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Trial record 1 of 1 for:    NCT03933904
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Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease

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ClinicalTrials.gov Identifier: NCT03933904
Recruitment Status : Not yet recruiting
First Posted : May 1, 2019
Last Update Posted : July 26, 2019
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

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

Condition or disease Intervention/treatment Phase
Castleman Disease Castleman's Disease, Multicentric Drug: Sirolimus 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.

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Study Type : Interventional  (Clinical Trial)
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
Estimated Study Start Date : August 1, 2019
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022


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.
Other Names:
  • Rapamune
  • Rapamycin




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. Proportion of patients achieving a lymph node response, following the modified Cheson response criteria [ Time Frame: 3, 6, 9, and 12 months ± 2 weeks ]


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Ages Eligible for Study:   18 Years 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 (insufficient response), 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 28 days of enrollment
  • Subjects cannot have previously received sirolimus monotherapy to treat iMCD
  • Subjects cannot have any of the following: ECOG >2; 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 ≤ 7.5 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 ≤ 50 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03933904


Contacts
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Contact: David C Fajgenbaum, MD, MBA, MS 215-614-0936 davidfa@pennmedicine.upenn.edu
Contact: Tracey Sikora 215-615-3238 tsikora@pennmedicine.upenn.edu

Locations
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United States, Arkansas
University of Arkansas for Medical Sciences Not yet recruiting
Little Rock, Arkansas, United States, 72205
Contact: Susan Panozzo    501-526-6990 ext 2457    panozzosusanB@uams.edu   
Principal Investigator: Frits van Rhee, MD, PHD         
United States, Pennsylvania
University of Pennsylvania Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: David C Fajgenbaum, MD, MBA, MSc    215-614-0936    davidfa@pennmedicine.upenn.edu   
Contact: Tracey Sikora    215-615-3238    tsikora@pennmedicine.upenn.edu   
Principal Investigator: David C Fajgenbaum, MD, MBA, MSc         
Sponsors and Collaborators
University of Pennsylvania
Investigators
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Principal Investigator: David C Fajgenbaum, MD, MBA, MS University of Pennsylvania

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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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 26, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no current plan to share IPD.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Pennsylvania:
Castleman
iMCD
Castleman's Disease
multicentric Castleman's disease
multicentric Castleman disease
idiopathic Castleman disease
idiopathic Castleman's disease
CD
MCD
Castleman Disease

Additional relevant MeSH terms:
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Castleman Disease
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Sirolimus
Everolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs