AzTrials
AzTrials

Soft Tissue SarcomaPhase 1/2ImmunoSarcNCT03277924

Trial of Sunitinib and/or Nivolumab Plus Chemotherapy in Advanced Soft Tissue and Bone Sarcomas

A Phase 1/2 study testing Sunitinib 37.5 MG, Sunitinib 25 MG [Sutent], Nivolumab 100 MG/10 ML [Opdivo] and Epirubicin in people with Soft Tissue Sarcoma and Bone Sarcoma, run by Grupo Espanol de Investigacion en Sarcomas at 13 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Phase I-II, single-arm, non-randomized, open-label, multicenter, international clinical trial, with two stages. Stage one has two cohorts (soft tissue sarcoma and bone sarcoma) and stage two has eight cohorts (DDCS, EMC, VS, SFT, CCS, ASPS, UPS, LMS and OS). Read more about this study

Who is it for?
Ages 12 to 80 years
Conditions the study is for
Soft Tissue Sarcoma, Bone Sarcoma
What is being tested?
Sunitinib 37.5 MG, Sunitinib 25 MG [Sutent], Nivolumab 100 MG/10 ML [Opdivo] and Epirubicin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
197 participants
Where
13 sitesin 3 countries
Study dates
31 May 2017to 30 Jun 2024
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 12 to 80 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • 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.
  • Age: 18-80 years.
  • 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).
  • Metastatic/advanced disease in progression in the last 6 months.
  • Measurable disease according to RECIST 1.1 criteria.
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  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
  • Adequate hepatic, renal, cardiac, and hematologic function.
  • 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
  • Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.
  • Females of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to enrollment and agree to use birth control measures during study treatment and for 7 months after its completion. Patients must not be pregnant or nursing at study entry. Women/men of reproductive potential must have agreed to use an effective contraceptive method.
  • INCLUSION CRITERIA 1, 5, 6, 7, 8, 9 AND 10 OF STAGE 1, ARE REPEATED IN ALL COHORTS OF STAGE 2.
  • Stage 2
  • Cohort 1-6
  • 2. Age: 12-80 years. 3. Diagnosis of dedifferentiated chondrosarcoma, extraskeletal myxoid chondrosarcoma, vascular sarcomas (including angiosarcoma, hemangioendothelioma and intimal sarcomas), solitary fibrous tumor (excluding dedifferentiated SFT), alveolar soft part sarcoma, and clear cell sarcoma confirmed by central pathology review. 4. Mandatory paraffin embedded tumor blocks must be provided for all subjects without exception for biomarker analysis before treatment. 5. Metastatic/locally advanced unresectable disease in progression in the last 6 months according to RECIST 1.1. Patients with recent diagnosis of metastatic disease can be eligible (if they are not candidates to anthracycline-based treatment).
  • 6. Patients should have previously received at least anthracyclines. Patients in the cohorts of subtypes sensitive to antiangiogenic therapy (SFT, ASPS, CCS, EMC or DDCS) are eligible even if not previously treated. 7. Previous therapy with antiangiogenics is allowed.
  • Cohort 7
  • 2. Age: 18-80 years. 3. Diagnosis of advanced/metastatic undifferentiated pleomorphic sarcoma (UPS) (cohort 7a) or leiomyosarcoma (LMS) (cohort 7b) confirmed by central pathology review. 4. Mandatory pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissue must be provided for all subjects without exception for central pathology review and the translational study. Archive tissue can be used for diagnosis confirmation but a recent biopsy (<3 months) is mandatory for translational research. If it is not available or is older than 3 months, the patient must be willing to have a pre-treatment re-biopsy of primary or metastatic tumor (baseline biopsy) within 28 days prior to enrollment. 7. The patient must be naïve of any previous treatment with anthracyclines (not even in adjuvant chemotherapy). 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.
  • Cohort 8
  • 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.
  • Age: 12-40 years.
  • 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.
  • 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.
  • 7. The patient must be naïve of any previous treatment. 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.

Who cannot join

  • Stage 1
  • Four or more previous lines of chemotherapy for the advanced disease.
  • Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
  • Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.).
  • Active, known or suspected autoimmune disease.
  • 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.
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  • 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).
  • Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
  • Other disease or illness within the past 6 months, including any of the following: • Myocardial infarction Severe or unstable angina • Coronary or peripheral artery bypass graft • Symptomatic congestive heart failure • Cerebrovascular accident or transient ischemic attack • Pulmonary embolism 9. Evidence of a bleeding diathesis. 10. Ongoing cardiac dysrhythmias > Grade 2. 11. Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg despite optimal medical therapy. 12. Psychiatric illness or social situation that would preclude study compliance. 13. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication. 14. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG. 15. Hemorrhage ≥ Grade 3 in the past 4 weeks. 16. History of allergy to study drug components. 17. Previous anticoagulants due to thrombotic events. 18. History of another cancer with the exception of adequately treated basal cell carcinoma or cervical cancer in situ. 19. Presence of brain or central nervous system metastases.
  • Stage 2
  • Cohort 1-6
  • Four or more previous lines of chemotherapy.
  • Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
  • Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.).
  • Active, known or suspected autoimmune disease.
  • 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.
  • 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).
  • Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
  • 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
  • Evidence of a bleeding diathesis.
  • Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg despite optimal medical therapy.
  • Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.
  • Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
  • Hemorrhage ≥ Grade 3 in the past 4 weeks.
  • History of allergy to study drug components.
  • 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.
  • 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.
  • Presence of brain or central nervous system metastases, unless they are controlled (completely resected or irradiated and/or asympthomatic, no need of steroids).
  • Unwilling to participate in the translational study (not providing mandatory biopsies at baseline).
  • Live vaccine 30 days or fewer prior to enrollment.
  • Cohort 7
  • Diagnosis of any sarcoma different from undifferentiated pleomorphic sarcoma and leiomyosarcoma.
  • 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.
  • Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
  • Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.).
  • Active, known or suspected autoimmune disease.
  • 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.
  • 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).
  • 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.
  • Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.
  • 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.
  • Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
  • History of allergy to study drug components.
  • 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.
  • 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).
  • Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily traken.
  • Cohort 8
  • Diagnosis of parosteal, periosteal osteosarcoma or any other bone sarcoma.
  • Previous systemic therapy.
  • Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
  • Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.).
  • Active, known or suspected autoimmune disease.
  • 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.
  • 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).
  • 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.
  • Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.
  • 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.
  • Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
  • History of allergy to study drug components.
  • 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.
  • 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).
  • Patient is unwilling to provide mandatory translational tumor samples or biopsies (if required) cannot be easily taken.

Trial locations and contacts

13 sites in 3 countries.

13 sites in 3 countries

Spain9 sites

  • Hospital Universitari Vall d'Hebrón

    Barcelona, 08035

  • Hospital de la Santa Creu i Sant Pau

    Barcelona, 08041

  • Hospital Universitario Fundación Jiménez Díaz

    Madrid, Madrid, 28040

  • Hospital Universitario 12 de Octubre

    Madrid, 28041

  • Hospital Universitario La Paz

    Madrid, 28046

  • Complejo Hospitalario Universitario de Canarias

    San Cristóbal de La Laguna, Santa Cruz De Tenerife, 38320

  • Hospital Universitario Virgen del Rocío

    Seville, 41013

  • Hospital Universitari i Politècnic La Fe

    Valencia, 46026

  • Hospital Universitario Miguel Servet

    Zaragoza, 50009

Other trials in Spain

Italy3 sites

  • Istituto Ortopedico Rizzoli

    Bologna, 40136

  • Candiolo Cancer Institute - FPO, IRCCS

    Candiolo, 10060

  • Istituto Nazionale dei Tumori

    Milan, 20133

Other trials in Italy

United Kingdom1 site

  • University College London Hospitals NHS Foundation Trust

    London, NW1 2PG

Other trials in United Kingdom

About this study

Official title: Phase I-II Trial of Sunitinib and/or Nivolumab Plus Chemotherapy in Advanced Soft Tissue and Bone Sarcomas

Phase I-II, single-arm, non-randomized, open-label, multicenter, international clinical trial, with two stages. Stage one has two cohorts (soft tissue sarcoma and bone sarcoma) and stage two has eight cohorts (DDCS, EMC, VS, SFT, CCS, ASPS, UPS, LMS and OS). Nine sites in Spain, 3 sites in Italy and 1 site in the United Kingdom.

Stage 1 (PHASE 1 and PHASE 2)

Read more

Objective: To determine the recommended dose of the sunitinib plus nivolumab combination for phase II part. 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.

Treatment: Adult patients will receive an initial induction phase (IP) from day 1 to day 14 of sunitinib 37.5 mg/day followed by a maintenance phase (MP) of sunitinib 37.5 mg/day continuously + nivolumab 3 mg/kg intravenous every 2 weeks infused over 1 hour. If three or more DLTs occur from day 15 to 42, for an initial set of 10 patients, sunitinib dose will be lowered to 25 mg/day or treatment schedule will be changed to 2 weeks on and one week off until recovery from toxicities.

Stage 2

C1 to 6

Objective: To evaluate the efficacy of the sunitinib plus nivolumab combination as measured by PFSR at 6 months (CS/DDCS, EMC, VS, SFT, CCS cohorts) and at 12 months (ASPS cohort).

Treatment: Adult patients will receive an initial induction phase (IP) from day 1 to day 14 of sunitinib 37.5 mg/day followed by a maintenance phase (MP) of sunitinib 25mg/day continuously + nivolumab 240mg every 2 weeks. Pediatric patients will receive an initial IP from day 1 to day 14 of (<18 years) sunitinib at 25 mg/day unless the body surface area (BSA) of the patient is >1.7. If BSA is >1.7, then sunitinib 37.5 mg/day will be given followed by a MP of sunitinib 25 mg/day continuously + nivolumab 240 mg every 2 weeks regimen (if weight ≥40 kg) or sunitinib 25 mg/day continuously + nivolumab 3 mg/kg every 2 weeks regimen (if weight <40kg).

C 7

Objective: To determine the MTD of the epirubicin + ifosfamide + nivolumab combination in undifferentiated pleomorphic sarcoma and of the doxorubicin + dacarbazine + nivolumab combination in leiomyosarcoma.

Treatment:Cohort 7a dose level 0: Patients will receive epirubicin dose of 60 mg/m2/d, d1 and d2 IV 20 minutes; followed by ifosfamide 3 g/m2/d d1-3, IV 3h with MESNA protection (40% of total dose of ifosfamide in each administration at 0, 3 and 6 h from ifosfamide initiation). Once finished Ifosfamide infusion of day 3, nivolumab is administered during 30 minutes, at dose of 360 mg IV, Q3W. GCSF support is mandatory. If three or more DLTs occur nivolumab dose will be lowered to dose level -1.

Cohort 7b dose level 0: Patients will receive doxorubicin at dose of 75 mg/m2/d, d1 IV 20 minutes; followed by dacarbazine 400 mg//m2/d IV 60 minutes. Dacarbazine is administered also on day 2 of cycle. Once finished Dacarbazine infusion of day 2, nivolumab is administered for 30 minutes, at dose of 360 mg IV, Q3W. GCSF support is mandatory. If three or more DLTs occur nivolumab dose will be lowered to dose level -1 where patients will receive doxorubicin at dose of 75 mg/m2/d, d1 IV 20 minutes; followed by dacarbazine 400 mg//m2/d IV 60 minutes. Dacarbazine is administered also on day 2 of cycle. Once finished dacarbazine infusion of day 2, nivolumab is administered for 30 minutes, at dose of 240 mg IV, Q3W. GCSF support is mandatory. One-year maintenance of nivolumab is foreseen in the absence of progressive disease.

C 8

Objectives:To determine the MTD of the MAP + nivolumab combination (phase I). Proportion of patients achieving good pathological response (phase II)

Treatment dose level 0: In the IP, patients will receive CDDP 120 mg/m2 in 48h IV infusion (days 1-2) followed by doxorubicin 75 mg/m2 in 48h IV infusion (days 3-4). CDDP and doxorubicin will be given on days 1-4 and 36-39. Nivolumab administration will start on day 4 at flat dose 240 mg (after the end of doxorubicin), being the following doses administered on days 18, 39, and 53 (240 mg). HD methotrexate at 12 g/m2 in 2-h infusion will be administered on days 22, 29, 57, and 64. Surgery will be performed after finishing IP. Adjuvant chemotherapy will be administered after surgery. During the MP patients will receive nivolumab on day 210, every two weeks up to day 364. If three or more DLTs occur, then nivolumab dose level -1 will be activated.

Read the detailed description

Stage 1

Sample size has been obtained for a one-arm one-stage survival design based on Brookmeyer-Crowley like test. The test statistic for survival probability is assumed to be based on the non-parametric estimate of the survival distribution. For STS 2nd line cohort sample size has been obtained for the primary endpoint progression-free survival rate (PFSR) at 6 months. Estimated accrual time: 24 months. A PFSR of 5% will be considered not promising, whereas a PFSRof 15% will be considered promising in this population. With a type I error α of 0.05 and a power of 0.80, 48 patients are needed in this cohort. For bone sarcoma 2nd line cohort sample size has been obtained under the same assumptions than above, but with a type I error α of 0.10, therefore 38 patients are needed in this cohort.

Stage 2

Cohorts 1-6:

COHORT 1 - Dedifferentiated Chondrosarcoma (DDCS): For DDCS sample size is obtained for the primary endpoint of 6-month progression-free survival rate, estimated accrual 24 months. A 6-m PFSR of 40% will be considered not promising whereas of 70% will be considered promising in this population. With a type I error α of 0.05 and a power of 0.90, 23 patients were estimated in this cohort. With one arm survival design based on survival probability a Brookmeyer-Crowley like test is assumed (Brookmeyer, 1982) [65]. If at least 14 cases over the 23 patients have a 6-m PFSR, then further investigation of the experimental treatment is warranted.

COHORT 2 - Extraskeletal Myxoid Chondrosarcoma (EMC): For EMC sample size is obtained for the primary endpoint of 6-month progression-free survival rate, and estimated accrual 24 months. A 6-m PFSR of 50% will be considered not promising whereas of 80% will be considered promising in this population. With a type I error α of 0.05 and a power of 0.90, 22 patients were estimated in this cohort. With Simon's two-stage Minimax design, at least 13 cases over the 20 first patients (stage 1) should have a 6-m PFSR. Then additional 2 patients would be accrued up to 22 patients. If at least 15 patients had a 6-m PFSR, further investigation of the drug is warranted.

COHORT 3 - Vascular sarcomas (VS) (including angiosarcoma, hemangioendothelioma and intimal sarcomas): For VS sample size is obtained for the primary endpoint of 6-month progression-free survival rate, and estimated accrual 24 months. A 6-m PFSR of 30% will be considered not promising whereas of 60% will be considered promising in this population. With a type I error α of 0.05 and a power of 0.90, 23 patients were estimated in this cohort. With Simon's two-stage Minimax design, at least 8 cases over the 18 first patients (stage 1) should have a 6-m PFSR. Then additional 5 patients would be accrued up to 23 patients. If at least 11 patients had a 6-m PFSR, further investigation of the drug is warranted.

COHORT 4 - Solitary Fibrous Tumor (SFT): For SFT cohort sample size is obtained for the primary endpoint of 6-month progression-free survival rate by Choi criteria, and estimated accrual of 24 months. A 6-m PFSR of 35% will be considered not promising whereas of 65% will be considered promising in this population. With a type I error α of 0.05 and a power of 0.90, 24 patients were estimated in this cohort. With Simon's two-stage Minimax design, at least 6 cases over the 14 first patients (stage 1) should have a 6-m PFSR. Then additional 10 patients would be accrued up to 24 patients. If at least 13 patients had a 6-m PFSR, further investigation of the drug is warranted.

COHORT 5 - Alveolar Soft Part Sarcoma (ASPS): For ASPS cohort sample size is obtained for the primary endpoint of 12-month progression-free survival rate by RECIST criteria, and estimated accrual 24 months. A 12-m PFSR of 40% will be considered not promising whereas of 75% will be considered promising in this population. With a type I error α of 0.05 and a power of 0.90, 18 patients were estimated in this cohort. With Simon's two stage Minimax design, at least 7 cases over the 12 first patients (stage 1) should have a 12-m PFSR. Then additional 6 patients would be accrued up to 18 patients. If at least 11 patients had a 12-m PFSR, further investigation of the drug is warranted.

COHORT 6 - Clear Cell Sarcoma (CCS): For CCS cohort sample size is obtained for the primary endpoint of 6-month progression-free survival rate by RECIST criteria, and estimated accrual 24 months. A 6-m PFSR of 25% will be considered not promising whereas of 55% will be considered promising in this population. With a type I error α of 0.05 and a power of 0.90, 23 patients were estimated in this cohort. With Simon's two-stage Minimax design, at least 4 cases over the 13 first patients (stage 1) should have a 6-m PFSR. Then additional 10 patients would be accrued up to 23 patients. If at least 10 patients had a 6-m PFSR, further investigation of the drug is warranted. An additional 5-7% of patients may be recruited to compensate for potential unevaluable participants.For the variables that follow binomial distributions, like the PFS rate and for the categorical variables, frequencies and percentages will be calculated as well as their confidence interval. If needed, to compare categorical variables both Chi-square test and Fisher's exact test will be performed. Besides, Kaplan-Meier estimations will be used for PFS. Where possible, exploratory analysis will include Cox models to estimate the impact of several factors on PFS.

Cohort 7: This cohort includes a phase 1b study (3+3 design plus expansion cohorts) and therefore no formal sample size has been calculated. Each subcohort (7a: UPS and 7b: LMS) will include between 10 and 20 patients respectively (including the expansions).

Cohort 8: A phase I/II is planned for this cohort. For the phase I part, the safety of the MAP + nivolumab combination will be assessed using a 3+3 design including 6 patients treated at the recommended phase II dose (RP2D). This phase I could include up to 12 patients approximately. Regarding the phase II part, for osteosarcoma with metastasis at presentation and resectable primary tumor, in patients with less than 40 years, sample size is obtained for the primary endpoint of histological response after 2 MAPs of induction. A proportion of 45% of good histological response (≥90% necrosis) will be considered not promising, whereas 68% will be considered promising in this population. With a type I error α of 0.05 and a power of 0.80, 31 patients were estimated in this cohort. With Simon's two-stage Minimax design, at least 7 cases over the 13 first patients (initial part) should have good histological response. Then, additional 18 eligible patients will be accrued up to 31 patients. If at least 19 patients had good histological response, further investigation of the drug is warranted.

Being tested
Sunitinib 37.5 MG, Sunitinib 25 MG [Sutent], Nivolumab 100 MG/10 ML [Opdivo], Epirubicin, Ifosfamide, Doxorubicin
Keywords
Dedifferentiated chondrosarcoma, Extraskeletal myxoid chondrosarcoma, Angiosarcoma, Hemangioendothelioma, Intimal sarcomas, Solitary fibrous tumor, Clear cell sarcoma, Alveolar soft-part sarcoma, Undifferentiated pleomorphic sarcoma, Leiomyosarcoma, Osteosarcoma, Synovial Sarcoma, Epithelioid Hemangioendothelioma, Epithelioid Sarcoma, Ewing's Sarcoma, Chondrosarcoma
Medical subject headings
Sarcoma, Bone Neoplasms, Chondrosarcoma, Extraskeletal Myxoid, Hemangiosarcoma, Hemangioendothelioma, Solitary Fibrous Tumors, Sarcoma, Clear Cell, Sarcoma, Alveolar Soft Part

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Sunitinib 37.5 MG, Sunitinib 25 MG [Sutent]Drug

    Also called Sutent

    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.

  • Nivolumab 100 MG/10 ML [Opdivo]Drug

    Also called Opdivo

    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.

  • EpirubicinDrug

    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.

  • IfosfamideDrug

    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.

  • DoxorubicinDrug

    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.

  • DacarbazineDrug

    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.

  • CisplatinDrug

    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.

  • MethotrexateDrug

    Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.

Study groups in NCT03277924
Study groupRoleWhat they receive
Sunitinib and/or nivolumab plus chemotherapy in advanced STS and BSExperimentalStage 1: IP d1-14 sunitinib 37.5mg/d then MP sunitinib 37.5mg/d+nivolumab 3mg/kg ev 2w. Stage 2: C1-6: IP d1-14 sunitinib 37.5mg/d then MP sunitinib 25mg/d+nivolumab 240mg ev 2w. C7a level 0: Epirubicin 60mg/m2/d, d1,2, ifosfamide 3g/m2/d d1-3 and nivolumab 360mg. 3 or more DLTs level -1 same treatment than in level 0, but nivolumab 240mg. C7b level 0: Doxorubicin 75mg/m2/d, d1, dacarbazine 400mg/m2/d (also on d2) and nivolumab 360mg. 3 or more DLTs level -1 same tratment than in level 0, but nivolumab 240mg. GCSF support is mandatory. 1-year maintenance of nivolumab. C8 level 0: In the IP, CDDP 120mg/m2 (d1-2), doxorubicin 75mg/m2 in (d3-4 and d36-39), nivolumab 240mg (d5), and on d18,39,53 and methotrexate 12g/m2 on d22,29,57,64, surgery and MP with nivolumab on d210, every 2 weeks up to d364. 3 or more DLTs level -1, with nivolumab 360mg on d4,36, surgery and MP with nivolumab on d210, ev 3 weeks up to d364.
Receives: Drug: Sunitinib 37.5 MG, Sunitinib 25 MG [Sutent]; Drug: Nivolumab 100 MG/10 ML [Opdivo]; Drug: Epirubicin; Drug: Ifosfamide; Drug: Doxorubicin; Drug: Dacarbazine; Drug: Cisplatin; Drug: Methotrexate

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: 6 months

  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.

    Measured: 6 months

  3. Stage 2 - Cohort 1-6: Progression-free survival rate (PFSR)

    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 enrollmentuntil month 6 after enrollment.

    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.

    Measured: 6 months for CS/DDCS, EMC, VS, SFT, and CCS and 12 months for ASPS

  4. Stage 2 - Cohort 7: Maximum tolerated dose (MTD)

    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.

    Measured: 1 year

  5. Stage 2 - Cohort 8: Maximum tolerated dose (MTD)

    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.

    Measured: 1 year

Secondary outcomes (11)

  1. Stage 1 and Stage 2 - 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.

    Measured: 2 years

  2. Stage 1 and Stage 2 - Objective 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).

    Measured: 2 months

  3. Stage 2 - Cohort 1-6 Correlation between efficacy and potential predictive biomarkers

    Assessed by finding relationships between clinical efficacy results and translational data.

    Measured: 2 years

  4. Stage 1 and Stage 2 - Safety profile: Adverse events

    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.

    Measured: 3 years

  5. Stage 1 (PHASE 2) and Stage 2 - Cohort 1-6 Clinical outcome

    Clinical outcomes of post protocol treatments assessed by observation of such treatments in follow-up stage.

    Measured: At 36 months

  6. Stage 2 - Cohort 1-6 Prognostic and response correlation

    Prognostic and response correlation with neutrophils/platelets; lymphocytes/platelets; andred blood cell distribution width (RDW), by assessing hematology tests at baseline, after 2 weeks (before nivolumab), after 1 month, at progression, and at response.

    Measured: 1 month

  7. Stage 1 (PHASE 1) and Stage 2 - Cohort 1-6 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.

    Measured: 6 months

  8. Stage 2 - Cohort 7 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.

    Measured: 6 months

  9. Stage 2 - Cohort 7 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.

    Measured: 2 years

  10. Stage 2 - Cohort 8 Pathological response

    Measured by percentage of necrosis in surgical specimen.

    Measured: At month 3

  11. Stage 1 (PHASE 2)

    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

    Measured: 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Sep 2017
  2. Study start31 May 2017
  3. Primary completion30 Jun 2024
  4. Study completion30 Jun 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
Phase I-II, single-arm, non-randomized, open-label, multicenter, international clinical trial
Masking
None (open label)
Enrolment
197 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03277924
Sponsor's protocol ID
GEIS-52
Acronym
ImmunoSarc
Status last verified
Aug 2024
First submitted
3 Aug 2017
Last updated
13 Aug 2024
Results posted
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Martin-Broto J, Strauss SJ, Palmerini E, Valverde C, Sebio A, Redondo A, Stacchiotti S, Grignani G, Aliberti S, Diaz-Beveridge R, Billalabeitia EG, Cruz J, Carrasco-Garcia I, Ibrahim T, Diaz-Martin J, Salguero-Aranda C, Gutierrez A, Mayordomo-Aranda E, Ramos R, Merino J, Collini P, Tirabosco R, Bague S, Romagosa C, Carrera MA, Ledesma P, Hindi N, Moura DS. IMMUNOSARC II Master Trial: Phase II Study of Sunitinib and Nivolumab in Clear Cell Sarcoma Cohort. Cancer Commun (Lond). 2026 Mar 12;46:0015. doi: 10.34133/cancomm.0015. eCollection 2026.

    PubMed 41836677

  • Martin-Broto J, Diaz-Beveridge R, Moura D, Ramos R, Martinez-Trufero J, Carrasco I, Sebio A, Gonzalez-Billalabeitia E, Gutierrez A, Fernandez-Jara J, Hernandez-Vargas L, Cruz J, Valverde C, Hindi N. Phase Ib Study for the Combination of Doxorubicin, Dacarbazine, and Nivolumab as the Upfront Treatment in Patients With Advanced Leiomyosarcoma: A Study by the Spanish Sarcoma Group (GEIS). J Clin Oncol. 2025 Jan 20;43(3):297-307. doi: 10.1200/JCO.24.00358. Epub 2024 Oct 2.

    PubMed 39356980

  • Martin-Broto J, Hindi N, Grignani G, Martinez-Trufero J, Redondo A, Valverde C, Stacchiotti S, Lopez-Pousa A, D'Ambrosio L, Gutierrez A, Perez-Vega H, Encinas-Tobajas V, de Alava E, Collini P, Pena-Chilet M, Dopazo J, Carrasco-Garcia I, Lopez-Alvarez M, Moura DS, Lopez-Martin JA. Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial. J Immunother Cancer. 2020 Nov;8(2):e001561. doi: 10.1136/jitc-2020-001561.

    PubMed 33203665

  • Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14.

    PubMed 31401903

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Sunitinib 37.5 MG, Sunitinib 25 MG [Sutent], Nivolumab 100 MG/10 ML [Opdivo] and Epirubicin in people with Soft Tissue Sarcoma and Bone Sarcoma, run by Grupo Espanol de Investigacion en Sarcomas at 13 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 32 inclusion and 84 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 13 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 13 sites in Spain, Italy, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Stage 1 - PHASE 1 (time frame: 6 months). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03277924, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Aug 2024.

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