Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease

A Phase II, Single-arm Open-label Multi-center Study of Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease

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

Study Overview

• Status: Active, not recruiting
• Conditions: Castleman Disease; Castleman's Disease, Multicentric
• Intervention / Treatment: Drug: Sirolimus

Detailed Description

Human herpesvirus(HHV)-8-negative, idiopathic multicentric Castleman disease (iMCD) is a rare hematologic illness. Current therapeutic options are limited and provide benefit for only a subset of patients. Blockade of IL-6 signaling with siltuximab or tocilizumab abrogates symptoms and improves lymphadenopathy in a portion of patients. However, 66% of patients in the siltuximab Phase II clinical trial did not meet response criteria, and recent studies found that IL-6 is not significantly elevated in many iMCD patients. Recent research has suggested a key role for the phosphoinositide 3-kinase(PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway in iMCD pathogenesis and off-label administration of sirolimus, an mTOR inhibitor, has shown clinical activity. Based on these experiences, we plan to evaluate the efficacy of sirolimus as a therapy for iMCD patients who are either unable to tolerate anti-IL-6 blockade therapy (siltuximab or tocilizumab), or who fail, relapse, or are refractory to such treatment. This study is a Phase II open label study of daily administration of sirolimus in up to 24 evaluable male or female adults. Participants with iMCD who have failed previous therapy will take daily oral sirolimus for 12 months. Information that is collected as per standard of care will be used to review efficacy, in addition to samples collected specifically for research.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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 uncontrolled infection or infectious disease(s) that is/are exclusionary for / mimickers of iMCD
• Subjects cannot have rheumatologic disease(s) that is/are exclusionary for / mimickers of iMCD
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sirolimus; 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; 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.; Other Names: Rapamycin; Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Disease Activity, as Measured by the CHAP Scale	The CHAP scale consists of C-reactive protein (CRP), hemoglobin, albumin, and Eastern Cooperative Oncology Group (ECOG) performance score, each with a subscale range of 0-4. Each criterion in the CHAP scoring system provides a graded measure for a patient's disease activity. The sum of the four scores provides an objective scale for measuring a patient's disease activity and monitoring how it changes over time (scale range 0-16). A higher score indicates greater disease activity.	12 months ± 2 weeks
Disease Activity, as Measured by the MCD-related Overall Symptom Score	MCD-related Overall Symptom Score is measured by 34 MCD-related outcome measures. These scores addressed fatigue, weight change, night sweats, etc. The scores were evaluated and graded (as per CTCAE version 4.0, May, 2009), which was used to assess the efficacy of the study intervention. Each symptom score was measured on a numeric scale, ranging from 1 (no symptom) to 5 (very severe or disabling). Scores were combined to create a combined score per patient at each time point. Patients were then assessed as having no response, a symptomatic response, or a durable symptomatic response. A symptomatic response was defined as a ≥50% decrease in the 34-point symptom score, a durable symptomatic response is a ≥50% decrease in the 34-point symptom score from baseline that was maintained for a minimum of 18 weeks.	Month 12
Proportion of Patients Achieving a Lymph Node Response, Following the Modified Cheson Response Criteria	Radiological response was assessed using the modified Cheson criteria, which quantify changes in lymph node size. A lymph node response was defined as a 25% reduction in bi-dimensional measurements of the largest lymph node compared to baseline. Patients were then assessed according to the following responses: Complete Response: All index lesion(s) must have regressed to normal size (≤1.0 cm in their greatest transverse diameter. No new sites of lymphadenopathy >1.5 cm in longest dimension. Partial Response: ≥50% decrease in sum of the products of the greatest diameters (SPD) of index lesion(s), and no new sites of lymphadenopathy >1.5 cm in longest dimension. Stable Disease: Failure to achieve a CR or PR (see above) without evidence of progressive disease. Progressive Disease: ≥50% increase from nadir in the SPD of any index lesion, or appearance of any new sites of lymphadenopathy that measure >1.5 cm in longest dimension during or at the end of therapy.	Month 12

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Joshua Brandstadter, MD, PhD, MSc, University of Pennsylvania

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 25, 2019
• Primary Completion (Actual): June 30, 2024
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: April 29, 2019
• First Submitted That Met QC Criteria: April 29, 2019
• First Posted (Actual): May 1, 2019

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 27, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: CD; MCD; iMCD; Castleman; Castleman's Disease; multicentric Castleman's disease; multicentric Castleman disease; idiopathic Castleman disease; idiopathic Castleman's disease; Castleman Disease
• Additional Relevant MeSH Terms: Immune System Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hemic and Lymphatic Diseases; Castleman Disease; Multi-centric Castleman's Disease; Macular dystrophy, corneal type 1; Organic Chemicals; Macrolides; Lactones; Sirolimus
• Other Study ID Numbers: 832465

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: There is no current plan to share IPD.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No