Clinical Trials /

Trial of Sunitinib Plus Nivolumab After Standard Treatment in Advanced Soft Tissue and Bone Sarcomas

NCT03277924

Description:

Phase I-II, single-arm, non-randomized, open-label, multicenter, international clinical trial, with two cohorts (Soft Tissue Sarcoma and Bone Sarcoma). Seven sites in Spain, 3 sites in Italy and 1 site in the United Kingdom. Adult patients will receive an initial induction phase from day 1 to day 14 of sunitinib 37.5 mg/day followed by a maintenance phase of sunitinib 25mg/day orally continuously + nivolumab 240mg intravenous every 2 weeks infused over 1 hour. Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision. Pediatric patients will receive an initial induction phase from day 1 to day 14 of sunitinib 25 mg/day, or 37.5 mg/day if BSA > 1.7, followed by a maintenance phase of sunitinib 25mg/day orally continuously + nivolumab 240mg intravenous every 2 weeks infused over 1 hour. Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision. The main goal is 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.

Related Conditions:
  • Alveolar Soft Part Sarcoma
  • Angiosarcoma
  • Chondrosarcoma
  • Clear Cell Sarcoma of Soft Tissue
  • Extraskeletal Myxoid Chondrosarcoma
  • Hemangioendothelioma
  • Intimal Sarcoma
  • Leiomyosarcoma
  • Osteosarcoma
  • Solitary Fibrous Tumor
  • Undifferentiated Pleomorphic Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trial of Sunitinib Plus Nivolumab After Standard Treatment in Advanced Soft Tissue and Bone Sarcomas
  • Official Title: Phase I-II Trial of Sunitinib Plus Nivolumab After Standard Treatment in Advanced Soft Tissue and Bone Sarcomas

Clinical Trial IDs

  • ORG STUDY ID: GEIS-52
  • NCT ID: NCT03277924

Conditions

  • Soft Tissue Sarcoma
  • Bone Sarcoma

Interventions

DrugSynonymsArms
Sunitinib 37.5 MG, Sunitinib 25 MG [Sutent]SutentSunitinib+Nivolumab
Nivolumab 100 MG/10 ML [Opdivo]OpdivoSunitinib+Nivolumab

Purpose

Phase I-II, single-arm, non-randomized, open-label, multicenter, international clinical trial, with two cohorts (Soft Tissue Sarcoma and Bone Sarcoma). Seven sites in Spain, 3 sites in Italy and 1 site in the United Kingdom. Adult patients will receive an initial induction phase from day 1 to day 14 of sunitinib 37.5 mg/day followed by a maintenance phase of sunitinib 25mg/day orally continuously + nivolumab 240mg intravenous every 2 weeks infused over 1 hour. Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision. Pediatric patients will receive an initial induction phase from day 1 to day 14 of sunitinib 25 mg/day, or 37.5 mg/day if BSA > 1.7, followed by a maintenance phase of sunitinib 25mg/day orally continuously + nivolumab 240mg intravenous every 2 weeks infused over 1 hour. Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision. The main goal is 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.

Detailed Description

      One arm survival design based on Lawless (Lawless, Statistical Models and Methods for
      Lifetime Data, John Wiley and Sons, 2003). Formulas are based on the assumptions of uniform
      accrual over time, no loss to follow-up, exponentially distributed death times.

      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 0.90, 43 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 32 patients are needed in this
      cohort.
    

Trial Arms

NameTypeDescriptionInterventions
Sunitinib+NivolumabExperimentalAdult patients will receive an initial induction phase from day 1 to day 14 of sunitinib 37.5 mg/day followed by a maintenance phase of sunitinib 25mg/day orally continuously + nivolumab 240mg intravenous every 2 weeks infused over 1 hour. Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision. Pediatric patients will receive an initial induction phase from day 1 to day 14 of sunitinib 25 mg/day, or 37.5 mg/day if BSA > 1.7, followed by a maintenance phase of sunitinib 25mg/day orally continuously + nivolumab 240mg intravenous every 2 weeks infused over 1 hour. Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision. Sunitinib (Sutent): Hard Capsule (12.5, 25 mg). Oral use. Nivolumab (Opdivo) 10 mg/mL concentrate for solution for infusion. Intravenous use
  • Sunitinib 37.5 MG, Sunitinib 25 MG [Sutent]
  • Nivolumab 100 MG/10 ML [Opdivo]

Eligibility Criteria

        INCLUSION CRITERIA:

          1. Patients (or legal tutors) must provide written informed consent prior to performance
             of study-specific procedures and must be willing to comply with treatment and
             follow‑up. Informed consent must be obtained prior to start of the screening process.
             Procedures conducted as part of the patient's routine clinical management (e.g. blood
             count, imaging tests, etc.) and obtained prior to signature of informed consent may be
             used for screening or baseline purposes as long as these procedures are conducted as
             specified in the protocol.

          2. Age: 12-80 years.

          3. Diagnosis of conventional high-grade (grades 2 or 3) and dedifferentiated
             chondrosarcoma, extraskeletal myxoid chondrosarcoma, vascular sarcomas (including
             angiosarcoma, hemangioendothelioma and intimal sarcomas), solitary fibrous tumor
             (excluding dedifferentiated SFT), alveolar soft part sarcoma, clear cell sarcoma,
             advanced undifferentiated pleomorphic sarcoma, leiomyosarcoma or osteosarcoma
             confirmed by central pathology review.

          4. 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).

          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
             elegible (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
             conventional CS/DDCS) are elegible even if not previously treated.

          7. Previous therapy with antiangiogenics is allowed.

          8. Measurable disease according to RECIST 1.1 criteria.

          9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.

         10. Adequate hepatic, renal, cardiac, and hematologic function.

         11. Laboratory tests as follows:

               -  Absolute neutrophil count ≥ 1,200/mm³

               -  Platelet count ≥ 100,000/mm³

               -  Bilirubin ≤ 1.5 mg/dL

               -  PT and INR ≤ 1.5 in the absence of anticoagulant therapy

               -  AST and ALT ≤ 2.5 times upper limit of normal

               -  Creatinine ≤ 1.5 mg/dL (or Cr clearance ≥ 60 ml/min)

               -  Calcium ≤ 12 mg/dL

         12. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.

         13. Females of childbearing potential must have a negative serum or urine pregnancy test
             within 7 days prior to enrollment and agree to use birth control measures during study
             treatment and for 6 months after its completion. Patients must not be pregnant or
             nursing at study entry. Women/men of reproductive potential must have agreed to use an
             effective contraceptive method.

        EXCLUSION CRITERIA:

          1. Four or more previous lines of chemotherapy.

          2. Previous anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti
             PD-L2 or anti CTLA-4 antibody.

          3. Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis,
             hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine,
             cytokine, etc.).

          4. Active, known or suspected autoimmune disease.

          5. A condition requiring systemic treatment with either corticosteroids (> 10 mg daily
             prednisone equivalents) or other immunosuppressive medications within 14 days of study
             drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg
             daily prednisone equivalents are permitted in the absence of active autoimmune
             disease.

          6. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive
             heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina
             pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration,
             unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI-CTCAE] version 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).

          7. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
             ribonucleic acid (HCV antibody) indicating acute or chronic infection.

          8. Other disease or illness within the past 6 months, including any of the following:

               -  Myocardial infarction

               -  Severe or unstable angina

               -  Coronary or peripheral artery bypass graft

               -  Symptomatic congestive heart failure

               -  Cerebrovascular accident or transient ischemic attack

               -  Pulmonary embolism

          9. Evidence of a bleeding diathesis.

         10. Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg despite optimal
             medical therapy.

         11. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite
             medication.

         12. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females)
             on baseline ECG.

         13. Hemorrhage ≥ Grade 3 in the past 4 weeks.

         14. History of allergy to study drug components.

         15. Anticoagulants due to thrombotic events, with the exception of deep venous thrombosis
             in limbs, with a stable dose of low-weigh heparine and in the absence of secondary
             hemorrages.

         16. History of another cancer in the previous 5 years with the exception of adequately
             treated squamous or basal cell carcinoma of the skin or cervical cancer in situ.

         17. Presence of brain or central nervous system metastases, unless they are controlled
             (completely resected or irradiated and/or asympthomatic, no need of steroids).

         18. Unwilling to participate in the translational study (not providing mandatory biopsies
             at baseline and at week 13).
      
Maximum Eligible Age:80 Years
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival rate (PFSR)
Time Frame:6 months
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:2 years
Safety Issue:
Description: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.
Measure:Objective response rate (ORR)
Time Frame:2 months
Safety Issue:
Description: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).
Measure:Efficacy measured through tumor response according to Choi criteria.
Time Frame:36 months
Safety Issue:
Description:The evaluation criteria will be based on the identification of target lesions in baseline and their follow-up until tumor progression.
Measure:Safety profile: Adverse events
Time Frame:36 months
Safety Issue:
Description: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.
Measure:Clinical outcome
Time Frame:At 36 months
Safety Issue:
Description:Clinical outcomes of post protocol treatments assessed by observation of such treatments in follow-up stage.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Grupo Espanol de Investigacion en Sarcomas

Trial Keywords

  • Conventional high-grade chondrosarcoma
  • Dedifferentiated chondrosarcoma
  • Extraskeletal myxoid chondrosarcoma
  • Angiosarcoma
  • Hemangioendothelioma
  • Intimal sarcomas
  • Solitary fibrous tumor
  • Clear cell sarcoma
  • Alveolar soft-part sarcoma
  • Advanced Undifferentiated Pleomorphic Sarcoma
  • Leiomyosarcoma
  • Osteosarcoma

Last Updated

March 25, 2020