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Sirolimus Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma

Primary Purpose

Kaposiform Hemangioendothelioma, Kasabach Merritt Phenomenon

Status
Completed
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Sirolimus
Prednisolone
Sponsored by
West China Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Kaposiform Hemangioendothelioma focused on measuring Kaposiform Hemangioendothelioma, Kasabach Merritt Phenomenon, Sirolimus, Prednisolone

Eligibility Criteria

1 Day - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Presenting a KHE with the following characteristics:

    1. Clinical features and histological findings consistent with progressive, non-resectable KHE associated with KMP.
    2. Patients must be 0 - 18 years of age at the time of study entry.
    3. Without functional impairment requiring treatment of corticosteroid.
  • Organ function requirements:

    1 Adequate liver function:

    1. Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN)for age, and
    2. ALT and AST less than or equal to 2.5 x upper limit normal (ULN) for age.

    2 Adequate renal function:

    1. 0-5 years of age maximum serum creatinine (mg/dL) of 0.8
    2. 6-10 years of age maximum serum creatinine (mg/dL) of 1.0
    3. 11-15 years of age maximum serum creatinine (mg/dL) of 1.2
    4. 16-18 years of age maximum serum creatinine (mg/dL) of 1.5
  • Adequate bone marrow function: Absolute Neutrophil Count (ANC) greater than or equal to 1 x 10 to the ninth/Liter.
  • Consent of parents (or the person having parental authority in families): Signed and dated written informed consent.

Exclusion Criteria:

  • Allergy to sirolimus or other rapamycin analogues.
  • Any known evidence of significant local or systemic uncontrolled infection, defined as receiving intravenous antibiotics at the time of randomization.
  • Patients must not be known to be Human Immunodeficiency Virus positive or known immunodeficiency. Testing is not required unless a condition is suspected.
  • Other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe malnutrition, chronic liver or renal disease, active upper gastrointestinal tract ulceration).
  • Impairment of gastrointestinal function or chronic gastrointestinal disease that may significantly alter the absorption of sirolimus.
  • Patients who have a history of malignancy.
  • Patients with an inability to participate or to follow the study treatment and assessment plan.

Sites / Locations

  • West China Hospital of Sichuan University

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Sirolimus

Sirolimus plus prednisolone

Arm Description

Sirolimus was initiated at a dosage of 0.8 mg/m2 administered twice daily. Subsequently, the sirolimus dosage was adjusted monthly to achieve trough levels between 10 and 15 ng/mL.

Sirolimus was initiated at a dosage of 0.8 mg/m2 administered twice daily. Subsequently, the sirolimus dosage was adjusted monthly to achieve trough levels between 10 and 15 ng/mL. Prednisolone was administered 2 mg/kg administered once daily. Should satisfactory clinical responses and hematologic stabilization ensue, prednisolone may be tapered and discontinued within the following 4-6 weeks.

Outcomes

Primary Outcome Measures

The changes of platelet counts
Platelet counts
The changes of fibrinogen levels
Fibrinogen levels
The changes in KHE volume
Response to therapy was measured by volumetric magnetic resonance imaging (MRI) analyses were performed at baseline and 6 and 12 months after treatment and were independently assessed by 2 radiologists. Changes in KHE size were classified as further growth (increase of β‰₯10%), no change (<10% increase and <10% decrease), partial involution (decrease of β‰₯10% and <75%), nearly complete involution (decrease of β‰₯75% and <100%), or complete involution (100%). Photographs of the mixed KHE were taken at months 0, 6 and 12 by a medical photographer.
The changes in the patient's symptoms and/or complications.
Improvement in the range of motion.

Secondary Outcome Measures

Frequency of adverse events
Frequency of adverse events (e.g. gastrointestinal disorders, blood and lymphatic system disorders, metabolic disorders or other abnormal laboratory results, skin disorders and general disorders, etc.) collected by investigator and reported by parents. All adverse events were collected and graded according to Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0). The causality of the adverse event was determined by the multidisciplinary staff and was classified as definitively not related, probably not related, possibly related, probably related, or definitively related. Any dose reductions, interruptions, or cessations enacted at the discretion of the investigators were recorded.
Change in blood biomarkers
Change in vascular endothelial growth factor (VEGF-A, C and D), IL-6, IL-8, angiopoietin 1 and 2. These parameters were measured via a series of correlative laboratory studies using blood samples.
Quality of life (QOL) in patients.
Pediatric Quality of Life Inventory (PedsQLTM) 4.0 Genetic Core Infant Scales (<2 years) or Pediatric Quality of Life Inventory (PedsQLTM) 4.0 Genetic Core Scales (2-18 years) were used.
Measuring the impact of KHE on family functioning.
PedsQLTM 4.0 Family Impact Module (FIM) was used.

Full Information

First Posted
June 9, 2017
Last Updated
April 19, 2022
Sponsor
West China Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03188068
Brief Title
Sirolimus Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma
Official Title
Sirolimus Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma With Kasabach-Merritt Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Completed
Study Start Date
June 1, 2017 (Actual)
Primary Completion Date
December 31, 2021 (Actual)
Study Completion Date
December 31, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
West China Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm that occurs predominantly in infancy or early childhood. KHE has a nearly equal sex ratio. The annual incidence of KHE has been estimated at 0.071 per 100,000 children. KHE presents with intermediate-malignant and locally aggressive characteristics but without distant metastases. This pilot trial studies sirolimus versus sirolimus plus pednisolone in treating patients diagnosed with kaposiform hemangioendothelioma (KHE) and Kasabach-Merritt phenomemon (KMP) that cannot be removed by surgery. The purpose of this study is to compare the efficacy and safety of orally administered sirolimus versus sirolimus plus pednisolone in the treatment of KHE associated with KMP.
Detailed Description
Kasabach-Merritt phenomemon (KMP) is a profound thrombocytopenia resulting from intralesional platelet trapping. It is now clear that KMP occurs with KHE and tufted angioma, not with infantile or congenital hemangiomas. KMP is typically associated with more aggressive lesions and poorer outcomes. Clinically significant KMP is a severe thrombocytopenia, generally below 30Γ— 109/L. Severe thrombocytopenia may indicate a severer tumor, a progressive tumor, partially or totally insensitive to therapy. In addition to severe, persistent thrombocytopenia characteristic of KMP, patients often manifest elevated D-dimer and low fibrinogen. Coagulopathy in addition to thrombocytopenia is associated with more aggressive presentations and may indicate current infection or inflammation. Additionally, KMP may be complicated by severe anemia due to blood sequestration and intra-lesional hemorrhaging. KHE with KMP have notably high morbidity and mortality rates, resulting predominantly from rapid tumor growth and infiltration, compression or destruction of vital structures, and hemodynamic instability. Consensus treatment guidelines from a multidisciplinary expert panel were published in 2013. Medical treatments with corticosteroids and/or vincristine have been recommended for the management of KHE. However, first-line treatment with corticosteroids is successful in only 10-27% of all cases, and treatment with vincristine is successful in 60-70% of patients. Moreover, vincristine monotherapy has not been confirmed to provide significant benefits in critically ill patients. Sirolimus (also known as rapamycin) is an inhibitor of the mammalian target of rapamycin (mTOR). In recent studies, sirolimus was shown to be effective in patients with complex vascular anomalies, including KHE. Our multicenter, retrospective study demonstrated that oral sirolimus is an effective and safe option for the treatment of progressive KHE. Additionally, our data emphasized that the KHE treatment regimen should be tailored to individual patients and guided by specific clinical circumstances. In cases of severe Kasabach-Merritt phenomenon (KMP), sirolimus in combination with the short-term administration of prednisolone is recommended for controlling life-threatening conditions.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Kaposiform Hemangioendothelioma, Kasabach Merritt Phenomenon
Keywords
Kaposiform Hemangioendothelioma, Kasabach Merritt Phenomenon, Sirolimus, Prednisolone

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sirolimus
Arm Type
Active Comparator
Arm Description
Sirolimus was initiated at a dosage of 0.8 mg/m2 administered twice daily. Subsequently, the sirolimus dosage was adjusted monthly to achieve trough levels between 10 and 15 ng/mL.
Arm Title
Sirolimus plus prednisolone
Arm Type
Active Comparator
Arm Description
Sirolimus was initiated at a dosage of 0.8 mg/m2 administered twice daily. Subsequently, the sirolimus dosage was adjusted monthly to achieve trough levels between 10 and 15 ng/mL. Prednisolone was administered 2 mg/kg administered once daily. Should satisfactory clinical responses and hematologic stabilization ensue, prednisolone may be tapered and discontinued within the following 4-6 weeks.
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
Rapamycin
Intervention Description
Oral administration
Intervention Type
Drug
Intervention Name(s)
Prednisolone
Intervention Description
Oral administered with sirolimus
Primary Outcome Measure Information:
Title
The changes of platelet counts
Description
Platelet counts
Time Frame
2 months
Title
The changes of fibrinogen levels
Description
Fibrinogen levels
Time Frame
2 months
Title
The changes in KHE volume
Description
Response to therapy was measured by volumetric magnetic resonance imaging (MRI) analyses were performed at baseline and 6 and 12 months after treatment and were independently assessed by 2 radiologists. Changes in KHE size were classified as further growth (increase of β‰₯10%), no change (<10% increase and <10% decrease), partial involution (decrease of β‰₯10% and <75%), nearly complete involution (decrease of β‰₯75% and <100%), or complete involution (100%). Photographs of the mixed KHE were taken at months 0, 6 and 12 by a medical photographer.
Time Frame
6 and 12 months
Title
The changes in the patient's symptoms and/or complications.
Description
Improvement in the range of motion.
Time Frame
6 and 12 months
Secondary Outcome Measure Information:
Title
Frequency of adverse events
Description
Frequency of adverse events (e.g. gastrointestinal disorders, blood and lymphatic system disorders, metabolic disorders or other abnormal laboratory results, skin disorders and general disorders, etc.) collected by investigator and reported by parents. All adverse events were collected and graded according to Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0). The causality of the adverse event was determined by the multidisciplinary staff and was classified as definitively not related, probably not related, possibly related, probably related, or definitively related. Any dose reductions, interruptions, or cessations enacted at the discretion of the investigators were recorded.
Time Frame
12 months
Title
Change in blood biomarkers
Description
Change in vascular endothelial growth factor (VEGF-A, C and D), IL-6, IL-8, angiopoietin 1 and 2. These parameters were measured via a series of correlative laboratory studies using blood samples.
Time Frame
6 and 12 months
Title
Quality of life (QOL) in patients.
Description
Pediatric Quality of Life Inventory (PedsQLTM) 4.0 Genetic Core Infant Scales (<2 years) or Pediatric Quality of Life Inventory (PedsQLTM) 4.0 Genetic Core Scales (2-18 years) were used.
Time Frame
12 months
Title
Measuring the impact of KHE on family functioning.
Description
PedsQLTM 4.0 Family Impact Module (FIM) was used.
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Day
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Presenting a KHE with the following characteristics: Clinical features and histological findings consistent with progressive, non-resectable KHE associated with KMP. Patients must be 0 - 18 years of age at the time of study entry. Without functional impairment requiring treatment of corticosteroid. Organ function requirements: 1 Adequate liver function: Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN)for age, and ALT and AST less than or equal to 2.5 x upper limit normal (ULN) for age. 2 Adequate renal function: 0-5 years of age maximum serum creatinine (mg/dL) of 0.8 6-10 years of age maximum serum creatinine (mg/dL) of 1.0 11-15 years of age maximum serum creatinine (mg/dL) of 1.2 16-18 years of age maximum serum creatinine (mg/dL) of 1.5 Adequate bone marrow function: Absolute Neutrophil Count (ANC) greater than or equal to 1 x 10 to the ninth/Liter. Consent of parents (or the person having parental authority in families): Signed and dated written informed consent. Exclusion Criteria: Allergy to sirolimus or other rapamycin analogues. Any known evidence of significant local or systemic uncontrolled infection, defined as receiving intravenous antibiotics at the time of randomization. Patients must not be known to be Human Immunodeficiency Virus positive or known immunodeficiency. Testing is not required unless a condition is suspected. Other concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe malnutrition, chronic liver or renal disease, active upper gastrointestinal tract ulceration). Impairment of gastrointestinal function or chronic gastrointestinal disease that may significantly alter the absorption of sirolimus. Patients who have a history of malignancy. Patients with an inability to participate or to follow the study treatment and assessment plan.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Yi Ji, MD, PhD
Organizational Affiliation
West China Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
West China Hospital of Sichuan University
City
Chengdu
State/Province
Sichuan
ZIP/Postal Code
610041
Country
China

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
28486787
Citation
Ji Y, Chen S, Xiang B, Li K, Xu Z, Yao W, Lu G, Liu X, Xia C, Wang Q, Li Y, Wang C, Yang K, Yang G, Tang X, Xu T, Wu H. Sirolimus for the treatment of progressive kaposiform hemangioendothelioma: A multicenter retrospective study. Int J Cancer. 2017 Aug 15;141(4):848-855. doi: 10.1002/ijc.30775. Epub 2017 May 26.
Results Reference
background
PubMed Identifier
28426496
Citation
Wang C, Li Y, Xiang B, Li F, Chen S, Li L, Ji Y. Successful Management of Pancreatic Kaposiform Hemangioendothelioma With Sirolimus: Case Report and Literature Review. Pancreas. 2017 May/Jun;46(5):e39-e41. doi: 10.1097/MPA.0000000000000801. No abstract available.
Results Reference
background
PubMed Identifier
28220608
Citation
Reichel A, Hamm H, Wiegering V, Wiewrodt B, Neubauer H, Ernestus K, Winkler B. Kaposiform hemangioendothelioma with Kasabach-Merritt syndrome: successful treatment with sirolimus. J Dtsch Dermatol Ges. 2017 Mar;15(3):329-331. doi: 10.1111/ddg.12987. Epub 2017 Feb 21. No abstract available.
Results Reference
background
PubMed Identifier
27981218
Citation
Alaqeel AM, Alfurayh NA, Alhedyani AA, Alajlan SM. Sirolimus for treatment of kaposiform hemangioendothelioma associated with Kasabach-Merritt phenomenon. JAAD Case Rep. 2016 Dec 5;2(6):457-461. doi: 10.1016/j.jdcr.2016.06.005. eCollection 2016 Nov. No abstract available.
Results Reference
background
PubMed Identifier
28579853
Citation
Mahajan P, Margolin J, Iacobas I. Kasabach-Merritt Phenomenon: Classic Presentation and Management Options. Clin Med Insights Blood Disord. 2017 Mar 16;10:1179545X17699849. doi: 10.1177/1179545X17699849. eCollection 2017.
Results Reference
background
PubMed Identifier
35030255
Citation
Ji Y, Chen S, Zhou J, Yang K, Zhang X, Xiang B, Qiu T, Gong X, Zhang Z, Lan Y, Hu F, Kong F, Qiu Q, Zhang Y. Sirolimus plus prednisolone vs sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized clinical trial. Blood. 2022 Mar 17;139(11):1619-1630. doi: 10.1182/blood.2021014027.
Results Reference
derived

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Sirolimus Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma

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