Tocilizumab for KSHV-Associated Multicentric Castleman Disease

• ClinicalTrials.gov Identifier: NCT01441063
• Recruitment Status: Completed
• First Posted: September 27, 2011
• Results First Posted: June 23, 2020
• Last Update Posted: October 27, 2020
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Robert Yarchoan, National Cancer Institute (NCI)

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Castleman Disease; Multicentric Castleman Disease; Giant Lymph Node Hyperplasia	Drug: Zidovudine; Drug: Tocilizumab; Drug: Valganciclovir (VGC)	Phase 2

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Pilot Study of Tocilizumab in Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV) - Associated Multicentric Castleman Disease
• Actual Study Start Date: September 13, 2011
• Actual Primary Completion Date: June 6, 2018
• Actual Study Completion Date: October 5, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tocilizumab; 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.	Drug: Zidovudine; Zidovudine (AZT) 600 mg orally q6 hours (every 6 hours); Other Name: Retrovir; Drug: Tocilizumab; Tocilizumab 8mg/kg every 2 weeks; Other Name: Actemra; Drug: Valganciclovir (VGC); Valganciclovir (VGC) 900 mg orally q12 hours (every 12 hours) on days 1-5 of a 14-day cycle.; Other Name: Valcyte

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With an Overall Clinical Benefit Response [ Time Frame: every 2 weeks for up to 12 weeks ]
   Overall clinical benefit response is defined as 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; and Partial Response (PR): At least 50% of the abnormalities probably or definitely attributed to KSHV-MCD must improve by the minimum amounts specified 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) assessed using a modified Kaposi sarcoma herpes virus-associated multicentric Castleman disease (KSHV- MCD) Clinical Benefit Response Criteria and the National Cancer Institute (NCI) KSHV-MCD criteria.

Secondary Outcome Measures :

1. Percentage of Participants With a Clinical Response [ Time Frame: up to 12 weeks ]
   Clinical response is defined as a Complete Response (CR): Full resolution of all signs and symptoms attributable to MCD, lasting 1 cycle (3-4 weeks depending on regimen; Symptom Free Disease (SFD:) Full resolution of all signs and symptoms attributable to MCD, not yet lasting 1 cycle (3-4 weeks depending on regimen); and Partial Response (PR): Improvement in at least 50% of signs and symptoms by at least 1 grade (NCI-Common Terminology Criteria for Adverse Events (CTCAE v4), with no increased MCD related increases, lasting 1 cycle (3-4 weeks depending on regimen) assessed by the National Cancer Institute Kaposi sarcoma herpes virus-associated multicentric Castleman disease (NCI KSHV-MCD) Response Criteria.
2. Percentage of Participants With a Biochemical Response [ Time Frame: up to 12 weeks ]
   A biochemical response is defined as a Complete Response (CR): Normalization of abnormalities attributed to MCD in the following labs: Complete blood count (CBC), Chem 20, C-Reactive protein (CRP), lasting 1 cycle (3-4 weeks depending on regimen); Partial Response (PR): 50% improvement in all labs abnormalities attributable to MCD, lasting 1 cycle (3-4 weeks depending on regimen), and was assessed by the National Cancer Institute (NCI) Kaposi sarcoma herpes virus-associated multicentric Castleman Disease (KSHV-MCD) Response Criteria.
3. Percentage of Participants With a Radiographic Response [ Time Frame: up to 12 weeks ]
   A radiographic response is defined as a Complete Response (CR): Normalization of all lymph nodes to <1.5 cm in greatest transverse dimension, decrease to < 1 cm of lymph nodes 1.1-1.5 cm at baseline (or 75% decrease in the sum of products of diameters (SPD)), Spleen < 12 cm greatest dimension, no pleural effusions; Complete Response unconfirmed (CRu): Residual lymph node mass >1.5 cm or splenomegaly > 12 cm that has decrease by >75% and does not change over one year; and Partial Response (PR): For lymph nodes, >50% decrease in SPD of 6 dominant nodes, for spleen 50% decrease in longest transverse dimension assessed by the National Cancer Institute (NCI) Kaposi sarcoma herpes virus-associated multicentric Castleman Disease (KSHV-MCD) Response Criteria.
4. Percentage of Participants With Kaposi Sarcoma Responses Per the Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) Response Criteria [ Time Frame: Baseline, week 7, and at off study visit, approximately 2 weeks following last study treatment for those with KS, up to 14 weeks. ]
   The ACTG Criteria is defined as a Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), and Symptom Free Disease (SFD). The terms Improved (I), Stable (S), Mixed (M) Response, and Worse (W) are also used to further describe participants who have SD or PR.
5. Changes in Plasma Exposure of Ritonavir in Response to Tocilizumab and Zidovudine (AZT) Metabolized by Cytochrome P450 (CYP450) [ Time Frame: 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. ]
   Cumulative plasma exposure of Ritonavir will be evaluated.
6. Changes in Plasma Exposure of Lopinavir in Response to Tocilizumab and AZT Metabolized by Cytochrome P450 (CYP450) [ Time Frame: 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. ]
   Cumulative plasma exposure of Lopinavir will be evaluated.
7. Changes in Plasma Exposure of Atazanavir in Response to Tocilizumab and Zidovudine (AZT) Metabolized by Cytochrome P450 (CYP450) [ Time Frame: 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. ]
   Cumulative plasma exposure of Atazanavir will be evaluated.
8. Changes in Plasma Exposure of Efavirenz in Response to Tocilizumab and Zidovudine (AZT) Metabolized by Cytochrome P450 (CYP450) [ Time Frame: 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. ]
   Cumulative plasma exposure of Efavirenz will be evaluated.
9. Percentage of Participants With Grade 3 or Greater Serious Adverse Events [ Time Frame: each cycle, up to 6 years, 8 months and 24 days. ]
   Here is the percentage of participants with Grade 3 or greater serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 3 is severe or medically significant, Grade 4 is life threatening, and Grade 5 is death.
10. Percentage of Participants With <Grade 3 Non- Serious Adverse Events [ Time Frame: each cycle, up to 6 years, 8 months and 24 days. ]
    Here is the percentage of participants with <Grade 3 non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. Grade 1 is mild and Grade 2 is moderate.
11. Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0) [ Time Frame: Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days. ]
    Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
12. Effect of Tocilizumab on the Pharmacokinetics (PK) of Antiretroviral Agents [ Time Frame: Cycle 1, Day 1 and Cycle 2-6 Day 1 ]
    Evaluate the effect of tocilizumab on the pharmacokinetics of antiretroviral agents that are cytochrome P3A4 (CYP3A4) substrates in patients with symptomatic Kaposi sarcoma herpes virus-associated multicentric Castleman Disease (KSHV-MCD).
13. Percentage of Participants Progression-free Survival at 4 Months [ Time Frame: 4 months ]
    Progression-free survival is defined as participants who progress or die by 4 months after the start of treatment with tocilizumab and tocilizumab /AZT/VGC.
14. Percentage of Participants With Overall Survival 4 Months After Treatment With Tocilizumab and Tocilizumab /Zidovudine (AZT)/Valganciclovir (VGC) [ Time Frame: 4 months ]
    Overall survival is defined as the percentage of participants alive at 4 months after the start of treatment with tocilizumab and tocilizumab /AZT/VGC.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Maryland

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Robert Yarchoan, M.D.; National Cancer Institute (NCI)

  Study Documents (Full-Text)

Documents provided by Robert Yarchoan, National Cancer Institute (NCI):

Study Protocol and Statistical Analysis Plan  [PDF] May 30, 2019

Informed Consent Form  [PDF] June 26, 2019

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications of Results:

Ramaswami R, Lurain K, Peer CJ, Serquiña 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.

Other Publications:

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.

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.

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.

• Responsible Party: Robert Yarchoan, Principal Investigator, National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01441063
• Other Study ID Numbers: 110233; 11-C-0233
• First Posted: September 27, 2011
• Results First Posted: June 23, 2020
• Last Update Posted: October 27, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Robert Yarchoan, National Cancer Institute (NCI):

Kaposi Sarcoma Herpesvirus; Human Immunodeficiency Virus; Tocilizumab; Multicentric Castleman Disease; Interleukin-6; Castleman Disease; Acquired Immunodeficiency Syndrome (AIDS); Human Herpesvirus-8

Additional relevant MeSH terms:

Castleman Disease; Lymphadenopathy; Hyperplasia; Pathologic Processes; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Zidovudine; Valganciclovir; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Anti-HIV Agents