Purpose

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

Conditions

Eligibility

Eligible Ages
Between 18 Years and 80 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  • Male or female, age 18-80
  • 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, with at least one abnormality being enlarged/evaluable lymph node(s) as described in Cheson criteria
  • 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, subjects cannot have received any systemic therapy(ies) intended to treat iMCD other than corticosteroids within 14 days of enrollment
  • Subjects cannot have previously received sirolimus monotherapy to treat iMCD
  • Subjects cannot have any of the following: ECOG >3; 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; 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 Design

Phase
Phase 2
Study Type
Interventional
Allocation
N/A
Intervention Model
Single Group Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Sirolimus
Oral sirolimus: loading dose of 7.5 mg/m^2, rounded to the nearest mg, on day 1. Starting on day 2, oral sirolimus daily at 2.5 mg/m^2/day (rounded to the nearest mg), target trough level 5-15 ng/mL by HPLC, for 12 months.
  • 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:
    • Rapamune
    • Rapamycin

Recruiting Locations

University of Arkansas for Medical Sciences
Little Rock, Arkansas 72205
Contact:
Brooke Carter
501-214-2499
JBCarter@uams.edu

University of Pennsylvania
Philadelphia, Pennsylvania 19104
Contact:
David C Fajgenbaum, MD, MBA, MSc
215-614-0209
davidfa@pennmedicine.upenn.edu

More Details

NCT ID
NCT03933904
Status
Recruiting
Sponsor
University of Pennsylvania

Study Contact

David C Fajgenbaum, MD, MBA, MS
215-614-0209
davidfa@pennmedicine.upenn.edu

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.