Phase II Multicohort Study of Trabectedin and Low-Dose Radiation Therapy in Advanced/Metastatic Soft Tissue and Bone Sarcomas
- Trial ID
- 2023-509215-81-00
- Protocol
- Geis-75
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase II multicohort trial is to evaluate the **overall response rate (ORR)** in irradiated nodules of patients with advanced or metastatic sarcomas, using the RECIST v1.1 criteria. This is clinically relevant as it assesses the efficacy of the combined treatment of trabectedin and low-dose radiation therapy in targeting specific tumor sites, potentially leading to improved treatment outcomes for patients with these aggressive cancers.
Secondary objectives include:
- Evaluating the overall response rate (ORR) considering all lesions according to RECIST v1.1 criteria.
- Assessing the progression-free survival rate (PFSR) at 6 months for all lesions based on RECIST v1.1 criteria.
- Determining the median progression-free survival (mPFS) for all lesions using RECIST v1.1 criteria.
- Evaluating the time to progression (TTP) of irradiated nodules according to RECIST v1.1 criteria.
- Assessing overall survival (OS).
- Evaluating variations in pain and analgesic use.
- Assessing variations in quality of life.
- Evaluating the safety profile according to CTCAE v5.0.
Participants
The clinical trial involves **adult and young adult patients** aged 16 to 75 years, diagnosed with advanced or metastatic **soft tissue sarcoma**, bone tumors such as osteosarcoma and chondrosarcoma, and small round-cell sarcomas including Ewing's sarcoma, rhabdomyosarcoma, desmoplastic small round-cell tumors, and other small round cell sarcomas. Both male and female participants are included, and the study does not involve a vulnerable population. Participants are required to have measurable disease and must have documented disease progression within six months prior to study entry. They should have been considered eligible for systemic chemotherapy and must have received at least one line of systemic therapy, with a maximum of three previous lines for advanced or metastatic disease, provided trabectedin was not included. The sponsor has not provided information regarding the total number of participants. The selection criteria emphasize adequate respiratory, bone marrow, and cardiac functions, as well as the use of effective contraception for participants of childbearing potential. Lifestyle considerations such as diet and physical activity are not specified in the trial data.
Plans and Procedures
The clinical trial is designed as a **Phase II multicohort study** to evaluate the efficacy of **trabectedin** in combination with low-dose radiation therapy in patients with advanced or metastatic sarcomas. The trial employs a **randomized, double-blind, controlled** methodology to ensure the reliability and validity of the results. The estimated duration of the trial is approximately four years, with recruitment starting in May 2021 and expected completion by May 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as adequate bone marrow function and normal cardiac function. During this visit, informed consent will be obtained, and baseline assessments will be conducted. Following the screening, eligible participants will be enrolled and randomized into treatment cohorts. The trial includes multiple follow-up visits to monitor the participants' response to treatment and assess any adverse events. These visits will occur on day 1 of every cycle until cycle 10, and then every other cycle thereafter. The end-of-study visit will be conducted to perform final assessments and gather data on the primary and secondary endpoints, including overall response rate and progression-free survival.
The expected length of participant involvement is determined by the treatment cycles, with a maximum treatment period of three cycles, each cycle lasting approximately three weeks. Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or withdraw consent. The trial aims to provide comprehensive data on the safety and efficacy of the treatment regimen, contributing valuable insights into the management of advanced or metastatic sarcomas.
Treatment
The clinical trial involves the administration of **Yondelis**, a pharmaceutical product containing the active substance **trabectedin**. Yondelis is formulated as a **powder for concentrate for solution for infusion**. The medication is administered via **intravenous infusion**. The dosage is calculated based on body surface area, with a maximum daily dose of **1.5 mg/m²**. The treatment period is limited to a maximum of three cycles. Trabectedin is a chemically derived substance, and the product is manufactured by Pharma Mar, S.A. The product is authorized under the marketing authorization number EU/1/07/417/002 and is classified under the ATC code L01CX01.
In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on evaluating the efficacy of trabectedin in combination with low-dose radiation therapy in patients with advanced or metastatic sarcomas. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
Efficacy in this clinical trial will be assessed primarily through the **Overall Response Rate (ORR)** in the irradiated nodules, as defined by the RECIST v1.1 criteria. This primary endpoint will be evaluated based on the number of subjects achieving a best overall response of complete response (CR) or partial response (PR) in the irradiated nodules, divided by the number of response-evaluable subjects. The assessment will be conducted through central radiology review, providing a reliable surrogate for palliative relief.
Secondary efficacy endpoints include the ORR considering all lesions, progression-free survival rate (PFSR) at 6 months, median progression-free survival (mPFS), time to progression (TTP) of irradiated nodules, and overall survival (OS). These parameters will also be evaluated according to RECIST v1.1 criteria and based on central radiology review. Additionally, changes in pain will be measured using the Brief Pain Inventory – Short Form (BPI-SF), and variations in quality of life will be assessed using the QLQ-C30 EORTC v3.0 questionnaire. These assessments will occur at specified intervals, including baseline and on day 1 of each treatment cycle, up to cycle 10, and then every other cycle thereafter.
The safety profile will be monitored by evaluating the type, incidence, severity, and timing of adverse events, using CTCAE v5.0 for grading and tabulation. This comprehensive approach ensures a thorough evaluation of both the efficacy and safety of the treatment regimen in patients with advanced or metastatic sarcomas.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow up. For minor patients, the informed consent is required from their parents/tutors according to local laws. Informed consent must be obtained prior to start of the screening process. Procedures conducted as part of the patient’s routine clinical management (e.g. blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol.
- Performance status ≤ 1 (ECOG).
- Adequate respiratory functions: FEV1 > 1L; DLCO > 40% (patients with pulmonary target lesions).
- Adequate bone marrow function (hemoglobin ≥ 9 g/dL, leukocytes ≥ 3,000/mm3, absolute neutrophil count (ANC) ≥ 1,500/mm3, platelets ≥ 100,000/mm3). Patients with creatinine clearance (based on Cockroft and Gault) ≥30 ml/min, albumin ≥ 25 g/L, ALT and AST ≤ 2.5 times the ULN, total bilirubin ≤ ULN, CPK ≤ 2.5 times ULN, alkaline phosphatase ≤ 2.5 times the ULN are acceptable. If the increase of alkaline phosphatase is > 2.5 times the ULN, then the alkaline phosphatase liver fraction and/or GGT must be ≤ ULN.
- Men or women of childbearing potential must use an effective method of contraception before entry into the study, throughout the trial treatment and for 5 months in men and 8 months in women after the last dose of trabectedin. Women of childbearing potential must have a negative urine pregnancy test before study entry.
- Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.
- HBV and HCV serologies must be performed prior to enrollment. If HbsAg is positive it is recommended to reject the existence of replicative phase (HbaAg+, DNA VHB+). If these were positives the inclusion is not recommended, remaining at investigators' discretion the preventive treatment with lamivudine. If a potential patient is positive for anti-HCV antibodies, presence of the virus should be ruled out with a qualitative PCR, or the patient should NOT be included in the study (if a qualitative PCR cannot be performed then patient will not be able to enter the study)
- Patient must have a central venous catheter for treatment, required for trabectedin administration.
- Age: 16-75 years for cohorts A, B, and C. For cohort D, allowed age is 10-75 years.
- Patients must have a diagnosis of soft tissue sarcoma (cohort A), bone tumors (osteosarcoma, chondrosarcoma) (cohort B) or small round-cell sarcomas (Ewing’s sarcoma, rhabdomyosarcoma, desmoplastic small round-cell tumors and other small round-cell sarcomas) (cohort C) or small round-cell sarcomas (Ewing’s sarcoma, rhabdomyosarcoma, desmoplastic small round-cell tumors and undifferentiated small round-cell sarcomas) (cohort D), with metastasis or locally advanced disease, and not suitable for metastasectomy or surgical resection or not oncologically recommended metastasectomy. A centralized diagnosis will be performed, and the central diagnosis confirmation will be mandatory prior to enrollment (tumor sample must be available and sent during screening).
- Disease distribution allows meeting with normal tissue constraints of radiation therapy. Radiation oncologist must confirm this point, taking into account that the dose for extremities will be 45 Gy while for non-extremity will be 30 Gy.
- Those lesions considered for radiation therapy must be related with a clinically relevant symptom. It is not necessary to irradiate all the lesions within one organ. Irradiating pulmonary lesions with infiltration of pleural serosa should be discouraged.
- Patients must have documentation of disease progression within 6 months prior to study entry.
- The patient must have been considered eligible for systemic chemotherapy. Patients should have received at least one line of systemic therapy (anthracycline-based in the case of Cohort A- STS, unless the patient is not candidate for treatment with anthracyclines), with a maximum of three previous lines for advanced/metastatic disease are allowed as long as trabectedin has not been included (all cohorts), nor irinotecan (cohort D only).
- Measurable disease, according to RECIST v1.1 criteria.
Exclusion Criteria
- Previous treatment with trabectedin (all cohorts) or irinotecan (cohort D) or radiotherapy (this latter just in case the previous radiotherapy treatment does not allow the radiotherapy treatment of this study due to tissue constrains).
- Liver inclusion in irradiation fields is not permitted, not even partially.
- Normal tissue constrains for radiation therapy.
- Performance status ≥ 2 (ECOG).
- Plasma bilirubin > ULN.
- Creatinine clearance <30ml/min.
- History of other neoplastic disease with the exception of basal cell carcinoma or in situ cervical cancer adequately treated or no evidence of recurrence for more than 5 years after primary tumor treatment.
- Severe chronic obstructive pulmonary disease (COPD) or other severe pulmonary diseases.
- Significant cardiovascular disease (for example, dyspnea > 2 NYHA).
- Significant systemic diseases grade 3 or higher on the NCI-CTCAE v5.0 scale, that limit patient availability, or according to investigator judgment may contribute significantly to treatment toxicity.
- Uncontrolled bacterial, mycotic or viral infections.
- Known positive test for infection by human immunodeficiency virus (HIV).
- Women who are pregnant or breast-feeding.
- Psychological, familiar, social or geographic circumstances that limit the patient’s ability to comply with the protocol or informed consent.
- Patients who have participated in another clinical trial and/or have received any other investigational product in the last 30 days prior to enrollment.
- Histologies other than those described in inclusion criteria.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 25 May 2021 | 92 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Irinotecán Hospira 20 mg/mL concentrado para solución para perfusión EFG. | Test | CONCENTRADO PARA SOLUCIÓN PARA PERFUSIÓN | SOLUTION FOR INFUSION | 25 | 12 | PRD1165400 |
Yondelis 1 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1.5 | 3 | PRD343315 |