Open trials

Inclusion criteria Cohort A

• The patient must voluntarily sign the informed consent form before any study test is conducted that is not part of routine patient care.
• Age ≥18 years old.
• Patients must have a diagnostic of Soft Tissue Sarcoma with metastasis limited to lung, and not suitable for metastasectomy or surgery resection or not oncologically recommended metastasectomy. A central diagnosis will be performed, the tumor sample must be available and sent prior to inclusion.
• Disease distribution allows meeting with normal tissue constraints of radiation therapy. Radiation oncologist must confirm this point.
• Metastatic spread could be present in two organs at maximum (i.e. lungs and pelvic fosa).
• Those lesions considered for radiation therapy have to be considered as target lesions as well. (i.e. in a patient with nodules in lungs, those lesions selected for radiation therapy have to include at least the target lesions).
• It is allowed that not all the lesions will be under radiation fields. As a general rule, it will be prioritized to select, as target-irradiating lesions, those with greater increase in size and those largest lesions. It should be discouraged to irradiate pulmonary lesions with infiltration of pleural serosa.
• Patients must have documentation of disease progression within 6 months prior to study entry.
• The patient must have been considered eligible for systemic chemotherapy. A maximum of two previous lines for advanced/metastatic disease are allowed as long as trabectedin has not been included.
• The following histological subtypes can be included:
  • Undifferentiated pleomorphic sarcoma (previously, malignant fibrous histiocytoma)
  • Leiomyosarcoma
  • Angiosarcoma/ epithelial hemangioendothelioma
  • Liposarcoma and its variants (well differentiated, dedifferentiated, myxoid/round cells, pleomorphic)
  • Synovial sarcoma
  • Fibrosarcoma and its variants (epithelial fibrosarcoma/low grade fibromyxoid sarcoma).
  • Hemangiopericytoma/solitary fibroid tumor.
  • Neurogenic sarcoma (Malignant peripheral nerve sheath tumor, MPNST).
  • Myxofibrosarcoma.
  • Epithelioid Sarcoma.
  • Unclassified sarcoma (spindle cell/epithelioid/pleomorphic/myxoid).
• Measurable disease, according to RECIST V 1.1 criteria
• Performance status ≤1 (ECOG).
• Adequate respiratory functions: FEV1 >1L, DLCO>40% (patients with pulmonary target lesions).
• Adequate bone marrow function (hemoglobin > 10 g/dl, leukocytes ≥ 3.000/mm3, neutrophils ≥ 1.500/mm3, platelets ≥ 100.000/mm3). Patients with plasma creatinine ≤ 1,6 mg/dl, transaminases ≤ 2.5 times the UNL, total bilirubin ≤ UNL, CPK ≤ 2.5 times UNL, alkaline phosphatase ≤ 2.5 times the UNL are acceptable. If the increase of alkaline phosphatase is > 2.5 times the UNL, then the alkaline phosphatase liver fraction and/or GGT must be ≤ UNL.
• Men or women of child bearing potential should be using an effective method of contraception before entry into the study and throughout the same and for 6 months after ending the study. 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.
• It should be performed HBV and HCV serologies prior to inclusion. 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.

Exclusion criteria Cohort A

• Previous treatment with trabectedin or previous treatment with radiotherapy (except if previous radiotherapy treatment plus planned study radiotherapy treatment allow tissues constrains.
• Performance status ≥2 (ECOG).
• Metastases out of those located in lungs.
• Plasma bilirubin > UNL.
• Creatinine > 1.6 mg/dL.
• History of other neoplastic disease with less than 5 years free of disease with the exception of basal cell carcinoma or in situ cervical cancer adequately treated.
• Severe 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 v4.03 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, familial, social or geographic circumstances that limit the patient's ability to comply with the protocol or informed consent.
• Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion.
• Histologies other than those described in inclusion criteria.

Inclusion criteria Cohort B

• The patient must voluntarily sign the informed consent form before any study test is conducted that is not part of routine patient care.
• Age ≥18 years old.
• Pathological diagnosis of Myxoid Liposarcoma, deep located and more than 5 cm or superficial more than 10 cm. A centralised diagnostic will be performed to confirm that patient can be included in the study.
• Tumor must be resectable and without evidence of regional or distal spread after adequate staging procedure. Tumor must be located in limbs or superficial trunk wall.
• Disease distribution allows meeting with normal tissue constraints of radiation therapy. Radiation oncologist must confirm this point.
• Measurable disease, according to RECIST V 1.1 criteria.
• Performance status 0-1 (ECOG).
• Adequate bone marrow function (hemoglobin > 10 g/dL, leukocytes ≥ 3.000/mm3, neutrophils ≥ 1.500/mm3, platelets ≥ 100.000/mm3). Patients with plasma creatinine ≤ 1,6 mg/dL, transaminases ≤ 2.5 times the UNL, total bilirubin ≤ UNL, CPK ≤ 2.5 times UNL, alkaline phosphatase ≤ 2.5 times the UNL are acceptable. If the increase of alkaline phosphatase is > 2.5 times the UNL, then the alkaline phosphatase liver fraction and/or GGT must be ≤ UNL.
• Men or women of child bearing potential should be using an effective method of contraception before entry into the study and throughout the same and for 6 months after ending the study. 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.
• It should be performed HBV and HCV serologies prior to inclusion. If HbsAg is positive it is recommended to reject the existence of replicative phase (HbaAg+, DNA HBV+). 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 may have had one previous chemotherapy line.
• Patient must have a Central Venous Catheter for treatment.

Exclusion criteria Cohort B

• Unresectable tumors (with limb sparing surgery).
• More than one previous chemotherapy treatment for local disease including trabectedin.
• Radiotherapy involving the tumoral bed.
• Performance status ≥ 2 (ECOG).
• Presence of metastases or lymph node involvement by the tumor.
• Location other than limb or superficial trunk wall.
• Plasma bilirubin > UNL.
• Creatinine > 1.6 mg/dL.
• History of other neoplastic disease with less than 5 years free of disease with the exception of basal cell carcinoma or in situ cervical cancer adequately treated.
• Significant cardiovascular disease (for example, dyspnea > 2 NYHA)
• Significant systemic diseases grade 3 or higher on the NCI-CTCAE v4.03 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, familial, social or geographic circumstances that limit the patient's ability to comply with the protocol or informed consent.
• Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion.

Inclusion criteria Cohorts C and D

• 1. The patient must voluntarily sign the informed consent form before performing any study-specific test that is not part of the patient's usual care.
• 2. Aged between 18 and 75 years.
• 3. The following histological subtypes may be included in cohort C: High grade leiomyosarcoma (G2-3), liposarcoma, if at least 30% of the tumour is dedifferentiated in radiologic study, pleomorphic liposarcoma. The percutaneous core biopsy should be done in the dedifferentiation component described in the CT scan. The following histological subtypes may be included in cohort D: well differentiated liposarcoma with cellular subvariant (WD liposarcoma G1) and dedifferentiated liposarcorcoma G2 (with less than 30% dedifferentiated component). A centralised diagnosis will be made to confirm that the patient can be included in the study. This point must be confirmed by the central surgeon reviewer.
• 4. The tumour must be located in the retroperitoneum and it must be resectable and without evidence of regional or distal spread after the appropriate staging process.
• 5. The location and size of the disease in the retroperitoneum must allow for compliance with radiotherapy limitations in healthy tissue. This point must be confirmed by the site's radiation oncologist and the central radiation oncologist reviewer.
• 6. Measurable disease according to CHOI criteria for cohort C and RECIST V 1.1 criteria for cohort D.
• 7. ECOG performance status 0–1.
• 8. Adequate haematological parameters (haemoglobin >10 g/dl, leukocytes ≥3,000/mm3, neutrophils ≥1,500/mm3, platelets ≥100,000/mm3). Patients with plasma creatinine ≤1.6 mg/dl, transaminases ≤2.5 times the ULN, total bilirubin ≤ ULN, CPK ≤2.5 times ULN, alkaline phosphatase ≤2.5 times ULN are acceptable. If the increase in alkaline phosphatase is >2.5 times the ULN, the liver fraction of alkaline phosphatase and/or GGT should be ≤ULN.
• 9. Fertile men or women must use an effective contraceptive method before starting the study, during the study and for 6 months following the conclusion thereof. Women of childbearing potential who participate in the study must undergo a pregnancy test before starting the study.
• 10. Normal cardiac function with LVEF ≥50% by echocardiogram or MUGA.
• 11. HBV and HCV serology must be performed before including the patient in the study. If HbsAg is positive, it is advisable to rule out a replicative phase (HbsAg*, DNA HBV+). If positive, the patient's inclusion in the trial is not recommended, and it is at the discretion of the investigator to administer preventive treatment with lamivudine. If a potential patient is positive to anti-HCV antibodies, the presence of the virus will be ruled out with a qualitative PCR, or the patient cannot be included in the study (if the qualitative PCR test cannot be performed on the patient, they cannot be included in the study).
• 12. Patient may have had one previous chemotherapy line (cohort D only).
• 13. The patient must have a central venous catheter for the administration of the treatment.

Exclusion criteria Cohorts C and D

• 1. Unresectable tumours.
• 2. Location other than the retroperitoneum.
• 3. Patients who have previously received systemic treatment with chemotherapy (trabectedin included). For cohort D, may have received one previous line of chemotherapy with any other agent.
• 4. Patients who underwent prior local treatment for RS: surgery or radiotherapy in the tumour bed.
• 5. ECOG performance status ≥2.
• 6. Presence of metastasis or lymph node involvement of the tumour.
• 7. Previous history of another neoplastic disease with less than 5 years free of disease except for basal cell carcinoma or properly treated in situ cervical cancer.
• 8. Significant cardiovascular disease (e.g. dyspnoea >2 NYHA).
• 9. A significant grade 3 or greater systemic disease on the NCI-CTCAE v4.03 scale, which may limit the availability of the patient or which, in the opinion of the investigator, may contribute to the toxicity caused by the study treatment.
• 10. Uncontrolled viral, mycotic or bacterial infections.
• 11. Known HIV-positive patients.
• 12. Pregnant or breast-feeding women.
• 13. Psychological, familial, social or geographical circumstances that limit the patient's ability to comply with the protocol or informed consent form.
• 14. Patients who have participated in another clinical trial and/or have received another investigational product in the 30 days prior to inclusion in the trial.

Participating Centers

1. Hospital Son Espases, Mallorca-Dr Pablo Luna
2. Hospital Puerta de Hierro, Madrid- Dr Ricardo Cubedo
3. Hospital Canarias, San Cristóbal de la Laguna- Dr Josefina Cruz
4. Hospital Miguel Servet, Zaragoza- Dr Javier Martínez Trufero
5. Hospital Virgen del Rocío, Sevilla- Dr Irene Carrasco
6. Hospital Vall d´Hebron, Barcelona- Dr Claudia Valverde
7. Hospital La Paz, Madrid- Dr Andrés Redondo
8. Hospital Gregorio Marañón, Madrid- Dr Rosa Álvarez
9. Hospital de la Santa Creu i Sant Pau, Barcelona- Dr Antonio López Pousa
10. Istituto Nazionale dei Tumori, Milano- Dr Alessandro Gronchi
11. Istituto di Candiolo-IRCC, Candiolo- Dr Giovanni Grignani
12. Centro di Referimento Oncologico, Aviano- Dra Angela Buonadonna
13. Institut Bergonié, Bordeaux-Dr Antoine Italiano
14. Claude Bernard, Lyon- Dr Jean-Yves Blay
15. Hospital Universitario Fundación Jiménez Díaz, Madrid- Dr Javier Martín Broto

Enrolment status Cohort A & B

Recruitment closed

Enrolment status Cohort C

Recruitment open

Enrolment status Cohort D

Recruitment open

Inclusion criteria

Patients must meet all of the following inclusion criteria to be eligible to enroll in this study:
• 1. Patients must provide written informed consent prior to performance of any study-specific procedures and must be willing to comply with treatment and follow-up. 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.), 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.
• 2. Age: 18-80 years.
• 3. Histologic diagnosis of soft tissue sarcoma (undifferentiated pleomorphic sarcoma, leiomyosarcoma, alveolar soft part sarcoma, malignant peripheral nerve sheath tumor) confirmed by central pathology review prior to enrolment with an archive tumor sample. A fresh paraffin embedded tumor tissue block must be provided for all subjects for biomarker analysis before and (when feasible) after treatment with investigational products.
• 4. Metastatic/advanced disease in progression in the last 6 months.
• 5. Patients have received at least one previous line of systemic therapy.
• 6. Measurable disease according to RECIST 1.1 criteria.
• 7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• 8. Adequate hepatic, renal, cardiac, and hematologic function.
• 9. Laboratory tests as follows:
  • Absolute neutrophil count ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Bilirubin ≤ 1.5 mg/dL
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine ≥ 1.5 mg/dL
• 10. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.
• 11. Females of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to enrollment and agree to use birth control measures during study treatment and for 3 months after its completion. Patients must not be pregnant or nursing at study entry. Women/men of reproductive potential must have agreed to use an effective contraceptive method.

Exclusion criteria

Patients meeting any of the following exclusion criteria are not eligible to enroll in this study:
• 1. Three or more systemic treatment lines (including both chemotherapy and targeted therapy) for advanced disease (localized unresectable or metastatic).
• 2. systemic treatment lines (including both chemotherapy and targeted therapy) for advanced disease (localized unresectable or metastatic).
• 3. Prior malignancy that required treatment or has shown evidence of recurrence (except for non-melanoma skin cancer, adequately treated cervical carcinoma in situ, superficial bladder carcinoma) during the 5 years prior to randomization. Cancer treated with curative intent for >5 years previously and without evidence of recurrence will be allowed.
• 4. Prior selinexor or another XPO1 inhibitor treatment.
• 5. Administration of a previous gemcitabine-containing treatment.
• 6. Any concurrent medical condition or disease (e.g. uncontrolled active hypertension, uncontrolled active diabetes, active systemic infection, etc.) that is likely to interfere with study procedures.
• 7. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to Cycle 1 Day 1 (C1D1). Patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 are acceptable.
• 8. Pregnant or breastfeeding females.
• 9. Body surface area (BSA)
• 10. Life expectancy of less than 3 months.
• 11. Major surgery within 4 weeks prior to C1D1.
• 12. Any active gastrointestinal dysfunction interfering with the patient’s ability to swallow tablets, or dysfunction that could interfere with absorption of study treatment.
• 13. Inability or unwillingness to take supportive medications such as anti-nausea and anti-anorexia agents as recommended by the NCCN CPGO for antiemesis and anorexia/cachexia (palliative care).
• 11. Any active, serious psychiatric, medical, or other conditions/situations that, in the opinion of the Investigator, could interfere with treatment, compliance, or the ability to give informed consent.
• 12. Presence of brain or central nervous system metastases, unless they are controlled (patients with treated and stable metastasis are eligible).

Participating centers

• 1. Hospital Clínico San Carlos, Madrid
• 2. Hospital Universitario La Paz, Madrid
• 3. Hospital Universitario Miguel Servet, Zaragoza
• 4. Hospital Universitario Vall d'Hebron, Barcelona
• 5. Hospital Universitario Fundación Jiménez Díaz, Madrid
• 6. Hospital de la Santa Creu i Sant Pau, Barcelona
• 7. Hospital General Universitario Gregorio Marañón, Madrid
• 8. Onkologikoa, Donostia
• 9. Hospital Universitario de Canarias, San Cristóbal de La Laguna
• 10. ICO Hospitalet, L'Hospitalet de Llobregat (Barcelona)
• 11. Hospital Universitario Virgen de la Arrixaca, Murcia

Current recruitment status

Open.

Inclusion criteria Cohorts 1-6. STAGE 1

• 1. Patients (or legal tutors) must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. 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.
• 2. Age: 12-80 years.
• 3. Diagnosis of soft tissue sarcoma (undifferentiated pleomorphic sarcoma, synovial sarcoma, alveolar soft part sarcoma, clear cell sarcoma, angiosarcoma, epithelioid hemangioendothelioma, solitary fibrous tumor,epithelioid sarcoma and extraskeletal myxoid chondrosarcoma) or bone sarcoma (osteosarcoma/high grade bone sarcoma, Ewing’s sarcoma, chondrosarcoma and dedifferentiated chondrosarcoma) confirmed by central pathology review. Mandatory paraffin embedded tumor blocks must be provided for all subjects without exception for biomarker analysis before treatment (first biopsy) and at end of month 3 or earlier (second biopsy).
• 4. Metastatic/advanced disease in progression in the last 6 months.
• 5. Measurable disease according to RECIST 1.1 criteria.
• 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• 7. Adequate hepatic, renal, cardiac, and hematologic function.
• 8. Laboratory tests as follows:
  • Absolute neutrophil count ≥ 1,200/mm³
  • Platelet count ≥ 100,000/mm³
  • Bilirubin ≤ 1.5 mg/dL
  • PT and INR ≤ 1.5 in the absence of anticoagulant therapy
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine ≤ 1.5 mg/dL (or Cr clearance ≥ 60 ml/min)
  • Calcium ≤ 12 mg/dL
• 9. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.
• 10. Females of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to enrollment and agree to use birth control measures during study treatment and for 7 months after its completion. Patients must not be pregnant or nursing at study entry. Women/men of reproductive potential must have agreed to use an effective contraceptive method.

Inclusion criteria Cohorts 1-6. STAGE 2

• 1. Patients (or legal tutors) must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. 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.
• 2. Age: 12-80 years.
• 3. Diagnosis of dedifferentiated chondrosarcoma, extraskeletal myxoid chondrosarcoma, vascular sarcomas (including angiosarcoma, hemangioendothelioma and intimal sarcomas), solitary fibrous tumor (excluding dedifferentiated SFT), alveolar soft part sarcoma, and clear cell sarcoma confirmed by central pathology review.
• 4. Mandatory paraffin embedded tumor blocks must be provided for all subjects without exception for biomarker analysis before treatment.
• 5. Metastatic/locally advanced unresectable disease in progression in the last 6 months according to RECIST 1.1. Patients with recent diagnosis of metastatic disease can be eligible (if they are not candidates to anthracycline-based treatment).
• 6. Patients should have previously received at least anthracyclines. Patients in the cohorts of subtypes sensitive to antiangiogenic therapy (SFT, ASPS, CCS, EMC or DDCS) are eligible even if not previously treated.
• 7. Previous therapy with antiangiogenics is allowed.
• 8. Measurable disease according to RECIST 1.1 criteria.
• 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• 10. Adequate hepatic, renal, cardiac, and hematologic function.
• 11. Laboratory tests as follows:
  • Absolute neutrophil count ≥ 1,200/mm³
  • Platelet count ≥ 100,000/mm³
  • Bilirubin ≤ 1.5 mg/dL
  • PT and INR ≤ 1.5 in the absence of anticoagulant therapy
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine ≤ 1.5 mg/dL (or Cr clearance ≥ 60 ml/min)
  • Calcium ≤ 12 mg/dL
• 12. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.
• 13. Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment and agree to use birth control measures during study treatment and for 6 months after its completion. Patients must not be pregnant or nursing at study entry. Women/men of reproductive potential must have agreed to use an effective contraceptive method.

Inclusion criteria Cohort 7

• 1. The patient or his/her legal tutors must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of 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.
• 2. Age: 18-80 years.
• 3. Diagnosis of advanced/metastatic undifferentiated pleomorphic sarcoma (UPS) (cohort 7a) or leiomyosarcoma (LMS) (cohort 7B) confirmed by central pathology review.
• 4. Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue must be provided for all subjects without exception for central pathology review and the translational study. Archive tissue can be used for diagnosis confirmation but a recent biopsy (
• 5. Measurable disease according to RECIST 1.1 criteria.
• 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• 7. The patient must be naïve of any previous treatment with anthracyclines (not even in adjuvant chemotherapy).
• 8. Adequate organ, hepatic, renal, cardiac, and hematologic function.
• 9. Laboratory tests as follows:
  • Absolute neutrophil count ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Bilirubin ≤ 9 mg/dL
  • PT and INR ≤ 1.5
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 60 mL/min)
  • Blood glucose;
• 10. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.
• 11. Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment. Patients must not be pregnant or nursing at study entry.
• 12. Women/men of reproductive potential must have agreed to use an effective contraceptive method during study treatment and for 6 months after the last dose of study drug.

Inclusion criteria Cohort 8

• 1. The patient or his/her legal tutors must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of 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.
• 2. Age: 12-40 years.
• 3. Diagnosis of resectable primary metastatic high-grade osteosarcoma confirmed by central pathology review. Resection of primary tumor +/- metastatic disease has to be feasible and planned.
• 4. Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue must be provided for all subjects without exception for central pathology review and the translational study. The patient must be willing to have a pre-treatment re-biopsy of primary or metastatic tumor (baseline biopsy) within 28 days prior to enrollment if diagnosis biopsy does not have enough remaining tissue for translational purposes.
• 5. Measurable disease according to RECIST 1.1 criteria.
• 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• 7. The patient must be naïve of any previous treatment.
• 8. Adequate organ, hepatic, renal, cardiac, and hematologic function.
• 9. Laboratory tests as follows:
  • Absolute neutrophil count ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • Hg > 9g/dL
  • Bilirubin ≤ 1.5 mg/dL
  • PT and INR ≤ 1.5
  • AST and ALT ≤ 2.5 times upper limit of normal
  • Creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 60 mL/min)
  • Blood glucose;
• 10. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.
• 11. Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment. Patients must not be pregnant or nursing at study entry.
• 12. Women/men of reproductive potential must have agreed to use an effective contraceptive method during study treatment and for 6 months after the last dose of study drug.

Exclusion criteria Cohorts 1-6. STAGE 1

• 1. Four or more previous lines of chemotherapy for advanced disease.
• 2. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
• 3. Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.).
• 4. Active, known or suspected autoimmune disease.
• 5. A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• 6. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI-CTCAE] version 4.0 Grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= Grade 3).
• 7. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
• 8. Other disease or illness within the past 6 months, including any of the following: - Myocardial infarction - Severe or unstable angina - Coronary or peripheral artery bypass graft - Symptomatic congestive heart failure - Cerebrovascular accident or transient ischemic attack - Pulmonary embolism.
• 9. Evidence of a bleeding diathesis.
• 10. Ongoing cardiac dysrhythmias > Grade 2.
• 11. Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg despite optimal medical therapy.
• 12. Psychiatric illness or social situation that would preclude study compliance.
• 13. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.
• 14. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
• 15. Hemorrhage ≥ Grade 3 in the past 4 weeks.
• 16. History of allergy to study drug components.
• 17. Previous anticoagulants due to thrombotic events.
• 18. History of another cancer with the exception of adequately treated basal cell carcinoma or cervical cancer in situ.
• 17. Presence of brain or central nervous system metastases.

Exclusion criteria Cohorts 1-6. STAGE 2

• 1. Four or more previous lines of chemotherapy.
• 2. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
• 3. Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.).
• 4. Active, known or suspected autoimmune disease.
• 5. A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• 6. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI-CTCAE] version 4.0 Grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= Grade 3).
• 7. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
• 8. Other disease or illness within the past 12 months, including any of the following: - Myocardial infarction - Severe or unstable angina - Coronary or peripheral artery bypass graft - Symptomatic congestive heart failure - Cerebrovascular accident or transient ischemic attack - Pulmonary embolism.
• 9. Evidence of a bleeding diathesis.
• 10. Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg despite optimal medical therapy.
• 11. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.
• 12. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
• 13. Hemorrhage ≥ Grade 3 in the past 4 weeks.
• 14. History of allergy to study drug components.
• 15. Anticoagulants due to thrombotic events, with the exception of deep venous thrombosis in limbs, with a stable dose of low-weigh heparine and in the absence of secondary hemorrages.
• 16. History of another cancer in the previous 5 years with the exception of adequately treated squamous or basal cell carcinoma of the skin or cervical cancer in situ.
• 17. Presence of brain or central nervous system metastases, unless they are controlled (completely resected or irradiated and/or asympthomatic, no need of steroids).
• 18. Unwilling to participate in the translational study (not providing mandatory biopsies at baseline).
• 19. Live vaccine 30 days or fewer prior to enrollment.

Exclusion criteria Cohort 7

• 1. Diagnosis of any sarcoma different from undifferentiated pleomorphic sarcoma and leiomyosarcoma.
• 2. Previous treatment with anthracyclines or any other systemic therapy for advanced sarcoma. The exception is hormone therapy or previous systemic therapy for a previous neoplasm (see exclusion criteria number 13), if this is controlled as long as previous therapy did not include anthracyclines. Adjuvant therapy not containing anthracyclines (eg: gemcitabine-docetaxel) is allowed.
• 3. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
• 4. Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.).
• 5. Active, known or suspected autoimmune disease.
• 6. A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• 7. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI-CTCAE] version 5.0 Grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= Grade 3).
• 8. HBV and HCV serologies must be preformed prior to inclusion. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection is not allowed.
• 9. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.
• 10. Any of the following diseases/illnesses within the previous 6 months:
  • Myocardial infarction.
  • Severe or unstable angina.
  • Coronary or peripheral artery bypass graft.
  • Symptomatic congestive heart failure.
  • Cerebrovascular accident or transient ischemic attack (TIA).
  • Pulmonary embolism.
  • Evidence of a bleeding diathesis.
  • Ongoing cardiac dysrhythmias > Grade 2.
• 11. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
• 12. History of allergy to study drug components.
• 13. History of another cancer with the exception of adequately treated basal cell carcinoma or in situ cervical cancer, or with a relapse-free interval longer than 3 years after treatment of the primary cancer with no substantial risk of recurrence.
• 14. Presence of brain or central nervous system metastases at the time of enrollment, unless they are controlled (completely resected or irradiated and/or asympthomatic, no need of steroids).
• 15. Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily taken.

Exclusion criteria Cohort 8

• 1. Diagnosis of parosteal, periosteal osteosarcoma or any other bone sarcoma.
• 2. Previous systemic therapy.
• 3. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
• 4. Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.).
• 5. Active, known or suspected autoimmune disease.
• 6. A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• 7. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI-CTCAE] version 5.0 Grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= Grade 3).
• 8. HBV and HCV serologies must be preformed prior to inclusion. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection is not allowed.
• 9. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.
• 10. Any of the following diseases/illnesses within the previous 6 months:
  • Myocardial infarction.
  • Severe or unstable angina.
  • Coronary or peripheral artery bypass graft.
  • Symptomatic congestive heart failure.
  • Cerebrovascular accident or transient ischemic attack (TIA).
  • Pulmonary embolism.
  • Evidence of a bleeding diathesis.
  • Ongoing cardiac dysrhythmias > Grade 2.
• 11. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
• 12. History of allergy to study drug components.
• 13. History of another cancer with the exception of adequately treated basal cell carcinoma or in situ cervical cancer, or with a relapse-free interval longer than 3 years after treatment of the primary cancer with no substantial risk of recurrence.
• 14. Presence of brain or central nervous system metastases at the time of enrollment, unless they are controlled (completely resected or irradiated and/or asympthomatic, no need of steroids).
• 15. Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot easily be taken.

Participating centers

• Hospital Univ. Virgen del Rocío, Sevilla
• Hospital Univ. Vall d'Hebron, Barcelona
• Hospital de la Santa Creu i Sant Pau, Barcelona
• Hospital Univ. 12 de Octubre, Madrid
• Hospital Univ. La Paz, Madrid
• Hospital Universitari i Politecnic La Fe, Valencia
• Hospital Univ. Miguel Servet, Zaragoza
• Hospital Universitario de Canarias, San Cistóbal de La Laguna (Sta. Cruz de Tenerife)
• Hospital Univ. Fundación Jiménez Díaz, Madrid

Enrolment status

• Recruiting
Updated in March 2023.

Inclusion criteria (Phase I)

• 1. The patient must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. 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.
• 2. Age ≥ 18 years.
• 3. Diagnosis of advanced/metastatic soft tissue sarcoma (undifferentiated pleomorphic sarcoma, leiomyosarcoma, myxoid and hypercellular myxoid liposarcoma, myxofibrosarcoma, NOS sarcoma, synovial sarcoma, fibrosarcoma, or malignant nerve sheath tumor) confirmed by central pathology review.
• 4. Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue must be provided for all subjects without exception for central pathology review and the translational study. If archive biopsy is not available or is older than 3 months, the patient must be willing to have a pre-treatment re-biopsy of primary or metastatic tumor (baseline biopsy) within 28 days prior to enrollment.
• 5. The patient must be willing to undergo a second mandatory biopsy just before the initiation of the 3rd cycle and agree that this sample is used for the translational study.
• 6. Measurable disease according to RECIST v1.1 criteria.
• 7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• 8. The patient must be naïve of any previous treatment with anthracyclines (not even in adjuvant chemotherapy).
• 9. Adequate organ, hepatic, renal, cardiac, and hematologic function.
• 10. Laboratory tests as follows:
  1. Absolute neutrophil count ≥ 1,200/mm³
  2. Platelet count ≥ 100,000/mm³
  3. Hg > 9 g/dL
  4. Bilirubin ≤ 1.5 mg/dL
  5. PT and INR ≤ 1.5
  6. AST and ALT ≤ 2.5 times ULN
  7. Creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 60 mL/min
  8. Blood glucose < 150 mg/dL
• 11. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.
• 12. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment. Patients must not be pregnant or nursing at study entry.
• 13. Women and men of reproductive potential must have agreed to use an effective contraceptive method during study treatment and for 3 months after the last dose of study drug.

Exclusion criteria (Phase I)

• 1. Diagnosis different from the elegible histological subtypes.
• 2. Previous treatment with doxorubicin, epirubicin, idarubicin, and/or other anthracyclines or any other systemic therapy. The exception is previous systemic therapy for a previous neoplasm (see exclusion criteria 10), if this is controlled, as long as it did not include anthracyclines.
• 3. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI CTCAE version 5.0 Grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= Grade 3).
• 4. HBV and HCV serologies must be performed prior to inclusion. 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).
• 5. Any of the following diseases/illnesses within the previous 6 months:
  1. Myocardial infarction
  2. Severe or unstable angin
  3. Coronary or peripheral artery bypass graft
  4. Cerebrovascular accident or transient ischemic attack (TIA)
  5. Pulmonary embolism
• 6. Evidence of a bleeding diathesis.
• 7. Ongoing cardiac dysrhythmias > Grade 2.
• 8. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
• 9. History of allergy to study drug components.
• 10. History of another cancer with the exception of adequately treated basal cell carcinoma or in situ cervical cancer, or with a relapse-free interval longer than 3 years after treatment of the primary cancer with no substantial risk of recurrence.
• 11. Presence of brain or central nervous system metastases at the time of enrollment.
• 12. Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily taken.

Inclusion criteria (Phase II)

• 1. The patient must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. 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.
• 2. Age ≥ 18 years.
• 3. Diagnosis of advanced/metastatic soft tissue sarcoma (undifferentiated pleomorphic sarcoma or leiomyosarcoma) confirmed by central pathology review.
• 4. Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue must be provided for all subjects without exception for central pathology review and the translational study. If archive biopsy is not available or is older than 3 months, the patient must be willing to have a pre-treatment re-biopsy of primary or metastatic tumor (baseline biopsy) within 28 days prior to enrollment.
• 5. Measurable disease according to RECIST v1.1 criteria.
• 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• 7. The patient must be naïve of any previous treatment with anthracyclines (not even in adjuvant chemotherapy).
• 8. Adequate organ, hepatic, renal, cardiac, and hematologic function.
• 9. Laboratory tests as follows:
  1. Absolute neutrophil count ≥ 1,200/mm³
  2. Platelet count ≥ 100,000/mm³
  3. Hg > 9 g/dL
  4. Bilirubin ≤ 1.5 mg/dL
  5. PT and INR ≤ 1.5
  6. AST and ALT ≤ 2.5 times ULN
  7. Creatinine ≤ 1.5 mg/dL or estimated creatinine clearance ≥ 60 mL/min
  8. Blood glucose < 150 mg/dL
• 10. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.
• 11. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to enrollment. Patients must not be pregnant or nursing at study entry.
• 12. Women and men of reproductive potential must have agreed to use an effective contraceptive method during study treatment and for 3 months after the last dose of study drug.

Exclusion Criteria (Phase II)

• 1. Diagnosis of any sarcoma different from undifferentiated pleomorphic sarcoma and leiomyosarcoma.
• 2. Previous treatment with doxorubicin, epirubicin, idarubicin, and/or other anthracyclines or any other systemic therapy. The exception is previous systemic therapy for a previous neoplasm (see exclusion criteria 10), if this is controlled, as long as it did not include anthracyclines.
• 3. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI CTCAE version 5.0 Grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= Grade 3).
• 4. HBV and HCV serologies must be performed prior to inclusion. 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).
• 5. Any of the following diseases/illnesses within the previous 6 months:
  1. Myocardial infarction
  2. Severe or unstable angina
  3. Coronary or peripheral artery bypass graft
  4. Cerebrovascular accident or transient ischemic attack (TIA)
  5. Pulmonary embolism
• 6. Evidence of a bleeding diathesis.
• 7. Ongoing cardiac dysrhythmias > Grade 2.
• 8. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
• 9. History of allergy to study drug components.
• 10. History of another cancer with the exception of adequately treated basal cell carcinoma or in situ cervical cancer, or with a relapse-free interval longer than 3 years after treatment of the primary cancer with no substantial risk of recurrence.
• 11. Presence of brain or central nervous system metastases at the time of enrollment.
• 12. Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily taken.

Participating centers

• Hospital Univ. Fundación Jiménez Díaz, Dr. J. Martín Broto
• Hospital Clínico San Carlos, Madrid
• Hospital Univ. La Paz, Madrid
• Hospital General Universitario, Valencia

Enrolment status

Próxima apertura.

Criterios de inclusión

• 1. Patients must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow up. 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.
• 2. Age: 16-75 years.
• 3. Patients must have a diagnosis of soft tissue sarcoma (cohort A), or 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), 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).
• 4. 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.
• 5. 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.
• 6. Patients must have documentation of disease progression within 6 months prior to study entry.
• 7. The patient must have been considered eligible for systemic chemotherapy. Patients should had 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.
• 8. The following sarcoma types are eligible:
  1. Soft tissue sarcoma
  2. Bone tumors (osteosarcoma, chondrosarcoma)
  3. Small round-cell sarcomas (Ewing’s sarcoma, rhabdomyosarcoma, desmoplastic small round-cell tumors and other small round cell sarcomas)
• 9. Measurable disease, according to RECIST v1.1 criteria.
• 10. Performance status ≤ 1 (ECOG).
• 11. Adequate respiratory functions: FEV1 > 1L; DLCO > 40% (patients with pulmonary target lesions).
• 12. 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 estimated creatinine clearance (based on Cockroft and Gault) ≥ 30 ml/min, albumin ≥ 25 g/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.
• 13. Men or women of childbearing potential must use an effective method of contraception before entry into the study and 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.
• 14. Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.
• 15. 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)
• 16. Patient must have a central venous catheter for treatment, required for trabectedin administration.

Exclusion criteria

• 1. Previous treatment with trabectedin or previous treatment with radiotherapy (this latter just in case the previous radiotherapy treatment does not allow the radiotherapy treatment of this study due to tissue constrains).
• 2. Liver inclusion in irradiation fields is not permitted, not even partially.
• 3. Normal tissue constrains for radiation therapy.
• 3. Normal tissue constrains for radiation therapy.
• 5. Plasma bilirubin > ULN.
• 6. Creatinine clearance <30ml/min.
• 7. 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.
• 8. Severe chronic obstructive pulmonary disease (COPD) or other severe pulmonary diseases.
• 9. Significant cardiovascular disease (for example, dyspnea > 2 NYHA).
• 10. 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.
• 11. Uncontrolled bacterial, mycotic or viral infections.
• 12. Known positive test for infection by human immunodeficiency virus (HIV).
• 13. Women who are pregnant or breast-feeding.
• 14. Psychological, familiar, social or geographic circumstances that limit the patient’s ability to comply with the protocol or informed consent.
• 15. Patients who have participated in another clinical trial and/or have received any other investigational product in the last 30 days prior to enrollment.
• 16. Histologies other than those described in inclusion criteria.

Participating Centers

• H. Univ. La Paz, Madrid
• H. Univ. de la Santa Creu i Sant Pau, Barcelona
• Fundación Jiménez Díaz, Madrid
• H. Univ. Vall d’Hebrón, Barcelona
• H. Univ. de Canarias, Santa Cruz de Tenerife
• H. General Univ. Gregorio Marañón, Madrid
• H. Clínico San Carlos, Madrid

Enrolment status

Reclutamiento abierto.

Inclusion criteria. Cohorts A, B, E, and F (PM14 monotherapy in advanced disease)

• 1. The patient must voluntarily sign the informed consent before any study test is conducted that is not part of routine patient care.
• 2. Age: 18-75 years.
• 3. Patients must have a diagnosis of soft tissue sarcoma with metastasis, and not suitable for metastasectomy or surgery resection or not oncologically recommended metastasectomy. A centralized diagnosis confirmation will be performed and the tumor sample must be available and sent prior to inclusion to this end.
• 4. A centralized diagnosis of sarcoma, which includes: undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, leiomyosarcoma, sclerosing epithelioid fibrosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumors, sarcoma NOS, fibrosarcoma, pleomorphic rhabdomyosarcoma, pleomorphic liposarcoma, epithelioid sarcoma, clear cell sarcoma, dedifferentiated or aggressive features in solitary fibrous tumor, extraskeletal myxoid chondrosarcoma, angiosarcoma, epithelioid hemangioendothelioma, … A centralized diagnosis of DD liposarcoma or myxoid/hypercellular liposarcoma or leiomyosarcoma must be confirmed for patients in cohort E.
• 5. Patients must have received a previous chemotherapy line in advanced disease unless contraindicated or not indicated.
• 6. Radiological disease progression must be documented within 6 months prior to study entry.
• 7. The patient must have been considered eligible for systemic chemotherapy. A maximum of two previous lines for advanced/metastatic disease are allowed.
• 8. Measurable disease according to RECIST v1.1 criteria.
• 9. Performance status ≤1 (ECOG).
• 10. Adequate bone marrow function (hemoglobin >10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3). Patients withcreatinine clearance ≥ 30 mL/min (Cockcroft and Gault’s formula), transaminases ≤ 2.5 times the ULN, total bilirubin ≤ ULN are acceptable.
• 11. Men or women of childbearing potential must be using an effective method of contraception before entry into the study and throughout the same and for 3 months (men) and 6 months (women) after ending study treatment. Women of childbearing potential must have a negative serum or urine pregnancy test before study entry.
• 12. Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.
• 13. HBV and HCV serologies must be performed prior to inclusion. 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).
• 14. Patient must have a central venous catheter for PM14 treatment.

Exclusion criteria. Cohorts A, B, E, and F (PM14 monotherapy in advanced disease)

• 1. Performance status ≥ 2 (ECOG).
• 2. Plasma bilirubin > ULN.
• 3. Creatinine > 1.6 mg/dL.
• 4. History of other cancer with less than 5 years free of disease with the exception of adequately treated basal cell carcinoma or in situ cervical cancer.
• 5. Patients who do not provide consent for mandatory biological samples (including those required for the translational study) cannot participate in the study.
• 6. Significant cardiovascular disease (for example, dyspnea > 2 NYHA).
• 7. Significant systemic diseases grade 3 or higher on the NCI-CTCAE v5.0 scale, that limit patient availability, or according to investigator judgment may significantly contribute to treatment toxicity.
• 8. Uncontrolled bacterial, mycotic or viral infections.
• 9. Women who are pregnant or breastfeeding.
• 10. Psychological, family, social or geographic circumstances that limit the patients’ ability to comply with the protocol or informed consent.
• 11. Patients participating in another clinical trial or receiving any other investigational product.
• 12. Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion.
• 13. Histologies other than those described in the inclusion criteria.

Exclusion criteria:. Cohort C (PM14 plus radiotherapy in advanced disease)

• 1. The patient must voluntarily sign the informed consent before any study test is conducted that is not part of routine patient care.
• 2. Age: 18-75 years.
• 3. Patients must have a diagnosis of advanced soft tissue sarcoma, or recurrent head & neck suitable for reirradiation or other advanced or metastatic solid tumor not suitable for metastasectomy or surgery resection or not oncologically recommended metastasectomy. A centralized diagnosis will be performed and the tumor sample must be available and sent prior to inclusion to this end. For phase II part, only soft tissue sarcomas will be enrolled.
• 4. Patients must have received a previous chemotherapy line in advanced disease.
• 5. Disease distribution must allow meeting with normal tissue constrains of radiation therapy. Radiation oncologist must confirm this point at local sites.
• 6. Metastatic spread could be present in several organs (i.e. lungs and pelvic fossa) however, not all the locations have to be irradiated.
• 7. Those lesions considered for radiation therapy have to be related to symptoms (for phase II).
• 8. It is allowed that not all the lesions will be under radiation fields. As a general rule, the priority is to select, as target-irradiating lesions, those with greater increase in size and those largest lesions if related with symptoms. Irradiating pulmonary lesions with infiltration of pleural serosa is discouraged.
• 9. Radiological disease progression must be documented within 6 months prior to study entry.
• 10. The patient must have been considered eligible for systemic chemotherapy. A maximum of two previous lines for advanced/metastatic disease are allowed.
• 11. The following histological subtypes can be included for the phase II part (central pathology review is mandatory before accrual): undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma, angiosarcoma, epithelial hemangioendothelioma, liposarcoma and its variants (well differentiated, dedifferentiated, myxoid/round cell, pleomorphic), synovial sarcoma, fibrosarcoma and its variants (epithelial fibrosarcoma/low grade fibromyxoid sarcoma), solitary fibrous tumor, malignant peripheral nerve sheath tumor (MPNST), myxofibrosarcoma, epithelioid sarcoma and (NOS) unclassified sarcoma.
• 12. Measurable disease according to RECIST v1.1 criteria.
• 13. Performance status ≤1 (ECOG).
• 14. Adequate respiratory functions: FEV1 > 1L; DLco > 40% (patients with pulmonary target lesions).
• 15. Adequate bone marrow function (hemoglobin > 10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3). Patients withcreatinine clearance ≥ 30 mL/min (Cockcroft and Gault’s formula), transaminases ≤ 2.5 times the ULN, total bilirubin ≤ ULN are acceptable.
• 16. Men or women of childbearing potential must be using an effective method of contraception before entry into the study and throughout the same and for 3 months (men) and 6 months (women) after ending study treatment. Women of childbearing potential must have a negative serum or urine pregnancy test before study entry.
• 17. Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.
• 18. HBV and HCV serologies must be performed prior to inclusion. 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).
• 19. Patient must have a central venous catheter for PM14 treatment.

Inclusion criteria. Cohort C (PM14 plus radiotherapy in advanced disease)

• 1. Previous treatment with radiotherapy (except if previous radiotherapy treatment plus planned study radiotherapy treatment allow tissue constrains).
• 2. Performance status ≥ 2 (ECOG).
• 3. Plasma bilirubin > ULN.
• 4. Creatinine > 1.6 mg/dL.
• 5. History of other cancer with less than 5 years free of disease with the exception of adequately treated basal cell carcinoma or in situ cervical cancer.
• 6. Severe COPD or other severe pulmonary diseases.
• 7. Significant cardiovascular disease (for example, dyspnea > 2 NYHA).
• 8. Significant systemic diseases grade 3 or higher on the NCI-CTCAE v5.0 scale, that limit patient availability, or according to investigator judgment may significantly contribute to treatment toxicity.
• 9. Patients who do not provide consent for mandatory biological samples (including those required for the translational study) cannot participate in the study.
• 10. Uncontrolled bacterial, mycotic or viral infections.
• 11. Women who are pregnant or breastfeeding.
• 12. Psychological, family, social or geographic circumstances that limit the patients’ ability to comply with the protocol or informed consent.
• 13. Patients participating in another clinical trial or receiving any other investigational product.
• 14. Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion.
• 15. Histologies other than those described in inclusion criteria.

Inclusion criteria. Cohort D (PM14 plus radiotherapy in localized disease)

• 1. The patient must voluntarily sign the informed consent before any study test is conducted that is not part of routine patient care.
• 2. Age: 18-75 years.
• 3. Patients must have a diagnosis of localized soft tissue sarcoma that lacks one or more of the following risk criteria: G3, deep and > 5 cm. At least G2 is required (i.e. G3, superficial and > 5 cm; or G3 < 5 cm deep; or G2, deep and > 5 cm, etc.).
• 4. Patients must be diagnosed by core-biopsy and the elapsed time between biopsy and enrollment must be shorter than 6 weeks.
• 5. Patients must be diagnosed by central pathology review with one of the following subtypes: leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, synovial sarcoma, sarcoma NOS, fibrosarcoma, myxoid liposarcoma, dedifferentiated liposarcoma, solitary fibrous tumor (the formerly malignant subtype).
• 6. Only those sarcomas of limbs or trunk wall will be eligible for this cohort.
• 7. Disease distribution allows meeting with normal tissue constraints of radiation therapy. Radiation oncologist must confirm this point at local sites.
• 8. Patients must have resectable primary tumor while it is allowed to enroll patients with metastatic spread that could be potentially resectable.
• 9. Patients must have criteria of operability for the primary tumor.
• 10. The patient must have been considered eligible for systemic chemotherapy.
• 11. Measurable disease according to RECIST v1.1 criteria.
• 12. Patients have to be candidates for MRI test.
• 13. Performance status ≤ 1 (ECOG).
• 14. Adequate bone marrow function (hemoglobin > 10 g/dL, neutrophils ≥ 1,500/mm3, platelets ≥ 100,000/mm3). Patients with plasma creatinine ≤ 1.6 mg/dL, transaminases ≤ 2.5 times the ULN, total bilirubin ≤ ULN are acceptable.
• 15. Men or women of childbearing potential must be using an effective method of contraception before entry into the study and throughout the same and for 3 months (men) and 6 months (women) after ending study treatment. Women of childbearing potential must have a negative serum or urine pregnancy test before study entry.
• 16. Normal cardiac function with a LVEF ≥ 50% by echocardiogram or MUGA.
• 17. It should be performed HBV and HCV serologies prior to inclusion. 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).
• 18. Patient must have a central venous catheter for treatment with PM14.

Exclusion criteria. Cohort D (PM14 plus radiotherapy in localized disease)

• 1. High-risk localized patients are not allowed to be enrolled (those G3, deep, and larger than 5 cm or those with risk of death at least 40% by sarculator nomogram).
• 2. Previous treatment with radiotherapy.
• 3. Primary tumor location other than those indicated in the inclusion criteria.
• 4. Histological subtypes other than those indicated in the inclusion criteria.
• 5. Unresectable or inoperable primary tumor.
• 6. Patients who do not provide consent for mandatory biological samples (including those required for the translational study) cannot participate in the study.
• 7. Performance status ≥ 2 (ECOG).
• 8. Plasma bilirubin > ULN.
• 9. Creatinine > 1.6 mg/dL.
• 10. History of other cancer with less than 5 years free of disease with the exception of adequately treated basal cell carcinoma or in situ cervical cancer.
• 11. Significant cardiovascular disease (for example, dyspnea > 2 NYHA).
• 12. Significant systemic diseases grade 3 or higher on the NCI-CTCAE v5.0 scale, that limit patient availability, or according to investigator judgment may significantly contribute to treatment toxicity.
• 13. Uncontrolled bacterial, mycotic or viral infections.
• 14. Women who are pregnant or breastfeeding.
• 15. Psychological, family, social or geographic circumstances that limit the patients’ ability to comply with the protocol or informed consent.
• 16. Patients participating in another clinical trial or receiving any other investigational product.
• 17. Patients who had participated in another clinical trial and/or had received any other investigational product in the last 30 days prior to inclusion.

Participating Centers

• H. Fundación Jiménez Díaz, Madrid (Dr. Javier Martín)
• H. Santa Creu i Sant Pau, Barcelona (Dr. Ana Sebio)
• H. U. Vall d’Hebrón, Barcelona (Dr. C. Valverde)
• H. U. Miguel Servet, Zaragoza (Dr. J. Martínez Trufero)
• H. U. Miguel Canarias, Tenerife (Dr. Josefina Cruz)
• H. C. San Carlos, Madrid (Dr. Antonio Casado)

Enrolment status

Reclutamiento abierto.