Clinical Study of Chemotherapy in the Treatment of Recurrent/Refractory Yolk Sac Tumor in Children (SCRRYST)

Clinical Study of Sirolimus Combined With Chemotherapy in the Treatment of Recurrent/Refractory Yolk Sac Tumor in Children

Remarkable progress has been made in treating germ-cell tumor (GCT) through the use of platinum-based regimens. However, part of yolk sac tumor (YST) with cisplatin resistance or recurrence is nevertheless prone to relapse after second-line treatment. This leaves a gap in effective treatment, which needs to be filled by novel therapeutic approaches. This paper is the first one to report the treatment combining sirolimus with nab-paclitaxel, ifosfamide, and carboplatin (S-TIC) for children with repeated relapsed or refractory yolk sac tumor (rrrYST).

Study Overview

• Status: Completed
• Conditions: Germ Cell Tumor; Yolk Sac Tumor
• Intervention / Treatment: Drug: sirolimus combined with chemotherapy in the treatment of recurrent/refractory yolk sac tumor in children

Detailed Description

According to the latest relevant foreign case analysis reports and clinical trial results, the TIP regimen remains the recommended treatment for patients with recurrent and refractory malignant germ-cell tumors based on previous data. Carboplatin has been proven effective and less toxic in children with MGCTs, while cisplatin is more commonly used in early stages. In our research group's previously explored TIC scheme (albumin paclitaxel + ifosfamide + carboplatin), cisplatin is often substituted with carboplatin. Additionally, albumin paclitaxel replaces traditional paclitaxel due to its lower adverse reaction rate and higher tumor tissue uptake accumulation, forming the TIC regimen. Our preliminary clinical work has shown that the TIC regimen effectively improves remission rates of recurrent refractory germ cell tumors, particularly yolk sac tumors. For a small number of children who are not responsive to the TIC regimen, combining Sirolimus (an mTOR inhibitor) significantly enhances remission rates of recurrent refractory yolk sac tumors. This approach can potentially lead to cure or achieve surgery and radiotherapy within a curative timeframe. Therefore, this study aims to determine the efficacy of combining mTOR inhibitor Sirolimus with the TIC chemotherapy regimen (albumin-paclitaxel + isocyclophosphamide + carboplatin) in treating recurrent or refractory vitelline cyst tumors, providing a novel and effective therapeutic option for children with recurrent and refractory MGCTs.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• China
  • Shandong
    • Jinan, Shandong, China, 250117
      • Shandong Cancer Hospital and Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria：

• The pediatric patient is required to present histological confirmation of an extracranial yolk sac tumor.
• At the time of enrollment, the patient must be 18 years of age or younger, with no restrictions based on gender
• The patient must exhibit disease progression following a minimum of two platinum-based chemotherapy regimens or experience a relapse after the completion of treatment
• The patient must have measurable lesions, documented in accordance with the RECIST criteria, or possess an unassessable disease with alpha-fetoprotein (AFP) levels exceeding five times the upper limit of normal
• The Lansky performance status score must be 50 or higher, and the patient's life expectancy should be greater than 12 weeks
• The patient must have fully recovered from any prior adverse effects related to anti-cancer treatments

Exclusion Criteria：

• a history of previous tumors
• organ failure, specifically involving the heart, brain, liver, or kidneys.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: sirolimus combined with chemotherapy treat recurrent/refractory yolk sac tumor in children; This study employed an open single-group clinical laboratory design method (Simon Phase II study) to investigate the efficacy and safety of combining sirolimus with TIC chemotherapy (albumin-paclitaxel + isocyclophosphamide + carboplatin) in the treatment of children with recurrent/refractory vitellocystoma. AFP levels were assessed after each course of treatment, while imaging evaluations were conducted every two courses. The remission rate following chemotherapy in this single-group clinical trial was compared to that reported in the literature for treating recurrent/refractory yolk sac tumor, evaluating overall remission rate (ORR) and progresion-free survival rate (PFS) and overall survival (OS), as well as monitoring and recording chemotherapy-related side effects.

Drug: sirolimus combined with chemotherapy in the treatment of recurrent/refractory yolk sac tumor in children; The planned treatment protocol comprised four cycles of the S-TIC regimen, which included sirolimus administered orally at a dose of 1 mg/m² from day 1 to day 21-28, nab-paclitaxel at a dose of 200 mg/m² on day 1, ifosfamide at a dose of 1200 mg/m² from day 2 to day 5, and carboplatin at a dose of 400 mg/m² on day 2. Additionally, mesna and sulfamethoxazole were prescribed to prevent hemorrhagic cystitis and Pneumocystis Jirovecii Pneumonia (PJP), respectively. Each cycle spanned a duration of three to four weeks. AFP levels were evaluated at the end of each cycle, and radiological assessments were conducted every two cycles. Surgical intervention decisions were made based on the results of these assessments.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR: Objective Response Rate Allocation 'Non-Randomized' implies that this is a multi-arm study, but only one arm has been specified. Objective Response Rate	Each treatment cycle spans 21 to 28 days (equivalent to every 3 to 4 weeks). Provided that the treatment criteria outlined in the study are satisfied, the second and subsequent cycles will commence on either the 22nd or 29th day. In the event of severe drug-related adverse reactions, treatment will be discontinued, and the patient will be classified as having PD. Tumor response assessment will entail the re-evaluation of AFP and LDH levels every cycle, alongside imaging examinations every two cycles. Should AFP levels demonstrate a continuous increase over two consecutive monitoring sessions following the initial treatment cycle, or if imaging results indicate tumor progression, a diagnosis of PD will be made, resulting in the termination of the clinical trial. For pediatric patients whose trials have been terminated, alternative anti-tumor therapies will be administered in accordance with their individual clinical conditions.	Each treatment cycle spans 3 to 4 weeks, 1-4 cycles, last at lest 3 to 16 weeks.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary endpoints included the progression-free survival (PFS) rate, overall survival (OS), and safety profile.	The study employed a Simon's two-stage optimal design with a one-sided alpha of 20% and 95% power to test the null hypothesis of ≤5% objective response rate (ORR) against the alternative hypothesis of ≥20% ORR. In the first stage, 10 patients were enrolled: if ≤1 patient achieved an objective response (CR/PR), the trial would be terminated for futility. Otherwise, enrollment would expand to a total of 32 patients. The regimen would be considered promising if ≥6 objective responses were observed in the final analysis. The median PFS and overall survival (OS) were estimated using the Kaplan-Meier method, implemented through the "survival" and "survminer" packages in R software (version 4.2.2). Correlations between OS and other endpoints were assessed at the patient level using Spearman's rank correlation coefficient (ρ).	After each patient completed the clinical trial, they underwent imaging assessment examinations at 3/6/9/12/18/24/30/36/48/60 months after the end of the treatment.

Collaborators and Investigators

• Sponsor: Shandong First Medical University
• Investigators: Principal Investigator: Jingfu Wang, MD, Shandong Cancer Hospital and Institute

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Actual): January 1, 2024
• Study Completion (Actual): February 1, 2024

Study Registration Dates

• First Submitted: March 26, 2024
• First Submitted That Met QC Criteria: March 26, 2024
• First Posted (Actual): April 2, 2024

Study Record Updates

• Last Update Posted (Estimated): September 19, 2025
• Last Update Submitted That Met QC Criteria: September 14, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: mTOR; sirolimus; germ cell tumor; multiply relapsed or cisplatin refractory yolk sac tumor
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Mesonephroma; Neoplasms, Germ Cell and Embryonal; Endodermal Sinus Tumor; Therapeutics; Drug Therapy
• Other Study ID Numbers: HERO2020

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
• product manufactured in and exported from the U.S.: No