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

• Status: Recruiting
• Trial end date: 2022-09-30
• Target enrollment: 0
• Participant gender: All

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, 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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Grupo Espanol de Investigacion en Sarcomas
• Treatments: Nivolumab; Sunitinib

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).