Clinical trial NCT01441063: Tocilizumab for KSHV-Associated Multicentric Castleman Disease
Official title: Pilot Study of Tocilizumab in Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV) - Associated Multicentric Castleman Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2011-09-27
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

Eligibility criteria: * INCLUSION CRITERIA:
* Pathologically confirmed Kaposi sarcoma (KS)-associated herpes virus multi-centric Castleman disease (KSHV-MCD)
* Age greater than or equal to 18
* At least one clinical symptom probably or definitely attributed to KSHV-MCD
* Intermittent or persistent fever for at least 1 week (\>38 degrees C)
* Fatigue (Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 or greater)
* Gastrointestinal symptoms \[includes nausea and anorexia\] (CTCAE Grade 1 or greater)
* Respiratory symptoms \[includes cough and airway hyperreactivity\]

(CTCAE Grade 1 or greater)

* At least one laboratory abnormality probably or definitely attributed to KSHVMCD
* Anemia (Hgb \[men\] \</=12.5 gm/dL, Hgb \[women\] \</= 11 gm/dL)
* Thrombocytopenia (\</=130,000/mm(3))
* Hypoalbuminemia (\<3.4 g/dl)
* Elevated C-reactive protein (CRP) (CRP \> 3 mg/L)\] probably or definitely attributable to KSHV-MCD
* No life- or organ-threatening manifestations of MCD
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
* Human Immunodeficiency Virus (HIV)-infected patients should be receiving or willing to initiate an effective combination antiretroviral therapy (cART) regimen
* Willingness to complete tuberculosis evaluation and start prophylactic antituberculosis therapy as soon as is medically feasible if patients have a reactive tuberculin skin 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

* Ability to understand and willingness to give informed consent
* Women of child bearing potential must agree to use birth control for the duration of the study

EXCLUSION CRITERIA:

* Uncontrolled bacterial, mycobacterial, or fungal infection
* 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.
* Pregnant or lactating women
* Any abnormality that would be scored as National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Grade 3 toxicity that is unrelated to HIV, its treatment, or to MCD that would preclude protocol treatment. Exceptions include:
* Lymphopenia
* Direct manifestations of Kaposi sarcoma or MCD
* Direct manifestation of HIV (i.e. low cluster of differentiation 4 (CD4) count)
* Direct manifestation of HIV therapy (i.e. Hyperbilirubinemia associated with protease inhibitors)
* Asymptomatic hyperuricemia
* Hypophosphatemia
* Elevated creatine kinase (CK) attributed to exercise
* Past or present history of malignant tumors other than Kaposi sarcoma unless one of the following:
* Complete remission for greater than or equal to 1 year from completion of therapy
* Completely resected basal cell carcinoma
* In situ squamous cell carcinoma of the cervix or anus
* Patients with concurrent Kaposi sarcoma requiring immediate cytotoxic chemotherapy
* History of tocilizumab therapy within prior three months
* History of rituximab or bevacizumab therapy within three months
* History of greater than or equal to 2 allergic reaction or any grade anaphylactic reaction during prior administration of tocilizumab

Primary outcomes:
measure: Percentage of Participants With an Overall Clinical Benefit Response
timeFrame: every 2 weeks for up to 12 weeks
Secondary outcomes:
measure: Percentage of Participants With a Clinical Response
timeFrame: up to 12 weeks
measure: Percentage of Participants With a Biochemical Response
timeFrame: up to 12 weeks
measure: Percentage of Participants With a Radiographic Response
timeFrame: up to 12 weeks
measure: Percentage of Participants With Kaposi Sarcoma Responses Per the Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) Response Criteria
timeFrame: Baseline, week 7, and at off study visit, approximately 2 weeks following last study treatment for those with KS, up to 14 weeks.
measure: Changes in Plasma Exposure of Ritonavir in Response to Tocilizumab and Zidovudine (AZT) Metabolized by Cytochrome P450 (CYP450)
timeFrame: Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.
measure: Changes in Plasma Exposure of Lopinavir in Response to Tocilizumab and AZT Metabolized by Cytochrome P450 (CYP450)
timeFrame: Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.
measure: Changes in Plasma Exposure of Atazanavir in Response to Tocilizumab and Zidovudine (AZT) Metabolized by Cytochrome P450 (CYP450)
timeFrame: Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.
measure: Changes in Plasma Exposure of Efavirenz in Response to Tocilizumab and Zidovudine (AZT) Metabolized by Cytochrome P450 (CYP450)
timeFrame: Cycle 1 Day 1: pre Tocilizumab, and 15 minutes, 24 hrs and 48 hrs post drug; Cycle 2-6: pre Tocilizumab dose and 15 minutes post drug dose.
measure: Percentage of Participants With Grade 3 or Greater Serious Adverse Events
timeFrame: each cycle, up to 6 years, 8 months and 24 days.
measure: Percentage of Participants With <Grade 3 Non- Serious Adverse Events
timeFrame: each cycle, up to 6 years, 8 months and 24 days.
measure: Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
timeFrame: Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
measure: Effect of Tocilizumab on the Pharmacokinetics (PK) of Antiretroviral Agents
timeFrame: Cycle 1, Day 1 and Cycle 2-6 Day 1
measure: Percentage of Participants Progression-free Survival at 4 Months
timeFrame: 4 months
measure: Percentage of Participants With Overall Survival 4 Months After Treatment With Tocilizumab and Tocilizumab /Zidovudine (AZT)/Valganciclovir (VGC)
timeFrame: 4 months
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Robert Yarchoan, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Uldrick TS, Polizzotto MN, Aleman K, Wyvill KM, Marshall V, Whitby D, Wang V, Pittaluga S, O'Mahony D, Steinberg SM, Little RF, Yarchoan R. Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease. Blood. 2014 Dec 4;124(24):3544-52. doi: 10.1182/blood-2014-07-586800. Epub 2014 Oct 20.
citation: Uldrick TS, Wang V, O'Mahony D, Aleman K, Wyvill KM, Marshall V, Steinberg SM, Pittaluga S, Maric I, Whitby D, Tosato G, Little RF, Yarchoan R. An interleukin-6-related systemic inflammatory syndrome in patients co-infected with Kaposi sarcoma-associated herpesvirus and HIV but without Multicentric Castleman disease. Clin Infect Dis. 2010 Aug 1;51(3):350-8. doi: 10.1086/654798.
citation: Brandt SJ, Bodine DM, Dunbar CE, Nienhuis AW. Dysregulated interleukin 6 expression produces a syndrome resembling Castleman's disease in mice. J Clin Invest. 1990 Aug;86(2):592-9. doi: 10.1172/JCI114749.
citation: Ramaswami R, Lurain K, Peer CJ, Serquina A, Wang V, Widell A, Goncalves P, Steinberg SM, Marshall V, George J, Figg WD, Whitby D, Ziegelbauer J, Uldrick TS, Yarchoan R. Tocilizumab in patients with symptomatic Kaposi sarcoma herpesvirus-associated multicentric Castleman disease. Blood. 2020 Jun 18;135(25):2316-2319. doi: 10.1182/blood.2019004602. No abstract available.