Tocilizumab for KSHV-Associated Multicentric Castleman Disease

NCT01441063 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 11023311-C-0233
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (1)

• 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.

  every 2 weeks for up to 12 weeks

Secondary Outcomes (14)

• Percentage of Participants With a Clinical Response

  up to 12 weeks

• Percentage of Participants With a Biochemical Response

  up to 12 weeks

• Percentage of Participants With a Radiographic Response

  up to 12 weeks

• Percentage of Participants With Kaposi Sarcoma Responses Per the Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) Response Criteria

  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)

  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.

Study Arms (1)

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.

Drug: Zidovudine; Drug: Tocilizumab; Drug: Valganciclovir (VGC)

Interventions

Zidovudine DRUG

Zidovudine (AZT) 600 mg orally q6 hours (every 6 hours)

Also known as: Retrovir

Tocilizumab

Tocilizumab DRUG

Tocilizumab 8mg/kg every 2 weeks

Also known as: Actemra

Tocilizumab

Valganciclovir (VGC) DRUG

Valganciclovir (VGC) 900 mg orally q12 hours (every 12 hours) on days 1-5 of a 14-day cycle.

Also known as: Valcyte

Tocilizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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.

  PMID: 25331113 BACKGROUND

• 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.

  PMID: 20583924 BACKGROUND

• 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.

  PMID: 2384605 BACKGROUND

• 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.

  PMID: 32276276 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Castleman Disease; Multi-centric Castleman's Disease; Sarcoma, Kaposi; Acquired Immunodeficiency Syndrome

Interventions

Zidovudine; tocilizumab; Valganciclovir

Condition Hierarchy (Ancestors)

Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Vascular Tissue; HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes

Intervention Hierarchy (Ancestors)

Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Dideoxynucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ganciclovir; Acyclovir; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Dr. Robert Yarchoan
• Organization: National Cancer Institute

robert.yarchoan@nih.gov

240-760-6075

Study Officials

• Robert Yarchoan, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 24, 2011
• First Posted: September 27, 2011
• Study Start: September 13, 2011
• Primary Completion: June 6, 2018
• Study Completion: October 5, 2020
• Last Updated: October 27, 2020
• Results First Posted: June 23, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)