Multicentre, randomized, open label study comparing the concomitant administration of trabectedin and low-dose radiotherapy versus trabectedin alone in patients with advanced sarcoma

Prior treatment

• Previous treatment with trabectedin/lurbinectedin or radiotherapy (this latter just in case the previous radiotherapy treatment does not allow the radiotherapy treatment of this study due to tissue constraints).
• Liver inclusion in irradiation fields should be avoided; however, partial inclusion is permitted provided that all dose constraints are strictly met.

Other illness

• History of other neoplastic diseases except for 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 pulmonary, cardiovascular (dyspnea > 2 NYHA) or 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).

Lab values

• Plasma bilirubin > ULN
• Creatinine clearance <30ml/min.

Other

• Women who are pregnant or breast-feeding.
• Those women who are not intended to follow the contraceptive guidelines outlined in the protocol.
• Psychological, familial, social, or geographic circumstances that limit the patient's ability to comply with the protocol or informed consent
• Performance status ≥ 2 (ECOG).

• Patients must provide written informed consent before the performance of study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained before the 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 before the signature of informed consent may be used for screening or baseline purposes if these procedures are conducted as specified in the protocol.
• Adequate bone marrow function (hemoglobin ≥ 9g/dL, leukocytes ≥ 3,000/mm3, absolute neutrophil count (ANC) ≥ 1,500/mm3, platelets ≥ 100,000/mm3). Patients with estimated creatinine clearance (based on Cockroft and Gault) ≥ 30 ml/min, albumin ≥ 25g/dL, 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 6 months after the last dose of trabectedin. Women of childbearing potential must have a negative urine pregnancy test before study entry
• Normal cardiac function with an LVEF ≥ 50% by echocardiogram or MUGA.
• HBV and HCV serologies must be performed before enrolment. If HbsAg is positive, it is recommended to reject the existence of a replicative phase (HbaAg+, DNA VHB+). If these were positives, the inclusion is not recommended, remaining at investigators' discretion about the preventive treatment with lamivudine. If a potential patient is positive for anti-HCV antibodies, the 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 the patient will not be able to enter the study).
• The patient must have a central venous catheter (preferable port-a-cath instead of Peripherally Inserted Central Catheters (PICC) for treatment, required for trabectedin/lurbinectedin administration
• Age: 16-75 years old
• Patients must have a diagnosis of STS (excluding GIST, Clear Cell Sarcoma, Alveolar Soft Part Sarcomas (ASPS), Extraskeletal Myxoid Chondrosarcoma, Epithelioid Haemangioendothelioma, Solitary Fibrous Tumors, extraskeletal Ewing sarcoma and other uncommon STS subtypes for which chemotherapy is not usually recommended), 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 before enrolment. Therefore, a representative tumor sample (FFPE block) must be available and sent to the central laboratory during the screening period.
• Disease distribution allows meeting with normal tissue constraints of radiation therapy. Radiation oncologists must confirm this point, considering that the dose for extremities and limb girdles will be 45Gy while for non-extremity will be 30Gy.
• Disease progression within 6 months before 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, unless the patient is not a candidate for treatment with anthracyclines), with a maximum of three previous lines for advanced/metastatic disease are allowed if trabectedin/lurbinectedin has not been included.
• Measurable disease, according to RECIST v1.1 criteria.
• Performance status ≤ 1 (ECOG).
• Adequate respiratory functions: FEV1 > 1L; DLCO > 40% (patients with pulmonary target lesions).