Different Doses of Sirolimus for the Maintenance Treatment of Kaposiform Hemangioendothelioma

Different Doses of Sirolimus for the Maintenance Treatment of Kaposiform Hemangioendothelioma: a Randomized Controlled Trial

The purpose of this study is to compare the efficacy and safety of different doses of sirolimus in the maintenance treatment of kaposiform hemangioendothelioma.

Study Overview

• Status: Recruiting
• Conditions: Hemangioendothelioma
• Intervention / Treatment: Drug: Sirolimus

Detailed Description

Kaposiform hemangioendothelioma (KHE) is a rare aggressive vascular neoplasm that occurs predominantly in infancy or early childhood, with an incidence of approximately 0.071/100,000. Currently, sirolimus is a promising treatment modality for KHE. Most scholars consider sirolimus blood concentration of 5-15 ng/ml to be an effective therapeutic concentration, while 10-15 ng/ml is the most commonly used blood concentration. However, long-term higher dose sirolimus treatment can cause some common adverse effects, such as oral mucositis which affects the quality of life of the patient. Finer control of the plasma concentration of sirolimus may contribute to the efficacy of treatment and reduce the incidence of complications. Previous studies have found good efficacy of low-dose sirolimus maintenance treatment for KHE. However, there is no high-level evidence to support this treatment strategy. Therefore, we conducted this study to find out whether an early reduction in sirolimus dose would benefit the prognosis of the patients.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yi Ji, MD, PhD; Phone Number: 86 28 85423453; Email: jijiyuanyuan@163.com
• Study Contact Backup: Name: Siyuan Chen, MD, PhD; Phone Number: 86 28 85422215; Email: siy_chen@163.com

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Recruiting
      • West China Hospital of Sichuan University
      • Contact: Yi Ji, MD, PhD; Phone Number: +86 28 85423453; Email: jijiyuanyuan@163.com
      • Contact: Siyuan Chen, MD, PhD; Phone Number: +862885422215; Email: siy_chen@163.com
      • Sub-Investigator: Jiangyuan Zhou, MD
      • Sub-Investigator: Yuru Lan, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 14 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Presenting a KHE with the following characteristics:

1. Male and female;
2. Between 0 and 14 years of age;

3. Diagnosis of KHE as determined by:

   • Biopsy;
   • Compatible MRI findings;
   • History and clinical features.
4. Patients were required to have adequate liver, renal and bone marrow function, and absence of active infection
5. Consent of parents (or the person with parental authority in families): signed and dated written informed consent.

Exclusion Criteria:

1. Patients contraindicated for the administration of sirolimus (e.g., those with an allergy to sirolimus or other rapamycin analog)
2. Exposure to chemotherapy, embolization, corticosteroids, propranolol, sclerotherapy or any other investigational agents within 1 weeks before enrolment on study;
3. Patients had a history of a major surgery within 2 weeks before enrollment;
4. Patients who have a history of treatment with sirolimus or other mTOR inhibitor;
5. Any known evidence of significant local or systemic uncontrolled infection, defined as receiving intravenous antibiotics at the time of enrollment;
6. Concurrent severe and/or uncontrolled medical diseases that could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe malnutrition, chronic liver or renal disease, active upper gastrointestinal tract ulceration).
7. Impairment of gastrointestinal function or chronic gastrointestinal disease that may significantly alter the absorption of sirolimus.

8. Patients with inadequate liver function:

   Total bilirubin higher than or equal to 1.5 × the upper limit of the normal (ULN) for age and alanine aminotransferase and aspartate aminotransferase higher than or equal to 2.5 × the ULN for age.

9. Patients with inadequate 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; 11-14 years of age maximum serum creatinine (mg/dL) of 1.2;

10. Adequate bone marrow function:

    Absolute neutrophil count lower than 1 × 109/L;

11. History of a malignancy within 5 years;
12. HIV infection or known immunodeficiency;
13. Indication for treatment with corticosteroids, vincristine, interferon-α, sirolimus, or tacrolimus for an indication other than IH;
14. Patients with an inability to participate in or follow-up during the study treatment and assessment plan;
15. Inability to give informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Regular dose of sirolimus; Sirolimus The plasma trough concentration of sirolimus is maintained within the range of 10-15 ng/ml by adjusting sirolimus dose, for 1 year.	Drug: Sirolimus; Use of different doses of the same drug; Other Names: Rapamycin; Rapamune
Experimental: Low dose of sirolimus; The plasma trough concentration of sirolimus is maintained within the range of 10-15 ng/ml by adjusting sirolimus dose, for 6 months. Then, The plasma trough concentration of sirolimus is maintained within the range of 5-8 ng/ml by adjusting sirolimus dose, for 6 months.	Drug: Sirolimus; Use of different doses of the same drug; Other Names: Rapamycin; Rapamune

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 ≥10%), no change (<10% increase and <10% decrease), partial involution (decrease of ≥10% and <75%), nearly complete involution (decrease of ≥75% and <100%), or complete involution (100%).	12 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, 6 months, 12 months.
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.	Baseline, 6 months, 12 months.
The changes in the patient's musculoskeletal complication.	The severity of musculoskeletal complication was scored by using a 4-point scale: 1, asymptomatic or mild symptoms, clinical or diagnostic observations only; 2, moderate symptoms, limiting age-appropriate instrumental activities of daily living; 3, severe or medically significant symptoms, disabling or limiting self-care activities of daily living; and 4, life-threatening consequences, with urgent intervention indicated.	Baseline, 3 monthss, 6 months, 9 months, 12 months.
The changes of platelet counts.	Platelet counts	Baseline, 3 monthss, 6 months, 9 months, 12 months.
The changes of fibrinogen levels.	Fibrinogen levels	Baseline, 3 monthss, 6 months, 9 months, 12 months.
The changes of D-dimer levels.	D-dimer levels	Baseline, 3 monthss, 6 months, 9 months, 12 months.

Collaborators and Investigators

• Sponsor: West China Hospital
• Investigators: Principal Investigator: Yi Ji, MD, PhD, West China hospital

Publications and helpful links

General Publications

• Ji Y, Chen S, Yang K, Xia C, Li L. Kaposiform hemangioendothelioma: current knowledge and future perspectives. Orphanet J Rare Dis. 2020 Feb 3;15(1):39. doi: 10.1186/s13023-020-1320-1.
• 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.
• Wang Z, Yao W, Sun H, Dong K, Ma Y, Chen L, Zheng S, Li K. Sirolimus therapy for kaposiform hemangioendothelioma with long-term follow-up. J Dermatol. 2019 Nov;46(11):956-961. doi: 10.1111/1346-8138.15076. Epub 2019 Sep 5.
• Croteau SE, Liang MG, Kozakewich HP, Alomari AI, Fishman SJ, Mulliken JB, Trenor CC 3rd. Kaposiform hemangioendothelioma: atypical features and risks of Kasabach-Merritt phenomenon in 107 referrals. J Pediatr. 2013 Jan;162(1):142-7. doi: 10.1016/j.jpeds.2012.06.044. Epub 2012 Aug 4.
• Rossler J, Baselga E, Davila V, Celis V, Diociaiuti A, El Hachem M, Mestre S, Haeberli D, Prokop A, Hanke C, Loichinger W, Quere I, Baumgartner I, Niemeyer CM, Kapp FG. Severe adverse events during sirolimus "off-label" therapy for vascular anomalies. Pediatr Blood Cancer. 2021 Aug;68(8):e28936. doi: 10.1002/pbc.28936. Epub 2021 Feb 13.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2022
• Primary Completion (Estimated): April 30, 2025
• Study Completion (Estimated): November 30, 2025

Study Registration Dates

• First Submitted: April 5, 2022
• First Submitted That Met QC Criteria: April 5, 2022
• First Posted (Actual): April 12, 2022

Study Record Updates

• Last Update Posted (Actual): January 24, 2024
• Last Update Submitted That Met QC Criteria: January 23, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Sirolimus; Hemangioendothelioma; Kaposiform hemangioendothelioma
• Additional Relevant MeSH Terms: Virus Diseases; Infections; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; DNA Virus Infections; Thrombocytopenia; Blood Platelet Disorders; Herpesviridae Infections; Sarcoma; Hemangioma; Neoplasms, Vascular Tissue; Sarcoma, Kaposi; Hemangioendothelioma; Kasabach-Merritt Syndrome; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: 2022-405

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No