Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease

NCT03933904 | Active Not Recruiting Phase 2 Results FDA Drug

• 1 other identifier: 832465
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to understand the impact of sirolimus on idiopathic multicentric Castleman disease.

Conditions

Castleman Disease; Castleman's Disease, Multicentric

Keywords

Castleman; iMCD; Castleman's Disease; multicentric Castleman's disease; multicentric Castleman disease; idiopathic Castleman disease; idiopathic Castleman's disease; CD; MCD; Castleman Disease

Outcome Measures

Primary Outcomes (1)

• Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR)

  Clinical Benefit Response (CBR): The CBR was defined by improvements in clinical symptoms such as fatigue, anorexia, fever, and night sweats.6 Laboratory markers such as hemoglobin levels and weight change were also included in the CBR criteria (Table 1). A CBR was considered positive if there was at least a 25% reduction in the size of the largest lymph node (measured by modified Cheson criteria), a significant improvement in at least one laboratory marker (e.g., hemoglobin), and improvement in at least one clinical symptom without worsening of others.

  12 ± 1 months

Secondary Outcomes (8)

• Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) Month 3

  Month 3

• Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) Month 6

  Month 6

• Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) Month 9

  Month 9

• Percentage of Patients That Remain on Study Drug for the Duration of the Study

  Up to 73 weeks

• Percentage of Patients That Indicate That They Are Currently Receiving Sirolimus at the End of the Follow Up Phase

  Up to 73 weeks

Study Arms (1)

Sirolimus

EXPERIMENTAL

Oral sirolimus: For adults, loading dose of 5 mg/m\^2, rounded to the nearest mg, on day 1. For adults, starting on day 2, oral sirolimus daily at 2.5 mg/m\^2/day (rounded to the nearest mg), target trough level 10-15 ng/mL by HPLC, for 12 months. For children, 2 mg/m\^2/day, target trough level 5-15 ng/mL by HPLC.

Drug: Sirolimus

Interventions

Sirolimus DRUG

Sirolimus (also known as rapamycin) inhibits the mTOR protein kinase and is approved by the USA FDA for the prevention of allograft rejection in renal transplant patients ≥ 13 years of age and for the treatment of lymphangioleiomyomatosis.

Also known as: Rapamune, Rapamycin

Sirolimus

Eligibility Criteria

• Age: 2 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female, age 2-80
• Documented disease history consistent with the diagnostic criteria for iMCD
• Failed/refractory (patient did not achieve sufficient disease control with anti-IL-6 therapy, as determined by the site investigator), relapsed (return of symptoms while on therapy), or inability to tolerate anti-IL-6 or anti-IL-6 receptor therapy
• Evidence of active disease, defined as at least two abnormalities in the criteria comprising the CBR criteria, including at least one objective measurement (hemoglobin, weight loss, or lymph node size)
• Ability to consume oral medication in the form of a tablet
• Ability to provide, or for a legally authorized representative to provide on their behalf, informed consent prior to any study-specific activities

You may not qualify if:

• Subjects cannot be pregnant or nursing females
• Except for anti-IL6 blockade therapy (siltuximab or tocilizumab), the last dose of which must be ≥ 14 days prior to enrollment (unless subjects cannot or are unwilling to undergo a 14 day washout period), subjects cannot have received any systemic therapy(ies) intended to treat iMCD other than corticosteroids within 28 days of enrollment
• Subjects cannot have previously received sirolimus monotherapy to treat iMCD
• Subjects cannot have any of the following: ECOG \>3 (or Karnofsky/Lansky score ≤ 60 in children); Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2 or creatinine \> 3.0 mg/dL; Absolute neutrophil count (ANC) \< 1000 x 109/L ((\< 500 x 109/L in children); Hemoglobin ≤ 6.5 g/dL (transfusion independent, defined as not receiving a red blood cell transfusion for ≥ 7 days prior); Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) laboratory values greater than three times the upper limit of normal; Albumin \< 2 g/dL (transfusion independent, defined as not receiving intravenous albumin for ≥ 7 days prior); Platelet count ≤ 40 x 109/L (transfusion independent, defined as not receiving platelet transfusion for ≥ 7 days prior); Pulmonary involvement or interstitial pneumonitis with dyspnea (adequate pulmonary function is defined as pulse oximetry \> 94% on room air if there is clinical indication for determination (e.g. dyspnea at rest, history of interstitial pneumonitis, etc.)); Fasting cholesterol \> 300 mg/dL or fasting triglyceride \> 400 mg/dL
• Subjects cannot have a prior malignancy except for: (1) adequately treated basal cell or squamous cell skin cancer, (2) in situ cervical cancer, or (3) other cancer for which the subject has not received treatment within one year prior to enrollment
• Subjects cannot have a documented history of human immunodeficiency virus (HIV) or HHV-8 infection, or severe combined immunodeficiency syndrome
• Subjects cannot have a history of liver or lung transplantation
• Subjects cannot have ongoing or planned participation in another clinical trial involving iMCD directed treatment or that involves immunomodulatory or anti-neoplastic treatment
• Subjects cannot have prior sensitivity / allergy to any formulation of sirolimus, its components or its analogues
• Subjects cannot have serious medical illness, or psychiatric illness or disorders that could potentially interfere with the completion of treatment according to this protocol or participation in the trial
• Subjects cannot have psychiatric disorders that compromises the ability to provide informed consent
• Subjects cannot have any other condition or finding that in the opinion of the investigator would make participation in this trial inappropriate

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (2)

University of Arkansas for Medical Sciences

Little Rock, Arkansas, 72205, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (3)

• van Rhee F, Oksenhendler E, Srkalovic G, Voorhees P, Lim M, Dispenzieri A, Ide M, Parente S, Schey S, Streetly M, Wong R, Wu D, Maillard I, Brandstadter J, Munshi N, Bowne W, Elenitoba-Johnson KS, Fossa A, Lechowicz MJ, Chandrakasan S, Pierson SK, Greenway A, Nasta S, Yoshizaki K, Kurzrock R, Uldrick TS, Casper C, Chadburn A, Fajgenbaum DC. International evidence-based consensus diagnostic and treatment guidelines for unicentric Castleman disease. Blood Adv. 2020 Dec 8;4(23):6039-6050. doi: 10.1182/bloodadvances.2020003334.

  PMID: 33284946 DERIVED

• Arenas DJ, Floess K, Kobrin D, Pai RL, Srkalovic MB, Tamakloe MA, Rasheed R, Ziglar J, Khor J, Parente SAT, Pierson SK, Martinez D, Wertheim GB, Kambayashi T, Baur J, Teachey DT, Fajgenbaum DC. Increased mTOR activation in idiopathic multicentric Castleman disease. Blood. 2020 May 7;135(19):1673-1684. doi: 10.1182/blood.2019002792.

  PMID: 32206779 DERIVED

• Fajgenbaum DC, Langan RA, Japp AS, Partridge HL, Pierson SK, Singh A, Arenas DJ, Ruth JR, Nabel CS, Stone K, Okumura M, Schwarer A, Jose FF, Hamerschlak N, Wertheim GB, Jordan MB, Cohen AD, Krymskaya V, Rubenstein A, Betts MR, Kambayashi T, van Rhee F, Uldrick TS. Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric Castleman disease. J Clin Invest. 2019 Aug 13;129(10):4451-4463. doi: 10.1172/JCI126091.

  PMID: 31408438 DERIVED

MeSH Terms

Conditions

Castleman Disease; Multi-centric Castleman's Disease; Macular dystrophy, corneal type 1

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

The study's single-arm, open-label design limited conclusions, as there was no control group and potential for bias. The small sample size, impacted by COVID-19 and off-label sirolimus use, reduced statistical power. A short follow-up (12 months plus 12 weeks) limited assessment of long-term efficacy and safety. Given iMCD's chronic nature, future studies should include larger cohorts, control arms, and extended follow-up to assess durability and safety.

Results Point of Contact

• Title: Dr. David Fajgenbaum
• Organization: Center for Cytokine Storm Treatment & Laboratory (CSTL), University of Pennsylvania

davidfa@pennmedicine.upenn.edu

215-614-0935

Study Officials

• Joshua Brandstadter, MD, PhD, MSc

  University of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 29, 2019
• First Posted: May 1, 2019
• Study Start: September 25, 2019
• Primary Completion: June 30, 2024
• Study Completion (Estimated): June 30, 2026
• Last Updated: March 3, 2026
• Results First Posted: August 8, 2025

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)