Castleman DiseasePhase 2NCT01441063
Tocilizumab for KSHV-Associated Multicentric Castleman Disease
A Phase 2 study testing Zidovudine, Tocilizumab and Valganciclovir (VGC) in people with Castleman Disease and Multicentric Castleman Disease, run by National Cancer Institute (NCI) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Castleman Disease, Multicentric Castleman Disease, Giant Lymph Node Hyperplasia
- What is being tested?
- Zidovudine, Tocilizumab and Valganciclovir (VGC)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 8 participants
- Where
- 1 siteUnited States
- Study dates
- 13 Sep 2011to 5 Oct 2020
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
Show all 20Show fewer
- 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
Who cannot join
- 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
Show all 19Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: Pilot Study of Tocilizumab in Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV) - Associated Multicentric Castleman Disease
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.
Read more
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.
Read the 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).
- Being tested
- Zidovudine, Tocilizumab, Valganciclovir (VGC)
- Keywords
- Kaposi Sarcoma Herpesvirus, Human Immunodeficiency Virus, Tocilizumab, Multicentric Castleman Disease, Interleukin-6, Castleman Disease, Acquired Immunodeficiency Syndrome (AIDS), Human Herpesvirus-8
- Medical subject headings
- Castleman Disease, Multi-centric Castleman's Disease, Sarcoma, Kaposi, Acquired Immunodeficiency Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ZidovudineDrug
Also called Retrovir
Zidovudine (AZT) 600 mg orally q6 hours (every 6 hours)
TocilizumabDrug
Also called Actemra
Tocilizumab 8mg/kg every 2 weeks
Valganciclovir (VGC)Drug
Also called Valcyte
Valganciclovir (VGC) 900 mg orally q12 hours (every 12 hours) on days 1-5 of a 14-day cycle.
| Study group | Role | What they receive |
|---|---|---|
| Tocilizumab | Experimental | 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. Receives: Drug: Zidovudine; Drug: Tocilizumab; Drug: Valganciclovir (VGC) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants With an Overall Clinical Benefit Response
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.
Measured: every 2 weeks for up to 12 weeks
Secondary outcomes (14)
Percentage of Participants With a Clinical Response
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.
Measured: up to 12 weeks
Percentage of Participants With a Biochemical Response
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.
Measured: up to 12 weeks
Percentage of Participants With a Radiographic Response
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.
Measured: up to 12 weeks
Percentage of Participants With Kaposi Sarcoma Responses Per the Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) Response Criteria
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.
Measured: Baseline, week 7, and at off study visit, approximately 2 weeks following last study treatment for those with KS, up to 14 weeks.
Changes in Plasma Exposure of Ritonavir in Response to Tocilizumab and Zidovudine (AZT) Metabolized by Cytochrome P450 (CYP450)
Cumulative plasma exposure of Ritonavir will be evaluated.
Measured: 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.
Changes in Plasma Exposure of Lopinavir in Response to Tocilizumab and AZT Metabolized by Cytochrome P450 (CYP450)
Cumulative plasma exposure of Lopinavir will be evaluated.
Measured: 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.
Changes in Plasma Exposure of Atazanavir in Response to Tocilizumab and Zidovudine (AZT) Metabolized by Cytochrome P450 (CYP450)
Cumulative plasma exposure of Atazanavir will be evaluated.
Measured: 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.
Changes in Plasma Exposure of Efavirenz in Response to Tocilizumab and Zidovudine (AZT) Metabolized by Cytochrome P450 (CYP450)
Cumulative plasma exposure of Efavirenz will be evaluated.
Measured: 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.
Percentage of Participants With Grade 3 or Greater Serious Adverse Events
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.
Measured: each cycle, up to 6 years, 8 months and 24 days.
Percentage of Participants With <Grade 3 Non- Serious Adverse Events
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.
Measured: each cycle, up to 6 years, 8 months and 24 days.
Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)
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.
Measured: Date treatment consent signed to date off study, approximately 6 years, 8 months and 24 days.
Effect of Tocilizumab on the Pharmacokinetics (PK) of Antiretroviral Agents
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).
Measured: Cycle 1, Day 1 and Cycle 2-6 Day 1
Percentage of Participants Progression-free Survival at 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.
Measured: 4 months
Percentage of Participants With Overall Survival 4 Months After Treatment With Tocilizumab and Tocilizumab /Zidovudine (AZT)/Valganciclovir (VGC)
Overall survival is defined as the percentage of participants alive at 4 months after the start of treatment with tocilizumab and tocilizumab /AZT/VGC.
Measured: 4 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Sep 2011 (estimated)
- Study start13 Sep 2011
- Primary completion6 Jun 2018
- Study completion5 Oct 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Castleman DiseaseStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 8 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Principal investigator, Robert Yarchoan, National Cancer Institute (NCI)
- Investigators
- Robert Yarchoan, M.D., Principal investigator, National Cancer Institute (NCI)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01441063
- Sponsor's protocol ID
- 110233
- Other IDs
- 11-C-0233
- Status last verified
- Oct 2020
- First submitted
- 24 Sep 2011
- Last updated
- 27 Oct 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
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.
PubMed 25331113Uldrick 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.
PubMed 20583924Brandt 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.
PubMed 2384605Ramaswami 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.
PubMed 32276276
Study at a glance
From the registry record, last updated by the sponsor on 27 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Study of Tocilizumab in Patients With Symptomatic Kaposi Sarcoma Herpesvirus (KSHV) - Associated Multicentric Castleman Disease
- ClinicalTrials.gov ID
- NCT01441063
- Acronym / sponsor ID
- 110233
- Keywords
- Kaposi Sarcoma Herpesvirus, Human Immunodeficiency Virus, Tocilizumab, Multicentric Castleman Disease, Interleukin-6, Castleman Disease, Acquired Immunodeficiency Syndrome (AIDS), Human Herpesvirus-8
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 8 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 13 Sep 2011 (actual)
- Primary completion
- 6 Jun 2018 (actual)
- Study completion
- 5 Oct 2020 (actual)
- First posted
- 27 Sep 2011 (estimated)
- Results
- Posted 23 Jun 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Tocilizumab | Experimental | Drug: Zidovudine, Drug: Tocilizumab, Drug: Valganciclovir (VGC)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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- 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)
Key exclusion criteria (19 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ZidovudineAlso: RetrovirZidovudine (AZT) 600 mg orally q6 hours (every 6 hours) | Drug | Tocilizumab |
| TocilizumabAlso: ActemraTocilizumab 8mg/kg every 2 weeks | Drug | Tocilizumab |
| Valganciclovir (VGC)Also: ValcyteValganciclovir (VGC) 900 mg orally q12 hours (every 12 hours) on days 1-5 of a 14-day cycle. | Drug | Tocilizumab |
Primary outcome
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.
14 secondary outcomes
Percentage of Participants With a Clinical Response
Time frame: up to 12 weeks
Percentage of Participants With a Biochemical Response
Time frame: up to 12 weeks
Percentage of Participants With a Radiographic Response
Time frame: up to 12 weeks
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.
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.
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.
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.
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.
Percentage of Participants With Grade 3 or Greater Serious Adverse Events
Time frame: each cycle, up to 6 years, 8 months and 24 days.
Percentage of Participants With <Grade 3 Non- Serious Adverse Events
Time frame: each cycle, up to 6 years, 8 months and 24 days.
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.
Effect of Tocilizumab on the Pharmacokinetics (PK) of Antiretroviral Agents
Time frame: Cycle 1, Day 1 and Cycle 2-6 Day 1
Percentage of Participants Progression-free Survival at 4 Months
Time frame: 4 months
Percentage of Participants With Overall Survival 4 Months After Treatment With Tocilizumab and Tocilizumab /Zidovudine (AZT)/Valganciclovir (VGC)
Time frame: 4 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Oct 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 25331113Uldrick 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.
- Background: PubMed 20583924Uldrick 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.
- Background: PubMed 2384605Brandt 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.
- Results publication: PubMed 32276276Ramaswami 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert Yarchoan, M.D. principal investigator
National Cancer Institute (NCI)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Zidovudine, Tocilizumab and Valganciclovir (VGC) in people with Castleman Disease and Multicentric Castleman Disease, run by National Cancer Institute (NCI) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Oct 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 Jun 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants With an Overall Clinical Benefit Response (time frame: every 2 weeks for up to 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01441063, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2020; AzTrials last refreshed its copy on 31 Oct 2026.