Patient case: 26-year-old female with chondrosarcoma; genetic feature: IDH1

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

Summary: 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 and 3 sites in Italy.
  Patients will receive sunitinib 37.5 mg/day (or recommended dose defined in phase I) orally continuously + nivolumab 3 mg/kg 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 response rate of 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.

Eligibility: Inclusion Criteria:
  1. Patients must provide written informed consent prior to performance of study-specific procedures and must be willing to comply with treatment and follow-up. Informed consent must be obtained prior to start of the screening process. Procedures conducted as part of the patient's routine clinical management (e.g. blood count, imaging tests, etc.) and obtained prior to signature of informed consent may be used for screening or baseline purposes as long as these procedures are conducted as specified in the protocol.
  2. Age: 18-80 years.
  3. Histologic diagnosis of soft tissue sarcoma (undifferentiated pleomorphic sarcoma, synovial sarcoma, alveolar soft part sarcoma, clear cell sarcoma, angiosarcoma, epithelioid hemangiosarcoma, solitary fibrous tumor and epithelioid sarcomas) or bone sarcoma (osteosarcoma/high grade bone sarcoma, Ewing sarcoma or dedifferentiated chondrosarcoma) confirmed by central pathology review. Mandatory paraffin embedded tumor blocks must be provided for all subjects without exception for biomarker analysis before treatment (first biopsy) and at end of month 3 or earlier (second biopsy).
  4. Metastatic/advanced disease in progression in the last 6 months.
  5. Patients have previously received at least anthracyclines.
  6. Measurable disease according to RECIST 1.1 criteria.
  7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
  8. Adequate hepatic, renal, cardiac, and hematologic function.
  9. Laboratory tests as follows:
  -  Absolute neutrophil count ≥ 1,200/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
  10. Left ventricular ejection fraction ≥ 50% by echocardiogram or MUGA scan.
  11. Females of childbearing potential must have a negative serum or urine pregnancy test within 24 hours prior to enrollment and agree to use birth control measures during study treatment and for 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.
  Exclusion Criteria:
  1. Three or more previous lines of chemotherapy for the advanced disease.
  2. Previous antiangiogenic agent, anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1), anti PD-L2 or anti CTLA-4 antibody.
  3. Prior immune-related adverse event (Grade 3 or higher immune-related pneumonitis, hepatitis, colitis, endocrinopathy) with prior immunotherapy (e.g. cancer vaccine, cytokine, etc.).
  4. Active, known or suspected autoimmune disease.
  5. A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. 6. Uncontrolled intercurrent illness including (not limited to): symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] III/IV), unstable angina pectoris or coronary angioplasty, or stenting within 24 weeks prior to registration, unstable cardiac arrhythmia (ongoing cardiac dysrhythmias of NCI CTCAE version 4.0 Grade >= 2), known psychiatric illness that would limit study compliance, intra-cardiac defibrillators, known cardiac metastases, or abnormal cardiac valve morphology (>= Grade 3).
  7. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
  8. Other disease or illness within the past 6 months, including any of the following:
  -  Myocardial infarction
  -  Severe or unstable angina
  -  Coronary or peripheral artery bypass graft
  -  Symptomatic congestive heart failure
  -  Cerebrovascular accident or transient ischemic attack
  -  Pulmonary embolism 9. Evidence of a bleeding diathesis. 10. Ongoing cardiac dysrhythmias > Grade 2. 11. Uncontrolled hypertension, defined as blood pressure > 150/100 mm Hg despite optimal medical therapy.
  12. Psychiatric illness or social situation that would preclude study compliance.
  13. Pre-existing thyroid abnormality, defined as abnormal thyroid function tests despite medication.
  14. Prolonged QTc interval (i.e., QTc > 450 msec for males or QTc > 470 msec for females) on baseline ECG.
  15. Hemorrhage ≥ Grade 3 in the past 4 weeks. 16. History of allergy to study drug components.

Relevance to patient case: not relevant