Clinical research is an essential work to improve the treatment of oncological patients. This work is fruitless if it is carried out without cooperation projects between several hospitals. The cooperative effort is especially important in handling sarcomas, not only because of their rarity, but also due to their biological heterogeneity and the variability of their clinical behavior.
GEIS 37
Phase I/IITRASTS study: Prospective, multicentric clinical Trial Phase I-II, exploring the combination of trabectedin and radiotherapy on soft tissues sarcomas, is open to patient recruiting. right now there is a free slot on Phase I Cohort A dose 1,5 mg/m2, required to be included in order to close Phase I of the trial. Cohort B, after closing Phase I, is open to recruiting on Phase II dose 1,5 mg/m2. Cohort C: patients with retroperitoneal and resectable soft tissue sarcoma (liposarcoma and leiomyosarcoma). Given the importance of the trial, we encourage you to keep adding patients.
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
- Hospital Son Espases, Mallorca-Dr Pablo Luna
- Hospital Puerta de Hierro, Madrid- Dr Ricardo Cubedo
- Hospital Canarias, San Cristóbal de la Laguna- Dr Josefina Cruz
- Hospital Miguel Servet, Zaragoza- Dr Javier Martínez Trufero
- Hospital Virgen del Rocío, Sevilla- Dr Irene Carrasco
- Hospital Vall d´Hebron, Barcelona- Dr Claudia Valverde
- Hospital La Paz, Madrid- Dr Andrés Redondo
- Hospital Gregorio Marañón, Madrid- Dr Rosa Álvarez
- Hospital de la Santa Creu i Sant Pau, Barcelona- Dr Antonio López Pousa
- Istituto Nazionale dei Tumori, Milano- Dr Alessandro Gronchi
- Istituto di Candiolo-IRCC, Candiolo- Dr Giovanni Grignani
- Centro di Referimento Oncologico, Aviano- Dra Angela Buonadonna
- Institut Bergonié, Bordeaux-Dr Antoine Italiano
- Claude Bernard, Lyon- Dr Jean-Yves Blay
- Hospital Universitario Fundación Jiménez Díaz, Madrid- Dr Javier Martín Broto
GEIS 75
Phase IIPhase II multicohort trial of trabectedin and low-dose radiation therapy in advanced/metastatic sarcomas
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:
- Soft tissue sarcoma
- Bone tumors (osteosarcoma, chondrosarcoma)
- 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
GEIS 75
Phase IIPhase II multicohort trial of trabectedin and low-dose radiation therapy in advanced/metastatic sarcomas
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. 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:
- Soft tissue sarcoma
- Bone tumors (osteosarcoma, chondrosarcoma)
- 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.
- 4. Performance status ≥ 2 (ECOG).
- 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.
Paticipant 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
GEIS 35
Phase II/IIIInternational Randomised Controlled Trial of Chemotherapy for the Treatment of Recurrent and Primary Refractory Ewing Sarcoma
Inclusion criteria
- Histologically confirmed ES.
- Disease recurrence or progression after completion of first line treatment.
OR
Refractory disease, defined by progression during first line treatment or within 12 weeks of its completion. Disease progression will be based on RECIST criteria (see Appendix 1). The appearance of new bone lesions on bone scan will require confirmation with cross-sectional imaging. - Soft tissue disease component evaluable by cross-sectional imaging (RECIST). Patients with bone disease without a measurable soft tissue component or bone marrow disease only will be eligible for the study but will not contribute to the phase II primary outcome measure.
- Age ≥4 years and more
- Patient assessed as medically fit to receive cytotoxic chemotherapy.
- Documented negative pregnancy test for female patients of childbearing potential.
- Patient agrees to use effective contraception during therapy and for 12 months after last trial treatment, where applicable.
- Written informed consent from the patient and/or parent/legal guardian.
Exclusion criteria
- Bone marrow infiltration resulting in Absolute Neutrophil Count (ANC)
- Cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous two weeks.
- Myeloablative therapy within previous eight weeks.
- Radiotherapy to target lesion within previous six weeks.
- Pregnant or breastfeeding women.
- Follow-up not possible due to social, geographic or psychological reasons.
Participating Centers
- Hospital Univ. Vall d Hebrón – Adultos: Claudia Valverde; Pediátricos: Luis Gros
- Hospital Univ. La Paz – Adultos: Andrés Redondo; Pediátricos: Pedro Rubio
- Hospital General Univ. Gregorio Marañón – Adultos: Rosa Álvarez; Pediátricos: Cristina Mata
- Hospital de la Santa Creu i Sant Pau – Adultos: Antonio López-Pousa; Pediátricos: Dra. Montserrat Torrent
- Hospital Univ. Virgen del Rocío – Adultos: Javier Martín Broto; Pediátricos: Catalina Márquez
- Hospital Universitario de Canarias: Adultos: Josefina Cruz; Pediátricos: Macarena González
- Hospital Univ. Miguel Servet: Adultos: Javier Martínez-Trufero; Pediátricos: Carlota Calvo
- Hospital Univ. Central de Asturias: Adultos: Pilar Blay; Pediátricos: José A Villegas
- Hospital Universitari i Politècnic La Fe: Adultos: Roberto P Díaz-Beveridge; Pediátricos: Adela Cañete
- Hospital Cruces: Adultos: Nuria Fuentes; Pediátricos: Aizpea Echebarria
- Hospital Univ. Ramón y Cajal – Adultos: Mª Angeles Vaz
- Hospital Univ. Virgen de la Victoria – Adultos: Isabel Sevilla
- ICO Hospitalet – Adultos: Xavier García-Del Muro
- Hospital Regional de Málaga – Pediátricos: Laura García
- Hospital Niño Jesús – Pediátricos: Fancisco Bautista
- Hospital Sant Joan de Deu – Pediátricos: Jaume Mora
GEIS 75
Fase IIEnsayo clínico Fase II multicohorte de trabectedina y radioterapia a bajas dosis en sarcomas avanzados/metastásicos.
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:
- Soft tissue sarcoma
- Bone tumors (osteosarcoma, chondrosarcoma)
- 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.
- 4. Performance status ≥ 2 (ECOG).
- 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.
Paticipant 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
GEIS 100
Fase IIInternational clinical research programme to improve outcomes in newly diagnosed Ewing sarcoma – Trial 1 (INTER-EWING-1)
Randomisation C – Maintenance chemotherapy randomisation (vinorelbine and cyclophosphamide vs none)
Inclusion criteria
- Entered into the INTER-EWING-1 study
- Received induction/ consolidation chemotherapy with a VDC/IE/VC/VAI/BuMel based regimen
- Have responded to induction treatment and not progressed
- Medically fit to receive treatment
- Absence of severe vincristine neuropathy – i.e. requiring discontinuation of vincristine treatment
- Adequate liver function: bilirubin
- Documented negative pregnancy test for female patients of childbearing potential
- Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active.
- Written informed consent from the patient and/or the parent/legal guardian
Exclusion criteria
- Urinary outflow obstruction that cannot be relieved prior to starting treatment
- Uncontrolled significant inter-current illness or active infection
- Active inflammation of the urinary bladder (cystitis)
- Known contraindication or hypersensitivity to any of the treatments or excipients
- Pregnant or breastfeeding women
Paticipant Centers
Participating sites (more sites will participate in due course):
Paediatric patients:
- Hospital Sant Joan de Deu
- Hospital Universitario Cruces (Bilbao)
- Hospital Univ. Regional de Málaga
- Hospital de la Santa Cruz y San Pablo
- Hospital General Univ. Gregorio Marañón
- Hospital Univ. Niño Jesús
- Hospital Univ. Valle de Hebrón
- Hospital Univ. Virgen del Rocío
- Hospital Universitario de Canarias
Adult patients:
- Hospital Univ. de Canarias
- Hospital Universitario Cruces (Bilbao)
- Hospital de la Santa Cruz y San Pablo
- Hospital Univ. Valle de Hebrón
- Hospital Univ. Virgen del Rocío
- Hospital Clínico Univ. Virgen de la Victoria
GEIS 42
Phase IIIThree versus five years of adjuvant imatinib as treatment of patients with operable gist with a high risk for recurrence: a randomised phase III study
Inclusion criteria
To be eligible for inclusion in the study, each patient must fulfil each of the criteria below.
- Age ≥18.
- Morphological and immunohistological documentation of GIST (immunostaining for KIT [CD117] and/or DOG-1 positive, or mutation of KIT or PDGFRA present in tumour tissue).
- Macroscopically complete resection of the tumour (either R0 or R1 surgery).
- Mutation analysis of KIT and PDGFR genes has been carried out.
- A high risk of GIST recurrence, either:
- gastric GIST with a mitotic count >10/50 HPFs or >10/5 mm2, or,
- non-gastric GIST with a mitotic count >5/50 HPFs, or
- non-gastric GIST treated with neoadjuvant imatinib and initially larger than 10 cm
- tumour rupture
- Tumour rupture (spillage of the tumour contents into the abdominal cavity) may have occurred before or at surgery. Tumour rupture is defined by spillage of the tumour contents into the abdominal cavity. A core needle biopsy from the tumour, or tumour bleed with no apparent spillage of the tumour contents, are not considered ruptures.
- If only a small amount of pretreatment tumour tissue is available from a core needle biopsy, it is acceptable to multiply the mitotic count obtained from fewer than 50 HPFs to approximate the counts obtained from 50 HPFs in surgical biopsies, or to multiply the count obtained from a tumour tissue area less than 5 mm2 to approximate the counts obtained from the 5 mm2 area. However, if only minimal amount of tumour tissue is available from a core needle biopsy (from 5 or fewer HPFs, or only 1 mitosis can be identified), multiplication should not be attempted and is not considered acceptable.
- Eastern Co-operative Oncology Group (ECOG) performance status ≤ 2.
- Adequate organ function defined as serum total bilirubin <1.5 x ULN (upper limit of normal), serum AST (SGOT) and ALT (SGPT) <2.5 x ULN, creatinine <1.5 x ULN; blood ANC (neutrophil count) ≥1.0 x 109/L, platelet count ≥100 x 109/L.
- Female patients of childbearing potential must have a negative pregnancy test within 14 days before initiation of study drug dosing. Postmenopausal women must have amenorrhea for at least 12 months to be considered of non-childbearing potential. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug. For female, a highly effective method for birth control must be used, which means that the method can achieve a failure rate of less than 1% per year when used consistently and correctly. All females of child-bearing potential must be informed of such methods, and must also, if sexually active, accept a monthly pregnancy test if randomised to prolonged imatinib use.
- Patient willing to be followed up at the study site regardless of the result of randomisation.
- Patient has provided a written, voluntary informed consent prior to study-specific screening procedures.
Exclusion criteria
- Presence of distant metastases or local recurrence of GIST.
- Not willing to donate tumour tissue and/or blood samples for the molecular studies.
- Presence of a substitution mutation at PDGFRA codon D842 (usually D842V).
- Administration of adjuvant imatinib longer than for 3 years is planned regardless of the result of randomisation, or “life long” imatinib administration is planned.
- Prior adjuvant (+ neoadjuvant) therapy with imatinib mesylate for at least 35 months has not been completed, or the total duration of prior adjuvant (+ neoadjuvant) imatinib exceeds the total of 38 months.
- Neoadjuvant imatinib for a duration that exceeds 12 months.
- A longer than 4-week break during adjuvant imatinib administration.
- The dose of adjuvant imatinib at the time of completion of 3 years of adjuvant imatinib was 200 mg per day or less or greater than 800 mg per day.
- Patient has received any investigational anti-cancer agents during adjuvant imatinib or between completion of adjuvant imatinib and the date of randomisation.
- Patient has been free of another malignancy for less than 5 years except if the other malignancy is not currently clinically significant nor requiring active intervention, or if the other malignancy is a basal cell skin cancer or a cervical carcinoma in situ a small (2 cm or less in diameter) node negative breast cancer (pT1N0M0), a low Gleason score (<8) local (T1 or T2) prostate cancer. Recent existence of any other recent malignant disease is not allowed.
- Patient with Grade III/IV cardiac disease as defined by the New York Heart Association Criteria (i.e., congestive heart failure, myocardial infarction within 6 months of study entry).
- Female patients who are pregnant or breast-feeding.
- Severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, severe chronic renal disease, or active uncontrolled infection).
- Known diagnosis of human immunodeficiency virus (HIV) infection.
- Patient with a significant history of non-compliance to medical regimens or with inability to grant reliable informed consent.
- Inability or difficulty in swallowing tablets.
- Patients with chronic or active hepatitis B.
- Patients that have been committed to an institution by official or juridical order. Only applicable in Germany.
- Patients that are dependent upon the sponsor, the trial site or the investigator. Only applicable in Germany.
Participating Centers
- Hospital Santa Creu I Sant Pau – Antonio Lopez Pousa
- Canarias University Hospital– Josefina Cruz
- Valencia University Hospital– Maria J Safont
- La Paz University Hospital– Virginia Martínez Marín
- Virgen Macarena University Hospital– David Vicente
- Virgen de la Victoria University Hospital– Isabel Sevilla
- Gregorio Marañón University Hospital– Rosa Álvarez
- Virgen del Rocío University Hospital– Javier Martín Broto
- Son Espases University Hospital– Pablo Luna
- Vall d’Hebron University Hospital– Claudia Valverde
- IVO – Andrés Poveda
- ICO Hospitalet – Xavier García del Muro
- Xeral Cies Hospital– Juan Antonio Carrasco
- ICO Badalona – Anna Estival González
- Puerta Hierro University Hospital-Majadahonda – Ricardo Cubedo
GEIS 26
Phase otherRare sarcoma registry; a helping tool to evaluate the number of cases from every subtype and their therapeutic approach by the Spanish Group of Sarcoma Research (GEIS)
Sarcoma types included
- Dermatofibrosarcoma protuberans (DFSP)
- Desmoid Tumors (Fibromatosis)
- Solitary Fibrous Tumor
- Inflammatory Myofibroblastic Tumor
- Chordoma
- Pigmented Villonodular Synovitis/ tenosynovial giant cell tumor
- PEComa/ recurrent angiomyolipoma /lymphangioleiomyomatosis
- Giant cell Tumor of bone
Participating Centers
- Reina Sofía Hospital
- Oncogranada Clinic
- Virgen de la Victoria Hospital. Málaga
- Virgen del Rocío Hospital
- Obispo Polanco Hospital
- Miguel Servet Hospital
- Zaragoza Clinical Hospital
- Marqués Valdecilla Hospital
- Albacete University Hospital
- Ciudad Real Hospital
- Virgen de la Salud Hospital
- León Hospital
- Salamanca Hospital
- Germans Trias i Pujol Hospital
- Santa Creu i Sant Pau Hospital
- Vall d'Hebron Hospital
- Sant Joan de Déu Hospital
- ICO Girona
- Ramón y Cajal Hospital
- San Carlos Clinical Hospital
- Gregorio Marañón Hospital
- Pta. Hierro Hospital
- Alcorcón Hospital
- Fuenlabrada Hospital
- 12 Octubre Hospital
- Ruber International Clinic
- Jiménez Díaz Foundation
- Gral. Alicante Hospital
- Provincial Castellón Hospital
- La Fe Hospital
- Clinical University Hospital
- IVO
- Arquitecto Marcide Hospital
- Santiago de Compostela Hospital
- Xeral Cies Hospital
- Son Espases Hospital
- Canarias University Hospital
- Dr. Negrín Hospital
- Insular Gran Canaria University Hospital
- San Pedro Hospital
- Navarra Hospital
- Navarra University Clinic
- Cruces University Hospital
- Basurto University Hospital
- Donostia-Osakidetza Hospital
- Central Asturias Hospital
- Virgen de la Arrixaca Hospital
- Morales Meseguer Hospital
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