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Clinical trial information and results are updated daily from ClinicalTrials.gov. The latest data update was conducted on 06/14/2021.

Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease

Clinicaltrials.gov identifier NCT03933904

Recruitment Status Recruiting

First Posted May 1, 2019

Last update posted July 20, 2020

Study Description

Brief summary:

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

  • Condition or Disease:Castleman Disease
    Castleman's Disease, Multicentric
  • Intervention/Treatment: Drug: Sirolimus
  • Phase: Phase 2
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 Design
  • Study Type: Interventional
  • Estimated Enrollment: 24 participants
  • Intervention Model: Single Group Assignment
  • Masking: None (Open Label) ()
  • Primary Purpose: Treatment
  • Official Title: A Phase II, Single-arm Open-label Multi-center Study of Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease
  • Actual Study Start Date: September 2019
  • Estimated Primary Completion Date: December 2022
  • Estimated Study Completion Date: December 2022
Arms and interventions
Arm Intervention/treatment
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.
Outcome Measures
  • Primary Outcome Measures: 1. Proportion of patients achieving a positive clinical benefit response (CBR) [ Time Frame: 12 ± 1 months ]
  • Secondary Outcome Measures: 1. Proportion of patients achieving a positive clinical benefit response (CBR) [ Time Frame: 3, 6, and 9 months ± 2 weeks ]
  • 2. Proportion of patients that remain on study drug for the duration of the study [ Time Frame: Up to 73 weeks ]
  • 3. Proportion of patients that indicate that they are currently receiving sirolimus at the end of the Follow Up Phase [ Time Frame: Up to 73 weeks ]
  • 4. Disease activity, as measured by the CHAP scale [ Time Frame: 3, 6, 9, and 12 months ± 2 weeks ]
    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.
  • 5. Disease activity, as measured by the MCD-related Overall Symptom Score [ Time Frame: 3, 6, 9, and 12 months ± 2 weeks ]
    MCD-related Overall Symptom Score is measured by 34 MCD-related outcome measures
  • 6. Proportion of patients achieving a lymph node response, following the modified Cheson response criteria [ Time Frame: 3, 6, 9, and 12 months ± 2 weeks ]
Eligibility Criteria
  • Ages Eligible for Study: 18 to 80 Years (Adult, Older Adult)
  • Sexes Eligible for Study: All
  • Accepts Healthy Volunteers: No
Criteria

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) 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 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

Contacts and Locations
Contacts

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

Contact: Tracey Sikora 215-615-3238 CDtrial@pennmedicine.upenn.edu

Locations

United States, Arkansas
University of Arkansas for Medical Sciences
Little Rock

United States, Pennsylvania
University of Pennsylvania
Philadelphia

Sponsors and Collaborators

University of Pennsylvania

Investigators

Principal Investigator: David C Fajgenbaum, MD, MBA, MS University of Pennsylvania

More Information
  • Responsible Party: University of Pennsylvania
  • ClinicalTrials.gov Identifier: NCT03933904 History of Changes
  • Other Study ID Numbers: 832465
  • First Posted: May 1, 2019 Key Record Dates
  • Last Update Posted: July 20, 2020
  • Last Verified: July 2020
  • Individual Participant
    Data (IPD) Sharing
    Statement:
  • Plan to Share IPD: No
  • Plan Description: There is no current plan to share IPD.
  • Studies a U.S. FDA-regulated Drug Product: Yes
  • Studies a U.S. FDA-regulated Device Product: No
  • Keywords provided by University of Pennsylvania: idiopathic Castleman's disease
    Castleman's Disease
    multicentric Castleman's disease
    CD
    iMCD
    Castleman
    multicentric Castleman disease
    idiopathic Castleman disease
    MCD
    Castleman Disease
  • Additional relevant MeSH terms: Castleman Disease