≥1g/dL not explained by transfusion 
To be considered a partial response, there may be no new indicator abnormalities probably or 
definitely attributed to KSHV-MCD; no indicator symptom may worsen by ≥1 CTCAE grade 
equivalent; and no indictor laboratory abnormality may worsen by the amount given in the 
criteria for progressive disease. 
6.2.2.5 Stable disease (SD): no change in signs and symptoms of KSHV-MCD that meet 
criteria for any of CR, PR or PD. 
6.2.2.6 Progressive disease (PD):  
PD is assessed based on the eight indicator abnormalities above. At least two indicator 
abnormalities must deteriorate by the minimum amounts specified below to constitute PD. The 
development of new indicator abnormalities not present in a specific patient at baseline is 
incorporated in the assessment of PD 
Deterioration in signs and symptoms require at least 1 CTCAE grade equivalent increase in 
severity. For symptom groups (e.g. gastrointestinal and respiratory), where multiple symptoms 


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within the group are present at least half of those attributable to KSHV-MCD must increase in 
severity by at least 1 CTCAE grade equivalent to consider the group as a whole to have 
deteriorated. 
Deterioration for each laboratory parameter requires an abnormal laboratory value meeting the 
following criteria: 
6.2.2.6.1 C-reactive protein increase by ≥50% of baseline (or the upper limit of normal, 
whichever is greater) 
6.2.2.6.2 Hemoglobin decrement 2g/dL not otherwise explained 
6.2.2.6.3 Platelet decrement ≥25 K/uL not otherwise explained 
6.2.2.6.4 Albumin decrement ≥0.5g/dL not otherwise explained 
 Kaposi’s Sarcoma Response 
6.2.3.1 Background 
Evaluation of the response of KS to an agent or regimen is difficult to grade by means 
of commonly used oncologic definitions.  However, in an effort to standardize the 
evaluation of therapy against KS, the AIDS Clinical Trial Group Oncology Committee 
has devised a set of staging and response definitions for KS.  We will use a 
modification of these criteria to assess responses, which is consistent with the criteria 
used in our previous KS studies.  It should be noted that there is some observer 
variability in the evaluation of the number, size, nodularity, and color of lesions, and 
this must be taken into account when measurements are interpreted. (See Appendix 4) 
For evaluation of less than complete responses in patients with more than 50 lesions at 
entry, only the previously selected 1 - 3 representative areas that contain at least 20 
lesions will be considered.  However, complete responses still require the absence of 
any detectable disease over the entire body (i.e. not confined to the representative 
areas). 
6.2.3.2 Evaluation Schedule 
For patients with Kaposi’s sarcoma (KS), clinical evaluation of the response of their KS 
will be assessed at baseline, week 7, and at off-study visit. (See Study Calendar, 
Section 3.4) When assessed, KS responses will be reported separately from responses 
assessed for MCD, and will not be considered part of the Overall Response of MCD 
outlined in Section 6.2.1.2. Additional studies at the end of therapy may be required for 
patients with visceral KS, these include, but are not limited to: bronchoscopy, 
gastrointestinal endoscopy, chest X-ray, and CT-scans. 
6.2.3.3 Definition of Kaposi Sarcoma Responses 
6.2.3.3.1 Complete Response 
6.2.3.3.1.1 The absence of any detectable residual disease, including tumor associated edema, 
persisting for at least 4 weeks. 


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6.2.3.3.1.2 For patients with pigmented macular skin lesions persisting after apparent complete 
response, a biopsy of at least one representative lesion is required to document the 
absence of malignant cells. 
6.2.3.3.1.3 For patients with visceral disease, an attempt at restaging with appropriate 
endoscopic or radiographic procedures should be made. If such procedures are 
medically contraindicated, the patient may be classified as having a clinical CR 
6.2.3.3.2 Clinical Complete Response 
6.2.3.3.2.1 The absence of any detectable residual disease, including tumor associated edema, 
persisting for at least 4 weeks. 
6.2.3.3.2.2 For patients with pigmented macular skin lesions persisting after apparent complete 
response, if a representative lesion has not been biopsied. 
6.2.3.3.2.3 For patients with visceral disease, the diagnostic radiologic or endoscopic study 
should be repeated if not medically contraindicated and found to be negative for 
evidence of disease. If such procedures are medically contraindicated but the patient 
has no clinical evidence of visceral disease, the patient may be classified as having a 
clinical CR 
6.2.3.3.3 Partial Response 
6.2.3.3.3.1 No progressive disease (see below and noting, that single lesions which split up into 
2 or more smaller lesions during the course of treatment will still be counted as one); 
no new lesions occurring in previously uninvolved areas of the body; no new visceral 
sites of involvement or the appearance or worsening of tumor-associated edema or 
effusions and: 
6.2.3.3.3.2 A 50% or greater decrease in the number of previously existing lesions lasting for at 
least 4 weeks or 
6.2.3.3.3.3 A 50% or greater decrease in the sum of the size (sum of the products of the largest 
perpendicular diameters) of the 5 marker lesions lasting for at least 4 weeks. 
6.2.3.3.3.4  Complete flattening of at least 50% of all previously raised lesions (i.e., 50% of all 
previously nodular or plaque-like lesions become macular) lasting for at least 4 
weeks or 
6.2.3.3.3.5 A 50% decrease in radiologically measurable visceral lesions sustained without 
evidence of re-growth for at least 4 weeks or 
6.2.3.3.3.6 Patients who otherwise meet the criteria for a CR but still have residual tumor-
associated edema or effusions will be classified as having a PR. 
6.2.3.3.4 Progressive Disease 
6.2.3.3.4.1 For those criteria that involve measurement of lesions in the clinic, the designation of 
progression should be made, when feasible, only when the criteria below have been 


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met in two measurements spaced at least 1 week apart. For the assignment of 
progressive disease for the primary outcome analysis, progression will be defined in 
comparison to baseline measurements. 
6.2.3.3.4.2 An increase of 25% or more over baseline in the number of lesions and/or the size 
(sum of the products of the largest perpendicular diameters) of the marker lesions or 
6.2.3.3.4.3 A change in character from macular to plaque-like or nodular of at least 25% of the 
lesions or 
6.2.3.3.4.4 New visceral sites of involvement or progression of visceral disease or 
6.2.3.3.4.5 The development of new or increasing tumor-associated edema or effusion that lasts 
at least 1 week and interferes with the patient’s normal activities. 
6.2.3.3.5 Stable Disease 
Any tumor measurement not meeting the criteria for Complete Response, Partial 
Response, or Progressive Disease. 
6.2.3.3.6 Overall Response (Major KS Response) 
Overall Response = Complete Response + Clinical Complete Response + Partial 
Response.   
6.2.3.4 Progression-free survival  
As Kaposi’s sarcoma is a disease in which recurrence is common, progression will be 
determined based on progression from best response.  Progression must be documented on two 
visits at least 1 week apart. Progression-free survival is defined as the time interval from the date 
of enrollment to the date of progression from best response. The criteria for progression from 
best response include: 
6.2.3.4.1 An increase of 25% or more over best response in the number of lesions and/or the 
size (sum of the products of the largest perpendicular diameters) of the marker lesions 
or 
6.2.3.4.2 A change in character from macular to plaque-like or nodular of at least 25% of the 
lesions or 
6.2.3.4.3 New visceral sites of involvement or progression of visceral disease or 
6.2.3.4.4 The development of new or increasing tumor-associated edema or effusion that lasts at 
least 1 week and interferes with the normal activities 
6.3 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  All 


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appropriate treatment areas should have access to a copy of the CTEP Active Version of 
CTCAE. 
7 
NIH REPORTING REQUIREMENTS / DATA SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING -  
 Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here. 
If the study is under review by an IC specific IRB, the following should be noted: 
x Reports referenced in policy 801 are made to the IC Specific IRB rather than to the 
OHSRP Office of Compliance and Training.   
x Section 5.2 of the policy 801 does not apply 
x Policy 802 does not apply   
 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here. 
 NCI Clinical Director Reporting 
Problems expeditiously reported to the OHSRP/IRB in iRIS will also be reported to the NCI 
Clinical Director.  A separate submission is not necessary as reports in iRIS will be available to 
the Clinical Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. 
Dahut at dahutw@mail.nih.gov and to NCICCRQA@mail.nih.gov within one business day of 
learning of the death. 
7.3 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
 Principal Investigator/Research Team  
The clinical research team will meet regularly (weekly when feasible) to discuss patients on this 
study receiving treatment that week. Decisions related to study treatment will be discussed and 
information from prior patients treated on the study will be used to guide any issues related to 
management of toxicities seen on the study, where appropriate.  
Patient data will be collected in a timely manner and reviewed by a physician Associate 
Investigator and/or the Principal Investigator, Robert Yarchoan, for toxicity.  Any toxicity 
tGrade 3 will be reviewed by the Principal Investigator or physician Associate Investigator. 


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Events meeting requirements for expedited reporting as described in Section 7.2.1 will be 
submitted within the appropriate timelines. 
The Principal Investigator will do continuous, close monitoring of this pilot study, and a Data 
and Safety Monitoring Board will not be used. CCR Safety Monitoring Committee (SMC) 
review is not necessary for this study. The principal investigator will personally conduct or 
supervise the investigation and provide appropriate delegation of responsibilities to other 
members of the research staff.  
8 
STATISTICAL CONSIDERATIONS   
8.1 
RACIAL/GENDER MAKE-UP 
Subjects from both genders and all racial/ethnic groups are eligible for this study if they meet the 
eligibility criteria outlined in section 2.1.  Outreach efforts will be made to extend accrual to a 
representative population. As a practical matter, it should be noted that historically in the US, 
KSHV associated malignancies have been relatively rare in females with HIV infection.  
However, our more recent studies have increasingly accrued female immigrants from Africa. 
8.2 
AGE EXCLUSION 
Patients under the age of 18 will be excluded.  This is a pilot clinical study of an agent with 
unknown safety profile in children and adolescents in a disease that is rare in children. 
Tocilizumab is current FDA approved for treatment of adults with rheumatoid arthritis. 
8.3 
SAMPLE SIZE CONSIDERATIONS AND STATISTICAL PLAN 
 Primary Objective 
The primary objective of this study is to estimate clinical benefit of tocilizumab 8mg/kg every 2 
weeks for up to 12 weeks in patients with symptomatic KSHV-MCD using a modified KSHV-
MCD Clinical Benefit Response Criteria.  
Sample size was determined based on the primary objective.  Clinical evidence of tocilizumab 
benefit will be based on achieving a Partial Response or better using the KSHV-MCD Clinical 
Benefit Response Criteria (Appendix 1) 
The study will be conducted using a two-stage phase II optimal design with alpha=0.10 and 
beta=0.10, in order to rule out 20% KSHV-MCD Clinical Benefit Partial Response or better as 
the best response and targeting a 50% KSHV-MCD Clinical Benefit Partial Response or better as 
a best response. Using this design, the study will initially accrue 10 patients in the first stage. If 
0-2 of 10 have a Clinical Benefit Partial Response or better, then accrual would stop, while 3+/10 
with responses would allow accrual to 17 total.  If 3-5 of 17 total patients respond, this would be 
inadequate, while 6+/17 with a response would be consistent with 50% and merit further 
evaluation in a subsequent study. The probability of early termination under the null hypothesis 
(20%) is 68%. 
 Secondary Objectives 
The following secondary outcomes will be evaluated with the following statistical 
considerations. 
8.3.2.1 Estimate best clinical, biochemical, radiographic, and overall responses in patients with 


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KSHV-MCD treated for up to 12 weeks with tocilizumab 8mg/kg every 2 weeks  
Biochemical, radiographic and overall responses, will also be described using NCI KSHV-MCD 
Response criteria, as we have done in other studies of KSHV-MCD (See Section 1.2, Table 1). 
Best responses in each category will be tabulated, with major responses are defined as follows: 
Major Clinical Response = Complete Response + Symptom Free Disease + Partial Response 
Major Biochemical Response = Complete Response + Partial Response. 
Major Radiographic Response = Complete Response + Complete Response unconfirmed + 
Partial Response. 
 
8.3.2.2 Evaluate responses as graded by the KSHV-MCD Clinical Benefit Response Criteria 
compared to the 04-C-0275 NCI KSHV-MCD response criteria 
 
Best responses in each category will be tabulated using NCI-KSHV-MCD response criteria and 
KSHV-MCD Clinical Benefit Criteria as outlined above. 
 
Additionally, at each assessment time-point, KSHV-MCD Clinical Benefit Response will be 
compared to: 
 
8.3.2.2.1 The combination of Clinical Response and Biochemical Response Criteria, using the 
04-C-0275 NCI KSHV-MCD criteria using the following categorization: 
8.3.2.2.1.1 Complete response (CR)  = Complete response in both categories 
8.3.2.2.1.2 Partial response (PR)  = Partial response or better in both categories 
8.3.2.2.1.3 Stable disease (SD)  = Stable disease or better in both categories 
8.3.2.2.1.4 Progressive disease (PD) = Progressive disease in any one category 
 
8.3.2.2.2 Clinical responses alone using NCI KSHV-MCD criteria, using the following 
categorization: 
8.3.2.2.2.1 Complete response (CR)  = Complete response + symptom free disease 
8.3.2.2.2.2 Partial response (PR)  = Partial response  
8.3.2.2.2.3 Stable disease (SD)  = Stable disease  
8.3.2.2.2.4 Progressive disease (PD) = Progressive disease  
A kappa statistic as well as other general measures of association and descriptive statistics may 
be calculated for each of these two comparisons. 
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Toxicities (including those possibly, probably, and definitely attributed to study treatment) will 
be assessed by grade.  Toxicities will be evaluated both per cycle and per patient.  All patients 
will be considered evaluable for toxicity. 
8.3.2.4 In patients with inadequate response to tocilizumab monotherapy:  explore preliminarily 
the activity of tocilizumab 8mg/kg every 2 weeks, combined with AZT 600 mg orally 
q6 hours and VGC 900 mg orally q12 hours on days 1-5 of a 14-day cycle. 
We will gather preliminary data on the activity of tocilizumab combined with AZT and VGC in 
evaluable patients.  All responses will be based on KSHV-MCD Clinical Benefit Response 
Criteria.  The number of patients receiving this combination will be determined by the number 
with an indication for treatment escalation with the addition of AZT and VGC.  We will also 
continue to assess the NCI KSHV-MCD (04-C-0275) response criteria. 
8.3.2.5 Evaluate effect of tocilizumab on KS 
In patients with concurrent Kaposi sarcoma, we will describe best KS response, using modified 
ACTG Response criteria, outlined in Section 6.2.3. 
8.3.2.6 Evaluate progression-free and overall survival  
For survival endpoints, subjects will be followed for up to approximately 4 months on this 
protocol. Long-term follow up will be feasible in patients co-enrolled in the KSHV-MCD 
Natural History Protocol, 04-C-0275 (See Sections 2.3 and 6.1.3.).  Progression-free and overall 
survival will be described using Kaplan-Meier methodology. 
8.3.2.7 Evaluate effect of tocilizumab on biochemical, immunologic, and virologic correlates of 
symptomatic KSHV-MCD and IL-6 excess 
We will evaluate longitudinal effect of tocilizumab monotherapy on individual biochemical (c-
reactive protein, hemoglobin, platelets, albumin, sodium, and ferritin), virologic (HHV-8 viral 
load, vIL-6), and immunologic (quantitative immunoglobulins, free light chains, sIL-6 receptor, 
IL-6, IL-10, and other inflammatory cytokines, anti-k 8.1 and anti-LANA antibodies) 
parameters, using both descriptive analyses and non-parametric comparisons at relevant time 
points. 
9 
HUMAN SUBJECTS PROTECTIONS  
9.1 
RATIONALE FOR SUBJECT SELECTION 
This protocol is designed for the treatment of all adult subjects with symptomatic KSHV-
associated MCD. The main epidemiologic group that would be potential subjects is those with 
HIV.  KSHV-MCD also occurs in elderly and other immunosuppressed populations.  Subjects 
are generally from areas where the prevalence of KSHV infection is high.  In the US, KSHV 
infection is most common in men who have sex with men (MSM). At the HAMB, women who 
have participated in our ongoing KSHV-MCD studies are immigrants from Africa. 
Strategies for recruitment will include announcements on ClinicalTrials.gov, letters to referring 
physicians, targeting HIV providers and those who provide primary care to the African 
immigrant community, AIDS treatment bulletins, and the International Castleman’s Disease 
Organization, and through a Google campaign.   


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9.2 
PARTICIPATION OF CHILDREN 
Patients under the age of 18 will be excluded.  This is a pilot clinical study of an agent with 
unknown safety profile in children and adolescents in a disease that is rare in children. 
Tocilizumab is currently FDA approved for treatment of adults with rheumatoid arthritis. 
9.3 
PARTICIPATION OF SUBJECTS UNABLE TO CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (section 9.5), all subjects ≥ age 18 will be offered the opportunity to fill in 
their wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation as needed for the following: an 
independent assessment of whether an individual has the capacity to provide consent; assistance 
in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the 
capacity to appoint a surrogate.  For those subjects that become incapacitated and do not have 
pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for 
appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and 
(b) who do not have a legal guardian or durable power of attorney, will be followed. 
9.4 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The investigational nature and objectives of this trial, the procedures and treatments involved and 
their attendant risks and discomforts, potential benefits, and potential alternative therapies will be 
carefully explained to the patient or the patients surrogate, and a signed informed consent 
document will be obtained. 
 Potential Benefits 
The potential benefit to individual patient-volunteers is that the protocol therapy may result in 
improvement of symptomatic KSHV-MCD associated symptoms.  It may also contribute 
towards the long-term control of KSHV-MCD, without leading to KS flares, as has been 
described in patients receiving B-cell depleting therapy with rituximab. Participation in a clinical 
study will help researchers better understand the pathophysiology of KSHV-MCD and KS, as 
well as allow for an evaluation of tocilizumab in patients with symptomatic KSHV-MCD. 
 Potential Risks and Discomforts 
There may be prospect of direct benefit to the patient-volunteers on this study.  Potential risks 
include the potential toxicity of tocilizumab in this patient population. Additionally, the safety of 
tocilizumab has not evaluated when used in combination with AZT and VGC.  See Section 10 
for potential toxicities of individual agents. Patients will be followed on study until resolution of 
acute adverse events, and clinical investigators will ensure that subjects receive appropriate 
medical care for any adverse events.  Measures to prevent infectious complications are outlined 
in Section 4.6.  Participation in clinical study may also have discomforts and inconveniences 
associated with additional studies. Additional risks include the small risk of complications 


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related to biopsies (when required) and blood draws, which include pain, bleeding, seroma 
formation, and infection.  The PI of the study will monitor all adverse events, following the Data 
and Safety Monitoring Plan outlined in Section 7.3. 
 Alternatives 
Alternative options for patients with symptomatic KSHV-MCD include treatment with other 
therapeutic regimens evaluated in 04-C-0275, or treatment off-study using one or more agents 
with activity in KSHV-MCD, such as rituximab.  Observation is usually discouraged in patients 
with symptomatic disease. 
9.5 
RISKS/BENEFITS ANALYSIS 
The risks to individual study subjects are reasonable in relation to the anticipated benefits.  This 
protocol evaluates tocilizumab, which is active in multicentric Castleman disease in patients not 
infected with KSHV, and is approved for this indication in Japan. Its use in KSHV-MCD has 
strong clinical and preclinical rationale and an acceptable infectious complication profile in 
comparison to rituximab.  Potential therapeutic benefits include limitation of cumulative 
anthracycline dosing (04-C-0275 has explored rituximab in combination with liposomal 
doxorubicin for this patient population), as well as a favorable toxicity profile in relation to 
worsening of concurrent KS. Additional risks include potential additive toxicities in patients 
requiring treatment intensification with AZT/VGC, as well as discomforts and inconvenience of 
additional studies associated with participation in a clinical study.  There is no FDA approved 
therapy for KSHV-MCD, and there is no consensus on the standard of care in this disease.  The 
major alternative for patients with symptomatic KSHV-MCD is participation in another study, or 
treatment off-study with a regimen with described activity.  The comparative risks and benefits 
are acceptable for an early phase clinical study, when compared to the alternatives for patients 
with symptomatic KSHV-MCD. 
9.6 
CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
Informed written consent will be obtained in all patients on this trial.  There will be no minors 
enrolled < 18 years old, so assent is unnecessary. All potential participants will be provided an 
IRB-approved informed consent form to review prior to their screening visit. The Principal 
Investigator or a physician Associate Investigator will discuss the risks, benefits and alternatives 
to participation in this study, and answer all patient questions regarding study participation. 
Informed consent will be obtained on an IRB approved informed consent form, with signatures 
obtained from the consenting physician, a witness, and the study subject. The original informed 
consent will be stored in the patient’s official hospital records, with a copy stored in the patient’s 
research chart, and a copy provided to the study subject. 
 Telephone Re-Consent 
The informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent.  
The original informed consent document will be sent back to the consenting investigator who 
will sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records. 


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The informed consent process will be documented in the medical record. 
10 PHARMACEUTICAL INFORMATION 
10.1 TOCILIZUMAB 
Please, refer to package insert. 
 Source:  
Tocilizumab (TCZ) is commercially available under the trade name Actemra®, and will be 
obtained from commercial sources from the Clinical Center Pharmacy. 
 
 
 Administration procedures:  
10.1.2.1 Allow the fully diluted ACTEMRA solution to reach room temperature prior to 
infusion. 
10.1.2.2 The infusion should be administered over 60 minutes, and must be administered with an 
infusion set. Do not administer as an intravenous push or bolus. 
10.2 ZIDOVUDINE (AZT) 
 Please, refer to package insert.Source:  
AZT is commercially available for both oral and IV injection use, and will be obtained by the 
Clinical Center pharmacy from commercial sources.  AZT oral formulations include Retrovir® 
tablets containing 300 mg.  Retrovir® intravenous infusion is formulated in a preservative free 
sterile water for injection with 10 mg AZT in each milliliter.  The maximum dose of 2.4 gram 
AZT daily in this protocol is higher than the recommended maximum dose in standard practice 
for HIV disease, but substantially lower than the 50-gram doses associated with acute overdose 
complications.  Additionally, the NCI phase I trial treated patients at up to 45 mg/kg/day 
intravenously, (approximately 3.1 grams daily) for two weeks, followed by up to 90 mg/kg/day 
orally (approximately 6.2 grams daily) for four weeks(69).  Toxicities were similar as that seen 
at lower doses and were primarily myelosuppression, tremors and confusion.  Thus, doses for 
this trial are conservative in magnitude and cycle duration (generally less than 2 weeks dosing at 
any given time). 
 Administration procedures 
10.2.2.1 Intravenous AZT 
Infuse intravenously over 1 hour.  Intravenous AZT should not be used if the patient is able to 
take oral AZT. 
10.3 VALGANCICLOVIR / GANCICLOVIR 
 Please, refer to package insert.Source  
Commercially available for both oral (VGC) and IV injection use (ganciclovir), and will be 
obtained by the Clinical Center pharmacy from commercial sources.  


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 Administration procedures:  
10.3.2.1 Intravenous administration: infuse 5 mg/kg over 1 hour every 12 hours in patients with 
normal renal function (refer to section 3.3.2.6.3. for instructions for use in renally 
impaired individuals). 
10.3.2.2 Oral administration: two 450 mg VGC (Valcyte®) tablets with food orally, every 12 
hours. 
10.3.2.3 DO NOT SUBSTITUTE ORAL CYTOVENE CAPSULES 
 
 


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Toedter, G., Hayden, K., Wagner, C., and Brodmerkel, C. (2008) Simultaneous detection 
of eight analytes in human serum by two commercially available platforms for multiplex 
cytokine analysis. Clin Vaccine Immunol 15, 42-48 
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Katsume, A., Saito, H., Yamada, Y., Yorozu, K., Ueda, O., Akamatsu, K., Nishimoto, N., 
Kishimoto, T., Yoshizaki, K., and Ohsugi, Y. (2002) Anti-interleukin 6 (IL-6) receptor 
antibody suppresses Castleman's disease like symptoms emerged in IL-6 transgenic mice. 
Cytokine 20, 304-311 


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Beck, J. T., Hsu, S. M., Wijdenes, J., Bataille, R., Klein, B., Vesole, D., Hayden, K., 
Jagannath, S., and Barlogie, B. (1994) Brief report: alleviation of systemic manifestations 
of Castleman's disease by monoclonal anti-interleukin-6 antibody. N Engl J Med 330, 
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van Rhee, F., Fayad, L., Voorhees, P., Furman, R., Lonial, S., Borghaei, H., Sokol, L., 
Crawford, J., Cornfeld, M., Qi, M., Qin, X., Herring, J., Casper, C., and Kurzrock, R. 
(2010) Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's 
disease. J Clin Oncol 28, 3701-3708 
47. 
Mihara, M., Kasutani, K., Okazaki, M., Nakamura, A., Kawai, S., Sugimoto, M., 
Matsumoto, Y., and Ohsugi, Y. (2005) Tocilizumab inhibits signal transduction mediated 
by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine 
family. Int Immunopharmacol 5, 1731-1740 
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Igawa, T., Ishii, S., Tachibana, T., Maeda, A., Higuchi, Y., Shimaoka, S., Moriyama, C., 
Watanabe, T., Takubo, R., Doi, Y., Wakabayashi, T., Hayasaka, A., Kadono, S., 
Miyazaki, T., Haraya, K., Sekimori, Y., Kojima, T., Nabuchi, Y., Aso, Y., Kawabe, Y., 
and Hattori, K. (2010) Antibody recycling by engineered pH-dependent antigen binding 
improves the duration of antigen neutralization. Nat Biotechnol 28, 1203-1207 
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Hashizume, M., and Mihara, M. (2009) Influence of humanized anti-IL-6R antibody, 
tocilizumab on the activity of soluble gp130, natural inhibitor of IL-6 signaling. 
Rheumatol Int 29, 397-401 
50. 
Song, S. N., Tomosugi, N., Kawabata, H., Ishikawa, T., Nishikawa, T., and Yoshizaki, K. 
(2010) Down-regulation of hepcidin resulting from long-term treatment with an anti-IL-6 
receptor antibody (tocilizumab) improves anemia of inflammation in multicentric 
Castleman disease. Blood 116, 3627-3634 
51. 
Cannon, J. S., Hamzeh, F., Moore, S., Nicholas, J., and Ambinder, R. F. (1999) Human 
herpesvirus 8-encoded thymidine kinase and phosphotransferase homologues confer 
sensitivity to ganciclovir. J Virol 73, 4786-4793. 
52. 
Gustafson, E. A., Schinazi, R. F., and Fingeroth, J. D. (2000) Human herpesvirus 8 open 
reading frame 21 is a thymidine and thymidylate kinase of narrow substrate specificity 
that efficiently phosphorylates zidovudine but not ganciclovir. J Virol 74, 684-692 
53. 
Kedes, D. H., and Ganem, D. (1997) Sensitivity of Kaposi's sarcoma-associated 
herpesvirus replication to antiviral drugs. Implications for potential therapy. J Clin Invest 
99, 2082-2086 
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Casper, C., Krantz, E. M., Corey, L., Kuntz, S. R., Wang, J., Selke, S., Hamilton, S., 
Huang, M. L., and Wald, A. (2008) Valganciclovir for suppression of human herpesvirus-
8 replication: a randomized, double-blind, placebo-controlled, crossover trial. J Infect Dis 
198, 23-30 
55. 
Casper, C., Nichols, W. G., Huang, M.-L., Corey, L., and Wald, A. (2004) Remission of 
HHV-8 and HIV-associated multicentric Castleman disease with ganciclovir treatment. 
Blood 103, 1632-1634 


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Jenner, R. G., Alba, M. M., Boshoff, C., and Kellam, P. (2001) Kaposi's sarcoma-
associated herpesvirus latent and lytic gene expression as revealed by DNA arrays. J 
Virol 75, 891-902 
57. 
Lu, M. (2004) Dissection of the Kaposi's sarcoma-associated herpesvirus gene expression 
program by using the viral DNA replication inhibitor cidofovir. Journal of virology 78, 
13637-13652 
58. 
Berezne, A., Agbalika, F., Oksenhendler, E., Casper, C., Nichols, W. G., Huang, M.-L., 
Corey, L., and Wald, A. (2004) Failure of cidofovir in HIV-associated multicentric 
Castleman disease. Blood 103, 4368-4369 
59. 
Bower, M. (2010) How I treat HIV-associated multicentric Castleman's disease. Blood  
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Aitken, A. E., and Morgan, E. T. (2007) Gene-specific effects of inflammatory cytokines 
on cytochrome P450 2C, 2B6 and 3A4 mRNA levels in human hepatocytes. Drug Metab 
Dispos 35, 1687-1693 
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Jover, R., Bort, R., Gomez-Lechon, M. J., and Castell, J. V. (2002) Down-regulation of 
human CYP3A4 by the inflammatory signal interleukin-6: molecular mechanism and 
transcription factors involved. FASEB J 16, 1799-1801 
62. 
Rivory, L. P., Slaviero, K. A., and Clarke, S. J. (2002) Hepatic cytochrome P450 3A drug 
metabolism is reduced in cancer patients who have an acute-phase response. Br J Cancer 
87, 277-280 
63. 
Mayo, P. R., Skeith, K., Russell, A. S., and Jamali, F. (2000) Decreased dromotropic 
response to verapamil despite pronounced increased drug concentration in rheumatoid 
arthritis. Br J Clin Pharmacol 50, 605-613 
64. 
Fournier, T., Medjoubi, N. N., and Porquet, D. (2000) Alpha-1-acid glycoprotein. 
Biochim Biophys Acta 1482, 157-171 
65. 
Schmitt, C., Kuhn, B., Zhang, X., Kivitz, A. J., and Grange, S. (2011) Disease-Drug-
Drug Interaction Involving Tocilizumab and Simvastatin in Patients With Rheumatoid 
Arthritis. Clin Pharmacol Ther  
66. 
Frey, N., Grange, S., and Woodworth, T. (2010) Population pharmacokinetic analysis of 
tocilizumab in patients with rheumatoid arthritis. J Clin Pharmacol 50, 754-766 
67. 
Cheson, B. D., Horning, S. J., Coiffier, B., Shipp, M. A., Fisher, R. I., Connors, J. M., 
Lister, T. A., Vose, J., Grillo-Lopez, A., Hagenbeek, A., Cabanillas, F., Klippensten, D., 
Hiddemann, W., Castellino, R., Harris, N. L., Armitage, J. O., Carter, W., Hoppe, R., and 
Canellos, G. P. (1999) Report of an international workshop to standardize response 
criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J 
Clin Oncol 17, 1244 
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Cheson, B. D., Pfistner, B., Juweid, M. E., Gascoyne, R. D., Specht, L., Horning, S. J., 
Coiffier, B., Fisher, R. I., Hagenbeek, A., Zucca, E., Rosen, S. T., Stroobants, S., Lister, 
T. A., Hoppe, R. T., Dreyling, M., Tobinai, K., Vose, J. M., Connors, J. M., Federico, M., 
and Diehl, V. (2007) Revised response criteria for malignant lymphoma. J Clin Oncol 25, 
579-586 


Abbreviated Title: Tocilizumab in KSHV-MCD 
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69. 
Yarchoan, R., and Broder, S. (1987) Progress in the Development of Antiviral Therapy 
for HTLV-III-Associated Diseases. in Important Advances in Oncology 1987 (Vincent T. 
DeVita, J., Hellman, S., and Rosenberg, S. A. eds.), J.B. Lippincott Company, 
Philadelphia. pp 293-311 
 
 


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12. APPENDICES 
 
12.1. APPENDIX 1: KSHV-MCD CLINICAL BENEFIT RESPONSE CRITERIA  
KSHV-MCD Clinical Benefit Response Criteria has been developed as a more streamlined tool 
for assessment of patients receiving therapy for KSHV-MCD, and does not depend on 
radiographic findings.  As such, it allows for same-day assessment of clinical benefit utilizing 
common symptoms and clinical laboratories. To evaluate clinical benefit in patients with KSHV-
MCD receiving therapy, clinical and laboratory responses are assessed in aggregate, and 
compared to baseline. This criterion allows for assessment of patients who may be deriving 
meaningful clinical benefit from therapy, but have not necessarily achieved an overall complete 
response by the original NCI KSHV-MCD response criteria.   
Evaluation of KSHV-MCD is complicated by the heterogeneous and non-specific nature of many 
symptoms and signs of KSHV-MCD and the common intercurrence of other pathologies in this 
group. For this reason, assessment of responses other than complete response is made on the 
basis of eight indicator abnormalities (four symptom groups and four laboratory parameters) that 
are most closely associated with disease activity: 
 
Indicator Abnormalities Assessed in Responses  
Symptoms 
Laboratory Abnormalities 
Fever (includes chills and rigors) 
Elevated C-reactive protein 
Fatigue (includes lethargy) 
Thrombocytopenia 
Gastrointestinal (includes nausea and 
anorexia) 
Anemia 
Respiratory (includes airway 
hyperreactivity and cough) 
Hypoalbuminemia 
 
For the purposes of response assessment, clinical symptoms attributed to MCD will be assigned 
an NCI-CTCAE grade equivalent, with response assessment based on changes in grade severity 
or symptom resolution. 
Increases in hemoglobin in patients who have received a transfusion do not count towards PR or 
CR for 3 weeks, and increases in albumin or platelet count in patients who have received a 
transfusion do not count towards PR or CR for 7 days. 
Complete Response (CR): 
Full resolution of all clinical symptoms and laboratory abnormalities (whether or not these are 
indicator abnormalities) probably or definitely attributable to MCD, lasting at least 3 weeks.  
Partial Response (PR):  
PR is assessed based on the eight indicator abnormalities above. At least 50% of the 
abnormalities probably or definitely attributed to KSHV-MCD must improve by the minimum 
amounts specified below to attain PR. 


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Only abnormalities present in a specific patient at baseline may count toward the achievement of 
a PR (e.g. if six of indicator abnormalities are present at baseline, at least three must meet the 
specified criteria to be considered a PR). 
Improvement in symptoms require at least 1 CTCAE grade equivalent improvement. For 
symptom groups (e.g. gastrointestinal and respiratory), where multiple symptoms within the 
group are present at least half of those attributable to KSHV-MCD must improve by at least 1 
CTCAE grade equivalent to consider the group as a whole to be improved. 
Improvement in for each laboratory parameters requires either normalization of the lab value or 
else the following: 
x C-reactive protein reduction to ≤50% of baseline 
x Hemoglobin increment 2g/dL not explained by transfusion 
x Platelet increment ≥50 K/uL not explained by transfusion 
x Albumin increment ≥1g/dL not explained by transfusion 
To be considered a partial response, there may be no new indicator abnormalities probably or 
definitely attributed to KSHV-MCD; no indicator symptom may worsen by ≥1 CTCAE grade 
equivalent; and no indictor laboratory abnormality may worsen by the amount given in the 
criteria for progressive disease. 
Stable disease (SD): no change in signs and symptoms of KSHV-MCD that meet criteria for any 
of CR, PR or PD. 
Progressive disease (PD):  
PD is assessed based on the eight indicator abnormalities above. At least two indicator 
abnormalities must deteriorate by the minimum amounts specified below to constitute PD. The 
development of new indicator abnormalities not present in a specific patient at baseline is 
incorporated in the assessment of PD 
Deterioration in signs and symptoms require at least 1 CTCAE grade equivalent increase in 
severity. For symptom groups (e.g. gastrointestinal and respiratory), where multiple symptoms 
within the group are present at least half of those attributable to KSHV-MCD must increase in 
severity by at least 1 CTCAE grade equivalent to consider the group as a whole to have 
deteriorated. 
Deterioration for each laboratory parameter requires an abnormal laboratory value meeting the 
following criteria: 
- C-reactive protein increase by ≥50% of baseline (or the upper limit of normal, 
whichever is greater) 
- Hemoglobin decrement 2g/dL not otherwise explained 
- Platelet decrement ≥25 K/uL not otherwise explained 
- Albumin decrement ≥0.5g/dL 
12.2. APPENDIX 2: KSHV-ASSOCIATED MULTICENTRIC CASTLEMAN DISEASE RESPONSE 
CRITERIA (EVALUATED IN 04-C-0275) 
Response Category 
Response and Criteria 
Clinical Response 
Complete Response (CR) 


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62 
 
 
Full resolution of all signs and symptoms attributable to MCD, 
lasting 1 cycle (3-4 weeks depending on regimen). Requires 
normalization of involved nodal areas on physical exam. 
 
Symptom Free Disease (SFD) 
Full resolution of all symptoms attributable to MCD. 
 
Partial Response (PR) 
Improvement in at least 50% of signs and symptoms by at least 
1 grade (NCI-CTCAE v3), with no increased MCD related 
increases, lasting 1 cycle (3-4 weeks depending on regimen) 
 
Stable Disease (SD) 
No change in signs and symptoms of MCD meeting criteria for 
CR, PR or PD. 
 
Progressive Disease (PD) 
Worsening of 2 or more symptoms by at least 1 Grade. 
 
Biochemical Response 
Complete Response (CR) 
Normalization of abnormalities attributed to MCD in the 
following labs: hemoglobin, platelets, albumin, sodium and C-
reactive protein (CRP), lasting 1 cycle (3-4 weeks depending 
on regimen). 
 
Partial Response (PR) 
At least 50% improvement in all labs abnormalities attributable 
to MCD, lasting 1 cycle (3-4 weeks depending on regimen). 
 
Stable Disease (SD) 
No change in biochemical parameters that meet criteria for CR, 
PR or PD 
 
Progressive Disease (PD) 
t 25% and 1 Grade worsening of at least 2 biochemical 
parameters attributable to MCD OR clear deterioration in one 
parameter with negative impact on physiologic or health status 
 
Radiographic Response 
Complete Response (CR) 
Normalization of all lymph nodes to  <1.5 cm in greatest 
transverse dimension, with decrease to < 1 cm of lymph nodes 
that measure 1.1-1.5 cm at baseline, or 75% decrease in sum 
products of the diameters (SPD) of measured lymph nodes. 
Spleen < 12 cm greatest dimension, no pleural effusions. 
 
Complete Response, unconfirmed (CRu) 
Residual lymph node mass >1.5 cm or spleen > 12 cm that has 
decrease by ≥75% and does not change over one year. 
 
Partial Response (PR) 
For lymph nodes, ≥ 50% decrease in SPD of 6 dominant 
nodes; for spleen ≥ 50% decrease in longest transverse 
dimension. 
 
Stable Disease (SD) 
Not meeting criteria for CR, CRu, PR or PD. 


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Progressive Disease (PD) 
For lymph nodes ≥ 25% increase in the SPD, for spleen 
increase ≥ 25% in longest dimension. 
 
Overall Response 
Complete Response (CR) 
CR in all categories. 
 
Partial Response (PR) 
PR or better in all categories. 
 
Stable Disease (SD) 
SD or better in all categories. 
 
Progressive Disease (PD) 
Progression in any one category. 
 
Based on signs and symptoms probably or definitely attributed to KSHV-MCD. 
 
Grade: Based on signs, symptoms and laboratory values Probably or Definitively Attributed to 
MCD
 
Grade 1 (meets all three criteria):  
x ECOG 0-1 
x All constitutional symptoms d1 
o Fatigue 
o Fever 
o Rigors/chills 
o Diaphoresis 
o Weight gain/edema 
o Weight loss/anorexia 
x All Laboratory Abnormalities d Grade 2, 
maximum 1 grade 3. 
o Hgb 
o Platelets 
o Leukopenia 
o Albumin 
o Na 
o CRP < 8 mg/L 
 
 
Grade 2: Not grade 1 or Grade 3 
Grade 3 (meets all 3 criteria): 
x ECOG 3-4 
x 2 or more symptoms Grade 4 by CTCAE 
o Fatigue 
o Fever 
o Rigors/chills 
o Diaphoresis 
o Weight gain/edema 
o Weight loss/anorexia 
x Any 2 or more laboratory abnormalities 
(above) t Grade 3, including CRP >30 
mg/L 
OR 
x Tumor or Disease threatens a vital 
organ
 
 
 


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12.3. APPENDIX 3: MCD RESPONSE ASSESSMENT TOOLS 


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MCD Clinical, Biochemical and Radiographic Responses By Cycle 
 
Patient Name  
 
 
 
MRN 
 
 
 
 
     
 
Regimen   
 
 
 
 
                                      
 
 
Last Day of Cycle 
Day 1 
Date 
Drugs 
Cycle 
Clinical 
Response 
I, S,  
M, W 
Biochemical 
Response 
I, S, 
M, W 
Radiographic 
Response 
LN / Spleen 
I, S, 
M, W 
Overall 
Grade 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
 
 
 
 
 
 
 
/ 
 
 
 
Overall Responses 
 
 
 
 
 
 
 
/ 
 
 
 
CR = Complete Response, SFD = symptom free disease, PR = Partial Response, SD = Stable Disease, PD = Progressive 
Disease.  
I = Improved, S= Stable, M= Mixed Response, W= Worse: Used to note cycle-to-cycle direction of response for patients 
with improvement or worsening that is categorized as SD or PR. 
Drugs: Toc = Tocilizumab, A/G= AZT + (val)ganciclovir, R-D = Rituximab + Doxil, I = interferon D (list dose), EPOCH-RR, 
B-A/G: bortezomib + A/G, O= other combination (list) 


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12.4. APPENDIX 4: MODIFIED ACTG KAPOSI SARCOMA RESPONSE WORKSHEETS 
 


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68 
 
 
12.5. APPENDIX 5: PERFORMANCE STATUS SCALES 
 
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. 
 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
11-C-0233 
PRINCIPAL INVESTIGATOR: 
Robert Yarchoan, MD 
STUDY TITLE:  
Pilot Study of Tocilizumab in Patients with Symptomatic Kaposi Sarcoma Herpesvirus 
(KSHV) - associated Multicentric Castleman Disease 
Continuing Review Approved by the IRB on 11/13/19 
Amendment Approved by the IRB on 06/26/19 (F) 
Date Posted to Web:  11/26/19 
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
 
Why is this study being done?  
This is a research study to gain information about a medication called tocilizumab when used to 
treat KSHV-associated multicentric Castleman disease (KSHV-MCD). KSHV stands for the 
Kaposi’s sarcoma herpes virus, and is also called human herpes virus-8, or HHV-8. In addition to 
causing KSHV-MCD, KSHV can cause several other tumors, including Kaposi sarcoma and a 
rare lymphoma called primary effusion lymphoma.  Patients with KSHV-MCD often have 
symptoms including fever, sweats, weight loss, fluid in the legs or abdomen, cough, stomach 
upset, loss of muscle, and poorly tolerate certain medications. They also have several common 
blood abnormalities such as anemia, low platelets, and evidence of inflammation.  People with 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 2 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
symptomatic MCD have very high levels of a protein called interleukin-6 (IL-6) that leads to 
some of these symptoms and blood abnormalities. Additionally, the virus makes several proteins, 
such as a viral form of IL-6, that are also important in causing the symptoms of KSHV-
associated MCD. The purpose of the research is to see if the medication, tocilizumab, which is a 
biologic agent that targets the receptor on cells for IL-6, leads to improvement in KSHV-MCD 
symptoms and blood abnormalities. Tocilizumab has previously been found to be effective in 
patients with a form of MCD not associated with KSHV and that is largely caused by human IL-
6.  It is also FDA approved (brand name Actemra™) for use in patients with rheumatoid arthritis. 
While tocilizumab does not directly block the action of viral IL-6, there is evidence that human 
IL-6 may be causing many of the symptoms in patients with KSHV-MCD.  Moreover, it is 
possible that by blocking the receptor of human IL-6, tocilizumab may lower the production of 
viral IL-6.  
If you do not have enough improvement in symptoms and blood abnormalities with tocilizumab 
alone, you may also be treated with additional medications that target certain cells infected with 
KSHV. These medications, zidovudine (otherwise known as AZT) and valganciclovir, when 
combined in the treatment of MCD are sometimes called “virus-activated cytotoxic therapy”.  It 
may be that for some people with KSHV-MCD, tocilizumab may be more active in combination 
with “virus-activated cytotoxic therapy”, and this study will gather information on this 
combination in some patient-volunteers. 
Why are you being asked to take part in this study? 
Individuals may be eligible to participate in the research study if they have biopsy proven 
KSHV-MCD, and have symptoms and certain blood abnormalities due to their KSHV-MCD. To 
be eligible for the trial, patient-volunteers must meet a number of other criteria to make sure that 
it is appropriate to participate in the study.  If you meet these criteria, you are being asked to take 
part in this study so that we may evaluate tocilizumab alone, or in some patient-volunteers, in 
combination with “virus-activated cytotoxic therapy” using zidovudine and valganciclovir. 
Patient-volunteers with HIV must agree to a regimen of combination highly active antiretroviral 
therapy (HAART). 
How many people will take part in this study?  
We plan to enroll up to 17 patient-volunteers in this study. 
Before you begin the study 
HIV Testing  
As part of this study, we will test you for infection with the human immunodeficiency virus 
(HIV), the virus that causes AIDS. If you are infected with HIV you will still be able to 
participate in this study. We will tell you what the results mean, how to find care, how to avoid 
infecting others, how we report HIV infection, and the importance of informing your partners at 
possible risk because of your HIV infection. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 3 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
 
Description of Research Study 
If you consent to participate in this study, you will receive therapy through a vein (IV) every 2 
weeks for up to 12 weeks. We will follow you for 4 weeks after you complete your sixth dose of 
tocilizumab to check for possible side effects of the drug and to make sure your KSHV-MCD 
does not worsen once therapy is stopped.  If your KSHV-MCD worsens during the course of 
your participation in the study, or does not show significant improvement, you will be offered to 
continue tocilizumab in combination with “virus-activated cytotoxic therapy” using zidovudine 
and valganciclovir.  Zidovudine and valganciclovir are provided as pills that are taken 4 times a 
day for 5 days out of every 2 weeks. 
 
During the first week of therapy, we will be taking daily blood samples for three days to see if 
tocilizumab has an effect on the levels of certain HAART drugs in your blood. We will also be 
collecting blood, urine and saliva throughout the study for monitoring your health as well as for 
other research purposes. A description of what will happen if you take part in this study and a list 
of potential risks and discomforts associated with participation in the study are listed below. 
What will happen if you take part in this research study?   
Before you begin the study, you will be evaluated by a physician investigator, as well as other 
members of the research team for eligibility in the study.  We will discuss your medical history 
in detail and will also perform a skin test to determine whether you have been exposed to 
tuberculosis in the past. A biopsy is required for participation. If you have already had a biopsy, 
we will work with you to have the biopsy sent to pathologists at the NCI for review. If you have 
not have not had a biopsy, we will arrange for a biopsy to confirm the diagnosis of KSHV-MCD. 
You will have a CT scan to evaluate the abnormalities commonly seen in KSHV-MCD, such as 
large lymph nodes and large spleen.  You will also have an 18[F]FDG-PET-CT scan to make 
sure that you do not have lymphoma.  If you also have Kaposi sarcoma, additional measurements 
and photographs will be performed to document the extent of KS, in some patients, additional 
studies to evaluate the extent of KS may be required, and a physician will discuss this with you. 
 
During the study, you will receive a tocilizumab every 2 weeks for a total of 6 doses.  Patients 
with HIV will be required to take HAART. Patients with a positive tuberculosis skin test will be 
required to take a medicine to prevent tuberculosis while on the study if you have not already 
completed a course of antibiotics for tuberculosis. During the first cycle, you will be evaluated 
by a physician prior to therapy, and you will have blood drawn daily for the first three days.  On 
subsequent cycles, a physician will evaluate you on the day you receive therapy.  If during this 
evaluation, it is determined that your response to tocilizumab is inadequate, you will be offered 
“virus-activated cytotoxic therapy” using zidovudine and valganciclovir.  Zidovudine and 
valganciclovir are provided as pills that are taken 4 times a day starting on the day you receive 
tocilizumab and continuing for 5 days.  Examples of reasons that “virus-activated cytotoxic 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 4 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
therapy” may be required including worsening of symptoms and/or blood work due to KSHV-
MCD anytime while on study, lack of any sign of improvement in KSHV-MCD after 4 weeks, or 
lack of evidence of substantial improvement after 8 weeks of tocilizumab.  
 
During each cycle, approximately 10 teaspoons of blood will be collected from a vein to be used 
for laboratory studies that are part of routine care for patients receiving therapy, as well as 
special research studies.  Saliva and urine will be collected during each cycle. If you have KS 
your KS will be re-measured and photographed on the day of your fourth dose of tocilizumab 
and at the end of the study. If your KS completely disappears, you will be asked to repeat any 
abnormal tests that you had when you entered the study, and this may include a skin biopsy.  
 
After you are finished taking the drugs, we will follow you in clinic 4 weeks later to make sure 
that you do not have any side effects from the drugs, and to make sure that your KSHV-MCD is 
not worse after discontinuing the medications.  
Your specimens and data may be used to evaluate genetic changes in genes involved in drug-
metabolism.  Using a commercially available test called the DMET™, NCI investigators can 
evaluate DNA from your blood cells for approximately 225 genes that are involved in the way 
your body processes medications. These genes may be involved in the way your body handles 
some of your HIV medications.  NIH researchers are interested in studying these genes, in a 
preliminary way, in patient-volunteers with KSHV-MCD who receive tocilizumab. The 
investigators conducting this study do not plan to provide you or your family with the results of 
any of the research tests or evaluations because at this time this information is not clinically 
meaningful and further research is necessary before these results may be clinically relevant. 
Once your samples are received, they are bar-coded and your name removed from the label. 
Your data will be entered into a computer database. However, patient-volunteers will not be 
personally identifiable by the scientists who perform the DNA tests. Your medical care will, in 
no way, be affected by your decision on whether or not you participate in this part of the study. 
You understand that personal possession of information about your genes could result in 
discrimination. However, you will receive no results of laboratory analysis of your sample, nor 
will these results become part of your medical record, as the results will be preliminary in nature. 
As a consequence of this, you will not be placed in the position of having information about your 
genes that you may not wish to reveal to others. Your research blood will not be used for 
clinically relevant genetic testing. As such, participation in this result will not obligate you to 
state that you have received genetic testing. In addition, your family will not have access to this 
investigational information. You will be given the opportunity to decide whether you would like 
to participate in this testing. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 5 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
The following Study Chart outlines what will happen if you choose to participate. 
 
 
 
 
 
p 
 
 
 
 
 
 
 
 
 
 
 
 
p 
 
 
 
 
 
Screening for Eligibility 
x 
Medical History and Physical Exam 
x 
Review of Biopsy 
x 
Blood and Urine Studies 
x 
18[F]FDG-PET scan 
x 
CT scan 
x 
Tuberculosis skin test 
After treatment 
x 
Clinic visit 4 weeks after completing therapy 
x 
Research blood and saliva samples 
x 
Long-term follow up may be possible under other KSHV-MCD 
protocols 
Treatment 
Tocilizumab:  
IV tocilizumab every 2 weeks for 6 cycles 
Addition of zidovudine  
and valganciclovir:  
Added if:  
x 
Worsening KSHV-MCD with tocilizumab alone OR 
x 
No evidence of improvement after 4 weeks OR 
x 
No substantial improvement after 8 weeks 
 
AZT is two tablets every 6 hours for 5 days, valganciclovir is 2 tablets every 12 
hours for 5 days 
Monitoring:  
Review of side effects 
Physical Exam,  
Blood Samples 
KS measurements and photography (in patients with KS) 
Research: 
Cycle 1 only (in patients with HIV), blood samples on days 1, 2, and 3 to 
measure levels of antiretroviral drugs 
Each cycle: Blood, urine and saliva samples 
Stop treatment: 
Completion of 6 cycles of tocilizumab 
Progressive KSHV-MCD that does not improve despite addition of zidovudine 
and valgancyclovir 
 
Patient preference 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 6 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
Standard of Care Treatment: 
Treatments required for those participating in the study may include standard medications.  For 
example, patient-volunteers who are HIV positive must agree to take combination antiretroviral 
therapy. If you take zidovudine as part of your participation on the study, your antiretroviral 
therapy may be adjusted during the weeks you take zidovudine, as zidovudine is an antiretroviral 
drug. Those who have a positive tuberculosis skin test will be prescribed medicine to prevent 
tuberculosis based on national guidelines. These treatments will not be experimental. Your 
doctors will describe your treatment plan to you in detail before asking you to sign this consent 
form.  Furthermore, participation in the study may include additional procedures to document the 
extent of KS in your case.  In such a case, you may be asked to sign a separate consent form for 
any additional treatment procedures not outlined in this consent. 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for 3 months after you finish study treatment.  If you think that you or your 
partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include: 
 
x abstinence  
x intrauterine device (IUD) 
x hormonal [birth control pills, injections, or implants] 
x tubal ligation 
x vasectomy 
x barrier methods [condoms] 
Risks or Discomforts of Participation 
What side effects or risks can I expect from tocilizumab? 
Likely (10% or greater incidence) 
o Discomfort from blood draws, catheter placement or biopsies 
Less Likely (less than 10% incidence) 
o Infections, mainly respiratory tract infections such as sinusitis or bronchitis 
o Sore throat 
o Abnormal liver tests 
o Headache 
o Cough 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 7 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
o Hoarseness 
o Dizziness  
o Stomach discomfort 
o Elevated blood pressure 
o Rash 
o Decrease in white blood cells or platelets 
o Elevated cholesterol 
Rare but Serious 
o Gastrointestinal perforation 
o Life threatening allergic reactions 
o Development of a second cancer 
 
What side effects or risks can I expect from “virus-activated cytoxic therapy” using 
zidovudine and valganciclovir? 
High Dose Zidovudine + Valganciclovir: Zidovudine, also called Retrovir™.  This medication 
is approved by the FDA to treat HIV infection.  In this study, the dose is considerably higher 
than what is used to treat HIV.  The zidovudine dose in this study is up to 4 times the standard 
dose used in HIV infection. It is given either as oral medication or through a vein, 4 times daily. 
Valganciclovir, also called Valcyte™, is approved for the treatment of CMV infection.  The 
doses used in this research study are similar to the doses used in CMV infection, but the schedule 
is different.  Potential side effects of the combination include:  
Likely: 
o Gastrointestinal distress which is usually worst when starting the medication 
o Loss of appetite. 
o Abnormal taste. 
o Diarrhea. 
o Headache. 
o Difficulty sleeping. 
o Dizziness. 
o Weakness and fatigue. 
o Fingernail changes. 
o Anemia (low red blood cell counts). 
Less likely: 
o Nausea and vomiting. 
o Abdominal pain. 
o Low white blood cell counts.  If white cell counts become very low, this will 
increase your risk for infections. 
o Low platelet counts.  If platelet counts are very low, you are at increased risk 
of bleeding.  If the platelet count is very low, you may need a platelet 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 8 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
transfusion 
o Tingling of fingers and/or toes.  
o High blood sugar levels. 
o Changes in vision due to damage to your retina. 
Rare, But Serious: 
o Liver damage. 
o Muscle damage. 
o Lactic acidosis, which a build-up of acid in your blood. The signs of lactic 
acidosis are deep and rapid breathing, vomiting, and abdominal pain. 
o Defects to the developing fetus. 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aim of this study is to see if tocilizumab alone (or in some cases, combined with zidovudine 
and valganciclovir) provides you with direct clinical benefit.  Potential benefits include partial or 
complete improvement of all symptoms or lab abnormalities that are due to your KSHV-MCD.  
We hope that you will get personal medical benefit from taking part in this study, but we cannot 
be certain. For patients with KS, we will be closely monitoring your KS, as the effect of 
tocilizumab on KS is unknown, but could potentially be beneficial, especially compared to 
rituximab, another drug used to treat KSHV-MCD, that frequently (in about 30-40% of patients) 
can lead to improvement in KSHV-MCD but a worsening of KS. We cannot predict whether you 
will benefit directly from taking part in this study, although the knowledge gained from this 
study may help others in the future who have KSHV-associated cancers.   
Alternative Approaches or Treatments 
KSHV-MCD is a rare disorder, and there are no FDA approved therapy options for the 
management of this disease.  Off-label use of several anti-viral drugs, biologic agents, and 
chemotherapy drugs has been shown to have activity in small studies performed by our group 
and others.  There are several alternative approaches available at the NCI under a separate 
protocol, including “virus-activated cytotoxic therapy” without tocilizumab, or rituximab 
combined with liposomal doxorubicin. Your physician will talk to you about these options, and 
the risks and benefits of these or other alternative approaches that might be offered outside of 
this clinical study.  Generally, patients with symptomatic KSHV-MCD have a progressive course 
of waxing and waning symptoms that is associated with a high risk of developing lymphoma 
and/or death, so observation is without therapy is generally not considered a viable option. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 9 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
What other choices do I have if I do not take part in this study?  
 
Instead of being in this study, you have these options: 
 
x Getting treatment or care for your KSHV-MCD without being in a study 
x Taking part in another study 
x Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat the 
cancer directly. Instead, it tries to improve how you feel. Comfort care tries to keep you 
as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
x if he/she believes that it is in your best interest 
x if your disease comes back during treatment 
x if you have side effects from the treatment that your doctor thinks are too severe 
x if new information shows that another treatment would be better for you 
 
In this case, you will be informed of the reason therapy is being stopped. 
 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the NCI, FDA or 
designated representatives. If you withdraw your consent and leave the trial, any samples of 
yours that have been obtained for the study and stored at the NCI can be destroyed upon request. 
However, any samples and data generated from the samples that have already been distributed to 
other researchers or placed in the research databases cannot be recalled and destroyed. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
x 
You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the 
Clinical Center, National Institutes of Health (NIH), or arranged for you 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 10 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
by the research team to be done outside the Clinical Center, NIH if the 
study related treatment is not available at the NIH.  
x 
There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have 
to pay for these costs if they are not covered by your insurance company. 
x 
Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
x 
Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private. However, we cannot guarantee total privacy. Organizations that may look at and/or 
copy your medical records for research, quality assurance, and data analysis include: 
 
x The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
x National Institutes of Health Intramural Institutional Review Board 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the 
Web site will include a summary of the results.  You can search this Web site at any time.  
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
x will be used for auditing or program evaluation internally by the NIH; or  
x must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
x is necessary for your medical treatment and you have consented to this disclosure;  
x is for other research.  


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 11 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
 
The National Institutes of Health and the research team for this study are using tocilizumab, 
zidovudine, and valganciclovir in investigator-initiated research.  This means that the drug 
companies that make these drugs are not sponsoring this study. One of the investigators on this 
study is the co-inventor on a patent describing the measurement of KSHV vIL-6.  This invention 
was made while the investigator was employee of the US Government under 45 Code of Federal 
Regulations Part 7.  All rights, title, and interest to this patent have been assigned to the U.S. 
Department of Health and Human Services.  The government conveys a portion of the royalties it 
receives to its employee inventors under the Federal Technology Transfer Act of 1986 (P.L. 99-
502). It is possible that the results of this study could lead to payments to NIH scientists and to 
the NIH.  By law, government scientists are required to receive such payments for their 
inventions.  You will not receive any money from the development of tocilizumab or of the 
blood test for vIL-6.  
 
Use of Specimens and Data for Future Research  
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 12 of 14 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
 
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes. Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 13 of 14 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Robert Yarchoan, M.D., Building 10, Room 6N106, Telephone:  240-760-
6075. You may also want to contact the lead research nurse, Ms. Anaida Widell at 240-760-
6074. You may also call the Clinical Center Patient Representative at 301-496-2626.  If you have 
any questions about the use of your specimens or data for future research studies, you may also 
contact the Office of the Clinical Director, Telephone: 240-760-6070.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER:  11-C-0233 
CONTINUATION: page 14 of 14 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM NOVEMBER 13, 2019 THROUGH DECEMBER 03, 2020.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name