Open trials

Inclusion Criteria

• Subjects must provide written informed consent prior to performance of studyspecific procedures or assessments and must be willing to comply with treatment and follow-up. Informed consent may be obtained prior to start of the specified screening window. Procedures conducted as part of the subject’s routine clinical management (e.g., blood count, imaging study such as bone scan) and obtained prior to signing of informed consent may be utilized for screening or baseline purposes provided these procedures are conducted as specified in the protocol
• Age 18 years or legal age of consent if greater than 18 years
• Histologically confirmed diagnosis of solitary fibrous tumor (strata 1) and extraskeletal myxoid chondrosarcoma (strata 2), non resectable locally advanced or metastatic disease
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Measurable disease criteria: At least one measurable lesion. All the cases will be evaluated with RECIST criteria and CHOI criteria (Hansfield Units must be provided)
• Protocol will be built in English. For Inform Consent language will be adapted for every different country
• Paraffin embedded tumors must be provided for centralized pathology review. Additionally, serum sample will be collected (3 for each patient) to analyze angiogenic serum biomarkers. If pharmacodynamic studies would be considered, a pre and post treatment biopsy should be performed in order to collect frozen and paraffin embedded tumor tissue
• Adequate organ system function
• Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception, as defined in Pregnancy Section in overall Safety Section during the study and for [x hours or days - based on half-life of compound] following the last dose of investigational product

Exclusion criteria

• Prior malignancy. Subjects who have had another malignancy and have been disease-free for 10 years, or subjects with a history of completely resected nonmelanomatous skin carcinoma or successfully treated in situ carcinoma are eligible
• Central nervous system (CNS) metastases at baseline, with the exception of those subjects who have previously-treated CNS metastases (surgery ± radiotherapy, radiosurgery, or gamma knife) and who meet both of the following criteria: a) are asymptomatic and b) have no requirement for steroids orenzyme-inducing anticonvulsants in prior X time interval
• Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding including, but not limited to: Active peptic ulcer disease, known intraluminal metastatic lesion/s with risk of bleeding, inflammatory bowel disease (e.g. ulcerative colitis, Chrohn’s disease), or other gastrointestinal conditions with increased risk of perforation, history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to beginning study treatment
• Clinically significant gastrointestinal abnormalities that may affect absorption of investigational product including, but not limited to: malabsorption syndrome, major resection of the stomach or small bowel
• Corrected QT interval (QTc) > 480 msecs. Correction method should be reported in CRT
• History of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, class II, III or IV congestive heart failure, as defined by the New York Heart Association (NYHA) (see Section YYY Appendix Y for description)
• Poorly controlled hypertension [defined as systolic blood pressure (SBP) of 140 mmHg or diastolic blood pressure (DBP) of 90mmHg]. Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry. Following antihypertensive medication initiation or adjustment, blood pressure (BP) must be re-assessed three times at approximately 2-minute intervals. At least 24 hours must have elapsed between anti-hypertensive medication initiation or adjustment and BP measurement. These three values should be averaged to obtain the mean diastolic blood pressure and the mean systolic blood pressure. The mean SBP / DBP ratio must be <140/90 mmHg (OR 150/90 mm Hg, if this criterion is approved by Safety Review Team) in order for a subject to be eligible for the study (see Section XXX for details on BP control and re-assessment prior to study enrollment)
• History of cerebrovascular accident including transient ischemic attack (TIA), pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months. Subjects with recent DVT who have been treated with therapeutic anti-coagulating agents for at least 6 weeks are eligible
• Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer (procedures such as catheter placement not considered to be major surgery)
• Evidence of active bleeding or bleeding diathesis
• Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that increase the risk of pulmonary hemorrhage. Lesions infiltrating major pulmonary vessels (contiguous tumor and vessels) are excluded; however, the presence of a tumor that is touching, but not infiltrating (abutting) the vessels is acceptable (CT with contrast is strongly recommended to evaluate such lesions). Large protruding endobronchial lesions in the main or lobar bronchi are excluded; however, endobronchial lesions in the segmented bronchi are allowed. Lesions extensively infiltrating the main or lobar bronchi are excluded; however, minor infiltrations in the wall of the bronchi are allowed
• Recent hemoptysis (³½ teaspoon of red blood within 8 weeks before first dose of study drug)
• Any serious and/or unstable pre-existing medical, psychiatric, or other condition that could interfere with subject’s safety, provision of informed consent, or compliance to study procedures
• Unable or unwilling to discontinue use of prohibited medications listed in Appendix C Section XX for at least 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of study drug and for the duration of the study (Appendix C) (Section XX)
• Treatment with any of the following anti-cancer therapies: radiation therapy, surgery or tumor embolization within 14 days prior to the first dose of pazoapnib or chemotherapy, immunotherapy, biologic therapy, investigational therapy or hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior to the first dose of pazopanib
• Administration of any non-oncologic investigational drug within 30 days or 5 half lives whichever is longer prior to receiving the first dose of study treatment
• Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that is progressing in severity, except alopecia

Participating Centers

1. Canarias University Hospital Canarias-Dr. Josefina Cruz Jurado (I. Coordinator)
2. Son Espases University Hospital Baleares-Dr. Javier Martín Broto (I. Coordinator)
3. Ramón y Cajal University Hospital Madrid- Dr. Mª Ángeles Vaz
4. La Paz University Hospital Madrid- Dr. Andrés Redondo
5. Virgen del Rocío University Hospital Andalucía- Dra. Pilar Sancho
6. Hospital de la Santa Creu i Sant Pau Cataluña- Dr. Antonio López-Pousa
7. Miguel Servet University Hospital Aragón- Dr. Javier Martínez Trufero

Enrolment status

Recruitment closed

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 cohort 1 (first phase) - STS and Bone Sarcomas

• 1) CDK4 overexpression (RNAm expression) and a low or normal expression of p16 (RNAm expression) meassured in paraffined tumour samples at baseline.
• 2) ECOG 0-1 at recruitment.
• 3) Diagnosis of soft tissue sarcoma or osteosarcoma (in both cases with metastasis or locally advanced non resectable).
• 4) Documented progression disease during the previous 6 months to the inclusion in the trial.
• 5) Patients should have the following laboratory ranges:
  • Recuento absoluto de neutrófilos ≥ 1.500/mm3 (1,5 x 109/L);
  • Plaquetas ≥ 100.000/mm3 (100 x 109/L);
  • Hemoglobina ≥ 9 g/dL (90 g/L);
  • Creatinina en sangre ≤ 1,5 x LSN o aclaramiento de creatinina estimada ≥ 60 mL/min;
  • Bilirrubina total en sangre ≤ 1,5 x LSN (≤ 3,0 x LSN si enfermedad de Gilbert);
  • AST y/o ALT ≤ 3 x LSN (≤ 5,0 x LSN si existe metástasis hepática);
  • Fosfatasa alcalina ≤ 2,5 x LSN (≤ 5,0 x LSN si existe metástasis ósea o hepática);
• 6) Patients should have signed in writting the informed consent to participe in the clinical trial, and to donate two paraffined tumour samples for the molecular analyses in the selection process.
• 7) Biopsy in baseline in case there are no available archive tumour samples obtained in the 3 months previous to starting the treatment.
• 8) Patients must have received at least one, two or three lines of standard treatment for advanced disease.
• 9) Age between 18 and 80 years (included).
• 10) Measurable disease according to RECIST 1.1 criteria.
• 11) Men or women of child bearing potential should be using an effective method of contraception throughout the treatment with palbociclib and for at least 90 days after the last dose. Women of childbearing potential must have a negative blood or urine pregnancy test before study entry. Men should be adviced to preserve sperm before starting the treatment due to risk of infertility.

Exclusion criteria cohort 1 (first phase) - STS and Bone Sarcomas

• 1) Previous treatment with any anti CDK4 or immune checkpoint control inhibitors.
• 2) Diagnosis of Ewing sarcoma or rhabdomyosarcoma.
• 3) Diagnosis of well differentiated/dedifferentiated liposarcoma.
• 4) Irradiated patients in the only available target lesion.
• 5) Patients who have received more than three lines of treatment for advanced disease.
• 6) History of another neoplastic disease except for base cell carcinoma or in situ cervical cancer adequately treated.
• 7) Serious cardiovascular disease (NYHA >= 2)
• 8) Grade 3 toxicity or superior according to CTCAE 4.0 if, according to the investigator's criteria, it can interfer in a significant way in the toxicity of the drug used in the trial.
• 9) Patients who have not recovered from a previous toxicity up to a CTCAE grade 1 due to an antineoplastic treatment with chemotherapy, radiotherapy, or biologic therapy (including monoclonal antibodies).
• 10) Patients who have not recovered from a minor or major surgery or who have underwent a major surgery in the 4 weeks previous to starting the treatment of the trial.
• 11) Metastasis in the central nervous system.
• 12) Pregnant or breastfeeding patients, or that expect to get pregnant during the treatment period.
• 13) Food or drugs known to be CYP3A4 inhibitors/inductors; CYP3A4 substrates with narrow therapeutic index, or that are known to extend the interval QTc.
• 14) Major surgery, chemotherapy, radiotherapy, any agent in investigation,or another antineoplastic therapy within the previous 4 weeks to inclusion. Patiets who have received previous radiotherapy of bone marrow ≥25% are not eligible, independent of when it was received.
• 15) QTc > 480 ms; personal or familial history of brief or long QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsades de Pointes (TdP).
• 16) Any of the following situations within the 6 months previous to the trial drug administration: Infarto de miocardio, angina severa/inestable, disritmias cardiacas actuales de Grado ≥ 2 NCI-CTCAE versión 4.0, fibrilación atrial de cualquier grado, implante de marcapasos en arteria coronaria/periférica, fallo cardiaco congestivo sintomático, accidente cerebrovascular incluyendo ataque isquémico transitorio, o embolismo pulmonar sintomático.
• 17) Known hypersensitivity to any PD 0332991 or excipients.
• 18) Active or recent suicidal tendencies or behaviour.

Inclusion criteria cohort 2 (second phase) - Chordomas

• 1) CDKN2A gene mutation.
• 2) ECOG 0-1 at recruitment.
• 3) Chordoma diagnosis (with metastasis or locally advanced non resectable) centrally confirmed.
• 4) Progression disease according to RECIST 1.1, within the previous year to inclusion, to prevous treatment (surgery, radiotherapy or systemic treatment).
• 5) Patients not candidates to surgical rescue or to radiotherapy at the moment of inclusion.
• 6) Patients should have the following laboratory results: .
  • Recuento absoluto de neutrófilos ≥ 1.500/mm3 (1,5 x 109/L);
  • Plaquetas ≥ 100.000/mm3 (100 x 109/L);
  • Hemoglobina ≥ 9 g/dL (90 g/L);
  • Creatinina en sangre ≤ 1,5 x LSN o aclaramiento de creatinina estimada ≥ 60 mL/min;
  • Bilirrubina total en sangre ≤ 1,5 x LSN (≤ 3,0 x LSN si enfermedad de Gilbert);
  • AST y/o ALT ≤ 3 x LSN (≤ 5,0 x LSN si existe metástasis hepática);
  • Fosfatasa alcalina ≤ 2,5 x LSN (≤ 5,0 x LSN si existe metástasis ósea o hepática);
• 7) Patients should have signed in writting the informed consent to participe in the clinical trial, and to donate the paraffined tumour samples for the molecular analyses in the selection process.
• 8) Biopsy in baseline in case there are no available archive tumour samples obtained in the 3 months previous to starting the treatment. In case there are tumour samples obtained during this period, there should have been no subsequent treatments.
• 9) Patients could have received up to 3 lines of systemic treatment previously.
• 10) Age between 18 and 80 (included).
• 11) Measurable disease according to RECIST 1.1. criteria.
• 12) Men or women of child bearing potential should be using an effective method of contraception throughout the treatment with palbociclib and for at least 90 days after the last dose. Women of childbearing potential must have a negative blood or urine pregnancy test before study entry. Men should be adviced to preserve sperm before starting the treatment due to risk of infertility.

Inclusion criteria cohort 2 (second phase) - Chordomas

• 1) Previous treatment with any anti CDK4 or immune checkpoint control inhibitors.
• 2) Diagnosis other to chordoma in central review.
• 3) Irradiated patients in the only available target lesion.
• 4) Patients who have received more than three lines of treatment for advanced disease.
• 5) History of another neoplastic disease except for base cell carcinoma or in situ cervical cancer adequately treated. This criterion will be individually assessed with the investigator team.
• 6) Serious cardiovascular disease (NYHA >= 2)
• 7) Grade 3 toxicity or superior according to CTCAE 5.0 if, according to the investigator's criteria, it can interfere in a significant way in the toxicity of the drug used in the trial.
• 8) Patients who have not recovered from a previous toxicity up to a CTCAE grade 1 due to an antineoplastic treatment with chemotherapy, radiotherapy, or biologic therapy (including monoclonal antibodies).
• 9) Patients who have not recovered from a minor or major surgery or who have underwent a major surgery in the 4 weeks previous to starting the treatment of the trial.
• 10) Metastasis in the central nervous system.
• 11) Pregnant or breastfeeding patients, or that expect to get pregnant during the treatment period.
• 12) Food or drugs known to be CYP3A4 inhibitors/inductors; CYP3A4 substrates with narrow therapeutic index, or that are known to extend the interval QTc.
• 13) Major surgery, chemotherapy, radiotherapy, any agent in investigation,or another antineoplastic therapy within the previous 4 weeks to inclusion. Patiets who have received previous radiotherapy of bone marrow ≥25% are not eligible, independent of when it was received.
• 14) QTc > 480 ms; personal or familial history of brief or long QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsades de Pointes (TdP).
• 15) Any of the following situations within the 6 months previous to the trial drug administration: Infarto de miocardio, angina severa/inestable, disritmias cardiacas actuales de Grado ≥ 2 NCI-CTCAE versión 5.0, fibrilación atrial de cualquier grado, implante de marcapasos en arteria coronaria/periférica, fallo cardiaco congestivo sintomático, accidente cerebrovascular incluyendo ataque isquémico transitorio, embolismo pulmonar sintomático, o enfermedad pulmonar intersticial (EPI) grave/neumonitis.
• 16) Known hypersensitivity to any PD 0332991 or excipients.
• 17) Active or recent suicidal tendencies or behaviour.

Participating Centers

• Hospital Universitario Virgen del Rocío -- Irene Carrasco
• Hospital Universitari i Politècnic La Fe -- Roberto Díaz
• Hospital Universitario Miguel Servet -- Javier Martínez Trufero
• Complejo Hospitalario Universitario de Santiago -- Yolanda Vidal
• Hospital Universitario Central de Asturias -- Juan Luis Garcí Llano
• Hospital de la Santa Creu i Sant Pau -- Antonio López
• Hospital Universitario 12 de Octubre -- Diego Jara
• Hospital Universitario Virgen de la Victoria -- Isabel Sevilla
• Hospital Universitari Germans Trias i Pujol -- Marc Cucurull
• Complejo Asistencial Universitario de León -- Luis Miguel De Sande
• Hospital General Universitario Gregorio Marañon -- Rosa Álvarez
• Hospital Universitari Vall d ́Hebron -- Claudia Valverde
• Hospital Universitario La Paz -- Andres Redondo
• Hospital Universitario de Canarias -- Josefina Cruz
• Instituto Valenciano de Oncología (IVO) -- Javier Lavernia
• Hospital Universitario Son Espases -- Pablo Luna
• Hospital Clínico Universitario Virgen de la Arrixaca -- Jerónimo Martínez
• Institut Català d ́Oncología d ́Hospitalet -- Xavier García del Muro
• Hospital Universitario Clínico San Carlos-- Antonio Casado Herráez
• Hospital Universitario Fundación Jiménez Díaz-- Javier Martín Broto

Enrolment status

Participating centers

Enrolled patients

Inclusion criteria

• 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.
• 2. Age: 18-80 years.
• 3. Histologic diagnosis of soft tissue sarcoma: liposarcoma (dedifferentiated and myxoid/round cell), leiomyosarcoma, undifferentiated pleomorphic sarcoma, synovial sarcoma confirmed, after enrolment, by central pathology review by a paraffin embedded tumor tissue.
• 4. Metastatic/advanced disease in progression in the last 6 months.
• 5. Patients had previously received at least anthracyclines if clinically indicated. Previous olaratumab administration is allowed.
• 6. Measurable disease according to RECIST 1.1 criteria.
• 7. ECOG Performance Status of 0-1.
• 8. Adequate hepatic, renal, cardiac, and hematologic function.
• 9. Laboratory tests as follows: Haemoglobin < 9g/dl; Absolute neutrophil count ≥ 1,500/mm³, Platelet count ≥ 100,000/mm³, Bilirubin ≤ 1.5 mg/dL, PT≤ 1.5 ULN and INR ≤ 1.5, AST and ALT ≤ 2.5 times upper limit of normal, Creatinine ≤ 1.5 mg/dL Calcium ≤ 2 mg/dL and Blood glucose < 150 mg/dL, Urine protein assessment: <2+, and/or <3.5g protein/24h
• 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 7 days prior to enrollment. Females of child-bearing potential and males and must agree to use highly effective contraceptive precautions during the trial and up to 6 months following the last dose of study drug. A highly effective method of birth control is defined as one that results in a low failure rate (that is, <1% per year) when used consistently and correctly, such as implants, injectables, combined oral contraceptives, some intrauterine contraceptive devices (IUDs), sexual abstinence, or a vasectomized partner.

Exceptions: Females not of child-bearing potential due to surgical sterilization (at least 6 weeks following surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by medical history or menopause. A “postmenopausal woman” is a woman meeting either of the following criteria:

• spontaneous amenorrhea for at least 12 months, not induced by a medical condition such as anorexia nervosa and not taking medications during the amenorrhea that induced the amenorrhea (for example, oral contraceptives, hormones, gonadotropin releasing hormone, antiestrogens, selective estrogen receptor modulators (SERMs), or chemotherapy
• spontaneous amenorrhea for 6 to 12 months and a follicle-stimulating hormone (FSH) level >40 mIU/mL

Exclusion criteria

• 1. No more than 2 previous lines of chemotherapy for advanced disease. Previous trabectedin not allowed.
• 2. Hipersensitivity to olaratumab.
• 3. The following histologies are not included: Ewing Sarcoma, extraskeletal osteosarcoma, extraskeletal myxoid chondrosarcoma, Kaposi's sarcoma, rhabdomyosarcoma and gastrointestinal stromal tumor (GIST).
• 4. 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).
• 5. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
• 6. Other disease or illness within the past 6 months, including any of the following:
  • Myocardial infarction
  • Coronary or peripheral artery bypass graft
  • Cerebrovascular accident or transient ischemic attack
  • Pulmonary embolism
• 7. The patient has electively planned or will require major surgery during the course of the study.
• 8. Social situation that would preclude study compliance.
• 9. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
• 10. Hemorrhage ≥ Grade 3 in the past 4 weeks.
• 11. Females who are pregnant or breast-feeding.

Participating centers

• Hospital Univ. Virgen del Rocío, Sevilla
• Hospital Univ. Vall d'Hebron, Barcelona
• Hospital General Univ. Gregorio Marañón, Madrid
• Hospital Universitari i Politècnic La Fe, Valencia

Enrolment status

Enrolment closed.

Participating centers	Patients in screening	Enrolled patients
Hospital Univ. Virgen del Rocío	-	5
Hospital Univ. Vall d'Hebron	-	4
Hospital Univ. Gregorio Marañón	-	3
Hospital Universitari i Politècnic La Fe	-	1

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 (<3 months) is mandatory for translational research. If it 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 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; <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 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; <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 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.