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出境医 / 临床实验 / Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease

Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease

Study Description
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.
Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: N/A
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 25, 2019
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 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.
Other Names:
  • Rapamune
  • Rapamycin
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
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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 (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
Contacts and Locations

Contacts
Layout table for location 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
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United States, Arkansas
University of Arkansas for Medical Sciences Recruiting
Little Rock, Arkansas, United States, 72205
Contact: Brooke Carter    501-214-2499 ext 25871    JBCarter@uams.edu   
Principal Investigator: Frits van Rhee, MD, PHD         
United States, Pennsylvania
University of Pennsylvania Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: David C Fajgenbaum, MD, MBA, MSc    215-614-0209    davidfa@pennmedicine.upenn.edu   
Contact: Tracey Sikora    215-615-3238    CDtrial@pennmedicine.upenn.edu   
Principal Investigator: David C Fajgenbaum, MD, MBA, MSc         
Sponsors and Collaborators
University of Pennsylvania
Investigators
Layout table for investigator information
Principal Investigator: David C Fajgenbaum, MD, MBA, MS University of Pennsylvania
Tracking Information
First Submitted Date  ICMJE April 29, 2019
First Posted Date  ICMJE May 1, 2019
Last Update Posted Date July 20, 2020
Actual Study Start Date  ICMJE September 25, 2019
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 29, 2019) 		Proportion of patients achieving a positive clinical benefit response (CBR) [ Time Frame: 12 ± 1 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 26, 2019)
  • Proportion of patients achieving a positive clinical benefit response (CBR) [ Time Frame: 3, 6, and 9 months ± 2 weeks ]
  • Proportion of patients that remain on study drug for the duration of the study [ Time Frame: Up to 73 weeks ]
  • 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 ]
  • 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.
  • 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
  • Proportion of patients achieving a lymph node response, following the modified Cheson response criteria [ Time Frame: 3, 6, 9, and 12 months ± 2 weeks ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 29, 2019)
  • Proportion of patients achieving a positive clinical benefit response (CBR) [ Time Frame: 3, 6, and 9 months ± 2 weeks ]
  • Proportion of patients that remain on study drug for the duration of the study [ Time Frame: Up to 73 weeks ]
  • 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 ]
  • Disease activity, as measured by the CHAP scale [ Time Frame: 3, 6, 9, and 12 months ± 2 weeks ]
  • Proportion of patients achieving a lymph node response, following the modified Cheson response criteria [ Time Frame: 3, 6, 9, and 12 months ± 2 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease
Official Title  ICMJE A Phase II, Single-arm Open-label Multi-center Study of Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease
Brief Summary The purpose of this study is to understand the impact of sirolimus on idiopathic multicentric Castleman disease.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Castleman Disease
  • Castleman's Disease, Multicentric
Intervention  ICMJE 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
Study Arms  ICMJE 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.
Intervention: Drug: Sirolimus
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, Fössa 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 29, 2019) 		24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date December 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: David C Fajgenbaum, MD, MBA, MS 215-614-0209 davidfa@pennmedicine.upenn.edu
Contact: Tracey Sikora 215-615-3238 CDtrial@pennmedicine.upenn.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03933904
Other Study ID Numbers  ICMJE 832465
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: There is no current plan to share IPD.
Responsible Party University of Pennsylvania
Study Sponsor  ICMJE University of Pennsylvania
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: David C Fajgenbaum, MD, MBA, MS University of Pennsylvania
PRS Account University of Pennsylvania
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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