Phase I-II trial of sunitinib and/or nivolumab plus chemotherapy in advanced soft tissue and bone sarcomas

2024-514776-40-00 Protocol GEIS-52 Phase I and Phase II (Integrated) - Other Ongoing, recruitment ended

Start 23 Mar 2017 · Status Ongoing, recruitment ended · 2 EU/EEA countries · 26 sites · Protocol GEIS-52

Overview

Sponsor-declared trial summary

Phase Phase I and Phase II (Integrated) - Other
Status Ongoing, recruitment ended
Participants planned 189
Countries 2
Sites 26

Advanced soft tissue and bone sarcomas

Stage 1: PHASE 1 Primary clinical study objective • To determine the recommended dose of the sunitinib plus nivolumab combination for phase II part. PHASE 2 Primary clinical study objective • To evaluate the efficacy of the sunitinib plus nivolumab combination as measured by the progression-free survival rate (PFSR) a…

Key facts

Sponsor
Asoc Grupo Espanol De Investigacion En Sarcomas
Participant type
Pediatric, Patients
Age range
0-17 years, 18-64 years, 65+ years
Gender
Male and Female
Therapeutic area
Diseases [C] - Neoplasms [C04]
Trial duration
23 Mar 2017 → ongoing
Decision date (initial)
2025-01-28
Transition trial
Yes
Low-intervention
No
Rare-disease indication
No
Vulnerable population
Yes

External identifiers

EU CT number
2024-514776-40-00
EudraCT number
2016-004040-10
ClinicalTrials.gov
NCT03277924

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Stage 1:
PHASE 1
Primary clinical study objective
• To determine the recommended dose of the sunitinib plus nivolumab combination for phase II part.

PHASE 2
Primary clinical study objective
• To evaluate the efficacy of the sunitinib plus nivolumab combination as measured by the progression-free survival rate (PFSR) at 6 months in patients with advanced soft tissue and bone sarcomas.

Stage 2:
Cohorts 1-6:
PHASE 2
Primary clinical study objective
• To evaluate the efficacy of the sunitinib plus nivolumab combination as measured by the progression-free survival rate (PFSR) at 6 months (CS/DDCS, EMC, VS, SFT, CCS cohorts) and at 12 months (ASPS cohort).

Cohort 7:
PHASE 1b
Primary clinical study objective
• To determine the maximum tolerated dose (MTD) of the epirubicin + ifosfamide + nivolumab combination in undifferentiated pleomorphic sarcoma and of the doxorubicin + dacarbazine + nivolumab combination in leiomyosarcoma.

Cohort 8:
PHASE 1
Primary clinical study objective
• To determine the maximum tolerated dose (MTD) of the MAP + nivolumab combination.

PHASE 2
Primary clinical study objective
• Proportion of patients achieving good pathological response.

Secondary objectives 29

  1. Stage 1. Phase 1. 1. To evaluate the safety profile according to CTCAE 4.0.
  2. Stage 1. Phase 1. 2. To evaluate efficacy according to progression-free survival rate (PFSR) at 6 months.
  3. Stage 1. Phase 1. 3. To evaluate overall survival (OS).
  4. Stage 1. Phase 1. 4. To determine the overall response rate (ORR).
  5. Stage 1. Phase 1. 5. To contribute to translational studies.
  6. Stage 1. Phase 2. 1. To evaluate overall survival (OS).
  7. Stage 1. Phase 2. 2. To determine the overall response rate (ORR).
  8. Stage 1. Phase 2. 3. To evaluate efficacy according to Choi response.
  9. Stage 1. Phase 2. 4. To evaluate the safety profile according to CTCAE 4.0.
  10. Stage 1. Phase 2. 5. To evaluate the outcome of post protocol treatments.
  11. Stage 1. Phase 2. 6. To contribute to translational studies.
  12. Stage 2. Cohorts 1-6. Phase 2. 1. To evaluate overall survival (OS).
  13. Stage 2. Cohorts 1-6. Phase 2. 2. To determine the overall response rate (ORR).
  14. Stage 2. Cohorts 1-6. Phase 2. 3. To evaluate the safety profile according to CTCAE 5.0.
  15. Stage 2. Cohorts 1-6- Phase 2. 4. To evaluate the outcome of post protocol treatments.
  16. Stage 2. Cohorts 1-6- Phase 2. 5. To evaluate the correlation between efficacy and potential predictive biomarkers.
  17. Stage 2. Cohorts 1-6- Phase 2. 6. To evaluate prognostic and response correlation with the following indicators: neutrophils/platelets; lymphocytes/platelets; and red blood cell distribution width (RDW).
  18. Stage 2. Cohort 7. Phase 1b. 1. To evaluate the safety profile according to CTCAE 5.0.
  19. Stage 2. Cohort 7. Phase 1b. 2. To determine the overall response rate (ORR).
  20. Stage 2. Cohort 7. Phase 1b. 3. To evaluate median progression-free survival (mPFS).
  21. Stage 2. Cohort 7. Phase 1b. 4. To evaluate median overall survival (mOS).
  22. Stage 2. Cohort 8. Phase 1. 1. To evaluate the safety profile according to CTCAE 5.0.
  23. Stage 2. Cohort 8. Phase 1. 2. To evaluate pathological response.
  24. Stage 2. Cohort 8. Phase 1. 3. To determine the overall response rate (ORR).
  25. Stage 2. Cohort 8. Phase 2. 1. To evaluate the safety profile according to CTCAE 5.0.
  26. Stage 2. Cohort 8. Phase 2. 2. To determine the overall response rate (ORR).
  27. Stage 2. Cohort 8. Phase 2. 3. To evaluate progression-free survival rate (PFSR) at 12 months after surgery.
  28. Stage 2. Cohort 8. Phase 2. 4. To evaluate median progression-free survival (mPFS).
  29. Stage 2. Cohort 8. Phase 2. 5. To evaluate median overall survival (mOS).

Conditions and MedDRA coding

Advanced soft tissue and bone sarcomas

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 47

  1. Stage 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. Stage 1. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.
  3. Stage 2. Cohorts 1-6. 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.
  4. Stage 2. Cohorts 1-6. 2. Age: 12-80 years.
  5. Stage 2. Cohorts 1-6. 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.
  6. Stage 2. Cohorts 1-6. 4. Mandatory paraffin embedded tumor blocks must be provided for all subjects without exception for biomarker analysis before treatment.
  7. Stage 2. Cohorts 1-6. 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).
  8. Stage 2. Cohorts 1-6. 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.
  9. Stage 2. Cohorts 1-6. 7. Previous therapy with antiangiogenics is allowed.
  10. Stage 2. Cohorts 1-6. 8. Measurable disease according to RECIST 1.1 criteria.
  11. Stage 2. Cohorts 1-6. 9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
  12. Stage 1. 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.
  13. Stage 2. Cohorts 1-6. 10. Adequate hepatic, renal, cardiac, and hematologic function.
  14. Stage 2. Cohorts 1-6. 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
  15. Stage 2. Cohorts 1-6. 12. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.
  16. Stage 2. Cohorts 1-6. 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.
  17. Stage 2. Cohort 7. 1. The patient or his/her legal tutors must provide written informed consent prior to performance 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. study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of
  18. Stage 2. Cohort 7. 2. Age: 18-80 years.
  19. Stage 2. Cohort 7. 3. Diagnosis of advanced/metastatic undifferentiated pleomorphic sarcoma (UPS) (cohort 7a) or leiomyosarcoma (LMS) (cohort 7b) confirmed by central pathology review.
  20. Stage 2. Cohort 7. 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.
  21. stage 2. Cohort 7. 5. Measurable disease according to RECIST v1.1 criteria.
  22. Stage 2. Cohort 7. 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
  23. Stage 1. Age: 18-80 years.
  24. Stage 2. Cohort 7. 7. The patient must be naïve of any previous treatment with anthracyclines (not even in adjuvant chemotherapy).
  25. stage 2. Cohort 7. 8. Adequate organ, hepatic, renal, cardiac, and hematologic function.
  26. Stage 2. Cohort 7. 9. Laboratory tests as follows: • Absolute neutrophil count ≥ 1,500/mm³ • Platelet count ≥ 100,000/mm³ • Hg > 9 g/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
  27. Stage 2. Cohort 7. 10. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.
  28. Stage 2. Cohort 7. 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.
  29. Stage 2. Cohort 7. 12. Women and 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.
  30. Stage 1. Histologic 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).
  31. Stage 1. Metastatic/advanced disease in progression in the last 6 months.
  32. Stage 1. Measurable disease according to RECIST 1.1 criteria.
  33. Stage 1. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
  34. Stage 1. Adequate hepatic, renal, cardiac, and hematologic function.
  35. Stage 1. 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 • AST and ALT ≤ 2.5 times upper limit of normal • Creatinine ≤ 1.5 mg/dL • Calcium ≤ 12 mg/dL • Blood glucose < 150 mg/dL
  36. Stage 2. 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.
  37. Stage 2. Cohort 8. 2. Age: 12-40 years.
  38. Satge 2. Cohort 8. 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.
  39. Stage 2. Cohort 8. 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.
  40. Stage 2. Cohort 8. 5. Measurable disease according to RECIST v1.1 criteria.
  41. Stage 2. Cohort 8. 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
  42. Stage 2. Cohort 8. 7. The patient must be naïve of any previous treatment.
  43. Stage 2. Cohort 8. 8. Adequate organ, hepatic, renal, cardiac, and hematologic function.
  44. Stage 2. Cohort 8. 9. Laboratory tests as follows: • Absolute neutrophil count ≥ 1,500/mm³ • Platelet count ≥ 100,000/mm³ • Hg > 9 g/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
  45. Stage 2. Cohort 8. 10. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan assessed within 28 days before enrollment.
  46. Stage 2. Cohort 8. 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.
  47. Stage 2. Cohort 8. 12. Women and 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 68

  1. Stage 1. 1. Four or more previous lines of chemotherapy for the advanced disease.
  2. Satge 1. 2. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
  3. Stage 1. 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. Stage 1. 4. Active, known or suspected autoimmune disease.
  5. Stage 1. 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. Stage 1. 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. Stage 1. 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. Stage 1. 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. Stage 1. 9. Evidence of a bleeding diathesis.
  10. Stage 1. 10. Ongoing cardiac dysrhythmias > Grade 2.
  11. Stage 1. 11. Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg despite optimal medical therapy.
  12. Stage 1. 12. Psychiatric illness or social situation that would preclude study compliance.
  13. Stage 1. 13. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.
  14. Stage 1. 14. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
  15. Stage 1. 15. Hemorrhage ≥ Grade 3 in the past 4 weeks.
  16. Stage 1. 16. History of allergy to study drug components.
  17. Stage 1. 17. Previous anticoagulants due to thrombotic events.
  18. Stage 1. 18. History of another cancer with the exception of adequately treated basal cell carcinoma or cervical cancer in situ.
  19. Stage 1. 19. Presence of brain or central nervous system metastases.
  20. Stage 2. Cohorts 1-6. 1. Four or more previous lines of chemotherapy.
  21. Stage 2. Cohorts 1-6. 2. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
  22. Stage 2. Cohorts 1-6. 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.).
  23. Stage 2. Cohorts 1-6. 4. Active, known or suspected autoimmune disease.
  24. Stage 2. Cohorts 1-6. 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.
  25. Stage 2. Cohorts 1-6. 6. Uncontrolled intercurrent illness (or within 12 months prior to first dose of study drug) including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting, 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).
  26. Stage 2. Cohorts 1-6. 7. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
  27. Stage 2. Cohorts 1-6. 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
  28. Stage 2. Cohorts 1-6. 9. Evidence of a bleeding diathesis.
  29. Stage 2. Cohorts 1-6. 10. Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg despite optimal medical therapy.
  30. Stage 2. Cohorts 1-6. 11. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.
  31. Stage 2. Cohorts 1-6. 12. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
  32. Stage 2. Cohorts 1-6. 13. Hemorrhage ≥ Grade 3 in the past 4 weeks.
  33. Stage 2. Cohorts 1-6. 14. History of allergy to study drug components.
  34. Stage 2. Cohorts 1-6. 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.
  35. Stage 2. Cohorts 1-6. 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.
  36. Stage 2. Cohorts 1-6. 17. Presence of brain or central nervous system metastases, unless they are controlled (completely resected or irradiated and/or asympthomatic, no need of steroids).
  37. Stage 2. Cohorts 1-6. 18. Unwilling to participate in the translational study (not providing mandatory biopsies at baseline).
  38. Stage 2. Cohorts 1-6. 19. Live vaccine 30 days or fewer prior to enrollment.
  39. Stage 2. Cohort 7. 1. Diagnosis of any sarcoma different from undifferentiated pleomorphic sarcoma and leiomyosarcoma.
  40. Stage 2. Cohort 7. 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.
  41. Stage 2. Cohort 7. 3. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
  42. Stage 2. Cohort 7. 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.).
  43. Stage 2. Cohort 7. 5. Active, known or suspected autoimmune disease.
  44. Stage 2. Cohort 7. 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.
  45. Stage 2. Cohort 7. 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).
  46. Stage 2. Cohort 7. 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.
  47. Stage 2. Cohort 7. 9. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.
  48. Stage 2. Cohort 7. 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.
  49. Stage 2. Cohort 7. 11. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
  50. Stage 2. Cohort 7. 12. History of allergy to study drug components.
  51. Stage 2. Cohort 7. 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.
  52. Stage 2. Cohort 7. 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).
  53. Stage 2. Cohort 7. 15. Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily traken.
  54. Stage 2. Cohort 8. 1. Diagnosis of parosteal, periosteal osteosarcoma or any other bone sarcoma.
  55. Stage 2. Cohort 8. 2. Previous systemic therapy.
  56. Stage 2. Cohort 8. 3. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
  57. Stage 2. Cohort 8. 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.).
  58. Stage 2. Cohort 8. 5. Active, known or suspected autoimmune disease.
  59. Stage 2 . Cohort 8. 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.
  60. Stage 2. Cohort 8. 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).
  61. Stage 2. Cohort 8. 8. HBV and HCV serologies must be performed 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.
  62. Stage 2. Cohort 8. 9. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.
  63. Stage 2. Cohort 8. 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.
  64. Stage 2. Cohort 8. 11. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
  65. Stage 2. Cohort 8. 12. History of allergy to study drug components.
  66. Stage 2. Cohort 8. 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.
  67. Stage 2. Cohort 8. 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).
  68. Stage 2. Cohort 8. 15. Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily taken.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

  1. Stage 1. Phase 1. The recommended dose of the sunitinib and nivolumab combination for phase II part will be determined by assessing adverse events according to CTCAE 4.0 and they will be used as a rule for escalating or diminishing dose levels according to the dose-limiting toxicities detailed in the protocol.
  2. Stage 1. Phase 2. Progression-free survival rate (PFSR): Efficacy measured by the PFSR at 6 months according to RECIST 1.1. PFSR at 6 months is defined as the percentage of patients who did not experience progression or death due to any cause since enrollment until month 6 after enrollment.
  3. Stage 2. Cohorts 1-6. Phase 2. 1. CS/DDCS, EMC, VS, SFT, and CCS cohorts: 6-month progression-free survival rate (PFSR): Efficacy measured by the PFSR at 6 months according to RECIST 1.1. PFSR at 6 months is defined as the percentage of patients who did not experience progression or death due to any cause since enrollment until month 6 after enrollment.
  4. Stage 2. Cohorts 1-6. Phase 2. 2. ASPS cohort: 12-month progression-free survival rate (PFSR): Efficacy measured by the PFSR at 12 months according to RECIST 1.1. PFSR at 12 months is defined as the percentage of patients who did not experience progression or death due to any cause since the date of enrollment until month 12 after enrollment.
  5. Stage 2. Cohort 7. Phase 1b. The maximum tolerated dose (MTD) of the epirubicin + ifosfamide + nivolumab combination will be determined by assessing adverse events according to CTCAE 5.0 and they will be used for adjusting dose levels according to the dose-limiting toxicities detailed in the protocol.
  6. Stage 2. Cohort 8. Phase 1. The maximum tolerated dose (MTD) of the MAP + nivolumab combination will be determined by assessing adverse events according to CTCAE 5.0 and they will be used for adjusting dose levels according to the dose-limiting toxicities detailed in the protocol.
  7. Stage 2. Cohort 8. Phase 2. Proportion of patients achieving good pathological response (≥90% necrosis) in the surgical specimen after neoadjuvant chemotherapy + nivolumab.

Secondary endpoints 30

  1. Stage 1. Phase 1. 1. Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 4.0.
  2. Stage 1. Phase 1. 2. Progression-free survival rate (PFSR): Efficacy measured by the PFSR at 6 months according to RECIST 1.1. PFSR at 6 months is defined as the percentage of patients who did not experience progression or death due to any cause since enrollment until month 6 after enrollment.
  3. Stage 1. Phase 1. 3. Overall survival (OS): OS is defined as the time between the date of enrollment and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive.
  4. Stage 1. Phase 1. 4. Overall response rate (ORR): ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 criteria).
  5. Stage 1. Phase 1. 5. Contribution to translational studies will be performed by providing biological samples.
  6. Stage 1. Phase 2. 1. Overall survival (OS): OS is defined as the time between the date of enrollment and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive.
  7. Stage 1. Phase 2. 2. Overall response rate (ORR): ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 criteria).
  8. Stage 1. Phase 2. 3. Efficacy measured through tumor response according to Choi criteria. The evaluation criteria will be based on the identification of target lesions in baseline and their follow up until tumor progression.
  9. Stage 1. Phase 2. 4. Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 4.0.
  10. Stage 1. Phase 2. 5. Clinical outcomes of post protocol treatments assessed by observation of such treatments in follow-up stage.
  11. Stage 1. Phase 2. 6. Contribution to translational studies will be performed by providing biological samples.
  12. Stage 2. Cohorts 1-6. Fase 2. 1. Overall survival (OS): OS is defined as the time between the date of enrollment and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive.
  13. Stage 2. Cohorts 1-6. Fase 2. 2. Overall response rate (ORR): ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 criteria).
  14. Stage 2. Cohorts 1-6. Fase 2. 3. Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 5.0.
  15. Stage 2. Cohorts 1-6. Fase 2. 4. Clinical outcomes of post protocol treatments assessed by observation of such treatments in follow-up stage.
  16. Stage 2. Cohorts 1-6. Fase 2. 5. Correlation between efficacy and potential predictive biomarkers assessed by finding relationships between clinical efficacy results and translational data.
  17. Stage 2. Cohorts 1-6. Fase 2. 6. Prognostic and response correlation with neutrophils/platelets; lymphocytes/platelets; and red blood cell distribution width (RDW), by assessing hematology tests at baseline, after 2 weeks (before nivolumab), after 1 month, at progression, and at response.
  18. Stage 2. Cohorts 1-6. Fase 2. 7. 6-month progression-free survival rate (PFSR): Efficacy measured by the PFSR at 6 months according to RECIST 1.1. PFSR at 6 months is defined as the percentage of patients who did not experience progression or death due to any cause since the date of enrollment until month 6 after enrollment.
  19. Stage 2. Cohort 7. Phase 1b. 1. Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 5.0.
  20. Stage 2. Cohort 7. Phase 1b. 2. Overall response rate (ORR): ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 criteria and central review).
  21. Stage 2. Cohort 7. Phase 1b. 3. Median progression-free survival (mPFS): PFS is defined as the time between the date of enrollment and the date of progression or death due to any cause.
  22. Stage 2. Cohort 7. Phase 1b. 4. Median overall survival (mOS): OS is defined as the time between the date of enrollment and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive.
  23. Stage 2. Cohort 8. Phase 1. 1. Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 5.0.
  24. Stage 2. Cohort 8. Phase 1. 2. Pathological response measured by percentage of necrosis in surgical specimen.
  25. Stage 2. Cohort 8. Phase 1. 3. Overall response rate (ORR): ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 criteria and central review).
  26. Stage 2. Cohort 8. Phase 2. 1. Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Toxicity will be graded and tabulated by using CTCAE 5.0.
  27. Stage 2. Cohort 8. Phase 2. 2. Overall response rate (ORR): ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 criteria and central review).
  28. Stage 2. Cohort 8. Phase 2. 3. 12-month progression-free survival rate (PFSR): Efficacy measured by the PFSR at 12 months after surgery according to RECIST 1.1. PFSR at 12 months is defined as the percentage of patients who did not experience progression or death due to any cause since the date of surgery until month 12 after surgery.
  29. Stage 2. Cohort 8. Phase 2. 4. Median progression-free survival (mPFS): PFS is defined as the time between the date of enrollment and the date of progression or death due to any cause.
  30. Stage 2. Cohort 8. Phase 2. 5. Median overall survival (mOS): OS is defined as the time between the date of enrollment and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sutent 12.5 mg hard capsules

PRD3432966 · Product

Active substance
Sunitinib
Substance synonyms
SU-011,248, N-(2-(DIETHYLAMINO)ETHYL)-5-((Z)-(5-FLUORO-2-OXO-1,2-DIHYDRO-3H-INDOL-3-YLIDENE)METHYL)-2,4-DIMETHYL-1H-PYRROLE-3-CARBOXAMIDE
Pharmaceutical form
CAPSULE, HARD
Route of administration
ORAL
Authorisation status
Authorised
ATC code
L01EX01 — -
Marketing authorisation
EU/1/06/347/001
MA holder
PFIZER EUROPE MA EEIG
MA country
Norway
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

OPDIVO 10 mg/mL concentrate for solution for infusion.

PRD2941372 · Product

Active substance
Nivolumab
Substance synonyms
BMS936558, ABP 206
Pharmaceutical form
SOLUTION FOR INFUSION
Route of administration
INTRAVENOUS USE
Authorisation status
Authorised
ATC code
L01FF01 — -
Marketing authorisation
EU/1/15/1014/001
MA holder
BRISTOL-MYERS SQUIBB PHARMA EEIG
MA country
EU
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Sutent 25 mg hard capsules

PRD3432965 · Product

Active substance
Sunitinib
Substance synonyms
SU-011,248, N-(2-(DIETHYLAMINO)ETHYL)-5-((Z)-(5-FLUORO-2-OXO-1,2-DIHYDRO-3H-INDOL-3-YLIDENE)METHYL)-2,4-DIMETHYL-1H-PYRROLE-3-CARBOXAMIDE
Pharmaceutical form
CAPSULE, HARD
Route of administration
ORAL USE
Authorisation status
Authorised
ATC code
L01EX01 — -
Marketing authorisation
EU/1/06/347/002
MA holder
PFIZER EUROPE MA EEIG
MA country
Liechtenstein
Paediatric formulation
No
Orphan designation
No
Modified vs. Marketing Authorisation
No

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Asoc Grupo Espanol De Investigacion En Sarcomas

5 Total trials 1 Recruiting 3 Ended
Academic / Non-commercial
Sponsor organisation
Asoc Grupo Espanol De Investigacion En Sarcomas
Address
Calle Del Conde De Aranda 20 Planta 5 Puerta Derecha
City
Madrid
Postcode
28001
Country
Spain

Scientific contact point

Organisation
Asoc Grupo Espanol De Investigacion En Sarcomas
Contact name
Adriana Rojo

Public contact point

Organisation
Asoc Grupo Espanol De Investigacion En Sarcomas
Contact name
Adriana Rojo

Locations

2 EU/EEA countries · 26 investigational sites

By country

CountryMS statusPlanned subjectsSites
Italy Ended 40 3
Spain Ongoing, recruitment ended 145 23
Rest of world
United Kingdom
 — 4 —

Investigational sites

Italy

3 sites · Ended
Istituto Nazionale Dei Tumori
Medical Oncology, Via Giacomo Venezian 1, 20133, Milan
Istituto Di Candiolo Fondazione Del Piemonte Per L'Oncologia IRCCS
Medical Oncology, Strada Provinciale 142 Orba Km 3,95, 10060, Candiolo
Istituto Ortopedico Rizzoli
Medical Oncology, Via Giulio Cesare Pupilli 1, 40136, Bologna

Spain

23 sites · Ongoing, recruitment ended
Hospital Universitario Y Politecnico La Fe
Medical Oncology, Avenida Fernando Abril Martorell 106, 46026, Valencia
University Hospital Virgen Del Rocio S.L.
Medical Oncology, Avenida De Manuel Siurot S/n, 41013, Sevilla
Hospital General Universitario Gregorio Maranon
Pediatric Oncology, Calle Del Doctor Esquerdo 46, 28007, Madrid
Hospital Universitari Vall D Hebron
Pediatric Oncology, Passeig De La Vall D'Hebron 119-129, 08035, Barcelona
Hospital Universitario De Canarias
Medical Oncology, Carretera Ofra S/N, 38320, San Cristobal De La Laguna
University Hospital Virgen Del Rocio S.L.
Pediatric Oncology, Avenida De Manuel Siurot S/n, 41013, Sevilla
Hospital Universitario 12 De Octubre
Medical Oncology, Avenida De Cordoba Sn, 28041, Madrid
Hospital Universitari Vall D Hebron
Medical Oncology, Passeig De La Vall D'Hebron 119-129, 08035, Barcelona
Hospital Universitario De Canarias
Pediatric Oncology, Carretera Ofra S/N, 38320, San Cristobal De La Laguna
Hospital Universitario La Paz
Pediatric Oncology, Paseo De La Castellana 261, 28046, Madrid
Hospital Clinico Universitario De Valencia
Medical Oncology, Avenida Blasco Ibanez 17, 46010, Valencia
Hospital Universitario Miguel Servet
Medical Oncology, Paseo De Isabel La Catolica 1-3, 50009, Zaragoza
Hospital De La Santa Creu I Sant Pau
Pediatric Oncology, Carrer De San Quinti 89, 08041, Barcelona
University Clinical Hospital Virgen De La Arrixaca
Medical Oncology, Carretera Madrid-Cartagena S/N, El Palmar, Murcia
Hospital Clinico San Carlos
Medical Oncology, Calle Del Profesor Martín Lagos S/n, 28040, Madrid
Hospital Universitario Y Politecnico La Fe
Pediatric Oncology, Avenida Fernando Abril Martorell 106, 46026, Valencia
Hospital Universitario Miguel Servet
Pediatric Oncology, Paseo De Isabel La Catolica 1-3, 50009, Zaragoza
Hospital Universitario 12 De Octubre
Pediatric Oncology, Avenida De Cordoba Sn, 28041, Madrid
Hospital De La Santa Creu I Sant Pau
Medical Oncology, Carrer De San Quinti 89, 08041, Barcelona
Hospital Infantil Universitario Nino Jesus
Pediatric Oncology, Avenida Menendez Pelayo 65, 28009, Madrid
Hospital Universitario Fundacion Jimenez Diaz
Medical Oncology, Avenida De Los Reyes Catolicos 2, 28040, Madrid
Hospital Universitario La Paz
Medical Oncology, Paseo De La Castellana 261, 28046, Madrid
Hospital Universitario De Leon
Medical Oncology, Calle Altos De Nava S/n, 24071, Leon

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Country Trial startTrial end Recruitment startRecruitment end Early termination
Italy 2018-02-23 2025-09-30 2021-02-02 2024-02-07
Spain 2017-03-23 2017-04-05 2024-06-30

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

TypeTitleVersion
Protocol (for publication) D1_Protocol 2024-514776-40-00 ITALY_Public 8
Protocol (for publication) D1_Protocol 2024-514776-40-00_Public 12
Recruitment arrangements (for publication) K1_Recruitment arrangements 1
Recruitment arrangements (for publication) K1_Recruitment arrangements 1
Subject information and informed consent form (for publication) L1_SIS and ICF Samples Adults_Public 4.0
Subject information and informed consent form (for publication) L1_SIS and ICF Samples C1-6 Adults_Public 6
Subject information and informed consent form (for publication) L1_SIS and ICF Samples C1-6 Minor_Public 3
Subject information and informed consent form (for publication) L1_SIS and ICF Samples C7 Adults_Public 2
Subject information and informed consent form (for publication) L1_SIS and ICF Samples C8 Adults_Public 3
Subject information and informed consent form (for publication) L1_SIS and ICF Samples C8 Minors_Public 3
Subject information and informed consent form (for publication) L1_SIS and ICF Study Adults_Public 4.0
Subject information and informed consent form (for publication) L1_SIS and ICF Study C1-6 Adults_Public 7
Subject information and informed consent form (for publication) L1_SIS and ICF Study C1-6 Minor_Public 4
Subject information and informed consent form (for publication) L1_SIS and ICF Study C7 Adults_Public 3
Subject information and informed consent form (for publication) L1_SIS and ICF Study C8 Adults_Public 3
Subject information and informed consent form (for publication) L1_SIS and ICF Study C8 Minors_Public 3
Subject information and informed consent form (for publication) L2_Other subject information material Letter to General practicioner 1.2
Summary of Product Characteristics (SmPC) (for publication) E2_SmPC Opdivo 1
Summary of Product Characteristics (SmPC) (for publication) E2_SmPC Sutent 1
Summary of Product Characteristics (SmPC) (for publication) E2_SmPC Sutent 1
Synopsis of the protocol (for publication) D1_Protocol synopsis 2024-514776-40-00_Public 11
Synopsis of the protocol (for publication) D1_Protocol synopsis ITALY IT 2024-514776-40-00_Public 8
Synopsis of the protocol (for publication) D1_Protocol synopsis Spain ES 2024-514776-40-00_Public 12

Application history

2 submissions — initial application plus substantial / non-substantial modifications

#TypeCodeSubmittedReference MSConclusionDecision date
1 INITIAL IN 2024-12-17 Spain Acceptable
2025-01-13
 2025-01-13
2 SUBSTANTIAL MODIFICATION SM-2 2026-01-30 Spain Acceptable
2026-03-23
 2026-03-24

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