Castleman Disease, Castleman's Disease, Multicentric
Conditions
Keywords
Castleman, iMCD, Castleman's Disease, multicentric Castleman's disease, multicentric Castleman disease, idiopathic Castleman disease, idiopathic Castleman's disease, CD, MCD, 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.
Interventions
DRUGSirolimus
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.
Sponsors
University of Pennsylvania
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) | 12 ± 1 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | Month 12 | 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. |
| Proportion of Patients Achieving a Lymph Node Response, Following the Modified Cheson Response Criteria | Month 12 | 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. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJoshua Brandstadter, MD, PhD, MSc
University of Pennsylvania
Participant flow
Recruitment details
Recruitment started 9/25/2019 and continued until 6/30/2024. Potential participants were informed about the study through various channels, including communication and fliers from licensed site investigators during routine clinical visits. Individuals who previously consented to be contacted for future research were reached by email or phone. Additional outreach was conducted through tools like Epic as well as through the Castleman Disease Collaborative Network (CDCN).
Pre-assignment details
Before assignment, participants underwent several steps to confirm eligibility. This included a washout period from any systemic therapies used to treat iMCD, as well as various laboratory tests to ensure they were healthy enough to participate and did not have any uncontrolled infections or conditions that could mimic iMCD.
Participants by arm
| Arm | Count |
|---|---|
| Sirolimus Oral sirolimus: Loading dose of 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 10-15 ng/mL by HPLC, for 12 months. | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Sirolimus |
|---|---|
| Age, Continuous | 57 years |
| Clinical Subtype Idiopathic Plasmacytic Lymphadenopathy (IPL) Subtype | 2 Participants |
| Clinical Subtype Not Otherwise Specified (NOS) Subtype | 3 Participants |
| Clinical Subtype Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis, and Organomegaly (TAFRO) Subtype | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Histopathological Subtype Hypervascular/Hyaline Vascular | 1 Participants |
| Histopathological Subtype Indeterminate | 2 Participants |
| Histopathological Subtype Mixed | 3 Participants |
| Histopathological Subtype Plasmacytic | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 7 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 7 / 7 |
| serious Total, serious adverse events | 1 / 7 |
Outcome results
Primary
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.
Time frame: 12 ± 1 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sirolimus | Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) | Achieved CBR | 2 Participants |
| Sirolimus | Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) | Did Not Achieve CBR | 2 Participants |
Secondary
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.
Time frame: 12 months ± 2 weeks
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Sirolimus | Disease Activity, as Measured by the CHAP Scale | 3 score on a scale | Standard Deviation 0.433 |
Secondary
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.
Time frame: Month 12
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Sirolimus | Disease Activity, as Measured by the MCD-related Overall Symptom Score | Achieved a Symptomatic Response | 1 Participants |
| Sirolimus | Disease Activity, as Measured by the MCD-related Overall Symptom Score | Achieved a Durable Symptomatic Response | 1 Participants |
| Sirolimus | Disease Activity, as Measured by the MCD-related Overall Symptom Score | No Response | 2 Participants |
Secondary
Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) Month 3
Time frame: Month 3
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sirolimus | Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) Month 3 | 1 Participants |
Secondary
Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) Month 6
Time frame: Month 6
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sirolimus | Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) Month 6 | 2 Participants |
Secondary
Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) Month 9
Time frame: Month 9
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sirolimus | Percentage of Patients Achieving a Positive Clinical Benefit Response (CBR) Month 9 | 2 Participants |
Secondary
Percentage of Patients That Indicate That They Are Currently Receiving Sirolimus at the End of the Follow Up Phase
Time frame: Up to 73 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sirolimus | Percentage of Patients That Indicate That They Are Currently Receiving Sirolimus at the End of the Follow Up Phase | 1 Participants |
Secondary
Percentage of Patients That Remain on Study Drug for the Duration of the Study
Time frame: Up to 73 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sirolimus | Percentage of Patients That Remain on Study Drug for the Duration of the Study | 4 Participants |
Secondary
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.
Time frame: Month 12
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sirolimus | Proportion of Patients Achieving a Lymph Node Response, Following the Modified Cheson Response Criteria | Achieved Complete Response | 1 participants |
| Sirolimus | Proportion of Patients Achieving a Lymph Node Response, Following the Modified Cheson Response Criteria | Progressive Disease | 2 participants |
| Sirolimus | Proportion of Patients Achieving a Lymph Node Response, Following the Modified Cheson Response Criteria | Stable Disease | 1 participants |