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

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ClinicalTrials.gov Identifier: NCT03277924
Recruitment Status : Recruiting
First Posted : September 11, 2017
Last Update Posted : March 26, 2020
Sponsor:
Information provided by (Responsible Party):
Grupo Espanol de Investigacion en Sarcomas

Brief 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.


Condition or disease Intervention/treatment Phase
Soft Tissue Sarcoma Bone Sarcoma Drug: Sunitinib 37.5 MG, Sunitinib 25 MG [Sutent] Drug: Nivolumab 100 MG/10 ML [Opdivo] Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 270 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Phase I-II, single-arm, non-randomized, open-label, multicenter, international clinical trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I-II Trial of Sunitinib Plus Nivolumab After Standard Treatment in Advanced Soft Tissue and Bone Sarcomas
Actual Study Start Date : May 31, 2017
Estimated Primary Completion Date : September 30, 2022
Estimated Study Completion Date : September 30, 2022


Arm Intervention/treatment
Experimental: Sunitinib+Nivolumab

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.

Sunitinib (Sutent): Hard Capsule (12.5, 25 mg). Oral use.

Nivolumab (Opdivo) 10 mg/mL concentrate for solution for infusion. Intravenous use

Drug: Sunitinib 37.5 MG, Sunitinib 25 MG [Sutent]
Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.
Other Name: Sutent

Drug: Nivolumab 100 MG/10 ML [Opdivo]
Treatment will continue until disease progression, development of unacceptable toxicity, non-compliance, withdrawal of consent by the patient or investigator decision.
Other Name: Opdivo




Primary Outcome Measures :
  1. Progression-free survival rate (PFSR) [ Time Frame: 6 months ]
    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 :
  1. Overall survival (OS) [ Time Frame: 2 years ]
    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.

  2. Objective response rate (ORR) [ Time Frame: 2 months ]
    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).

  3. Efficacy measured through tumor response according to Choi criteria. [ Time Frame: 36 months ]
    The evaluation criteria will be based on the identification of target lesions in baseline and their follow-up until tumor progression.

  4. Safety profile: Adverse events [ Time Frame: 36 months ]
    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.

  5. Clinical outcome [ Time Frame: At 36 months ]
    Clinical outcomes of post protocol treatments assessed by observation of such treatments in follow-up stage.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03277924


Contacts
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Contact: Patricio Ledesma +34 971439900 ensayos@sofpromed.com

Locations
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Italy
Istituto Ortopedico Rizzoli Not yet recruiting
Bologna, Italy, 40136
Contact: Stefano Ferrari         
Candiolo Cancer Institute - FPO, IRCCS Not yet recruiting
Candiolo, Italy, 10060
Contact: Giovanni Grignani         
Istituto Nazionale dei Tumori Not yet recruiting
Milano, Italy, 20133
Contact: Silvia Stacchiotti         
Spain
Hospital Universitari Vall d'Hebrón Recruiting
Barcelona, Spain, 08035
Contact: Claudia Valverde         
Hospital de la Santa Creu i Sant Pau Recruiting
Barcelona, Spain, 08041
Contact: Antonio López Pousa         
Hospital Universitario 12 de Octubre Recruiting
Madrid, Spain, 28041
Contact: José Antonio López Martín         
Hospital Universitario La Paz Recruiting
Madrid, Spain, 28046
Contact: Andrés Redondo         
Hospital Universitario Virgen del Rocío Recruiting
Sevilla, Spain, 41013
Contact: Javier Martín Broto         
Hospital Universitari i Politècnic La Fe Recruiting
Valencia, Spain, 46026
Contact: Roberto Díaz de Beveridge         
Hospital Universitario Miguel Servet Recruiting
Zaragoza, Spain, 50009
Contact: Javier Martínez Trufero         
United Kingdom
University College London Hospitals NHS Foundation Trust Not yet recruiting
London, United Kingdom, NW1 2PG
Contact: Sandra Strauss         
Sponsors and Collaborators
Grupo Espanol de Investigacion en Sarcomas
Investigators
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Study Director: Javier Martín Broto Hospitales Universitarios Virgen del Rocío
Study Director: José Antonio López Martín Hospital Universitrario 12 de Octubre
Principal Investigator: Andrés Redondo Hospital Universitario La Paz
Principal Investigator: Claudia Valverde Hospital Universitari Vall d'Hebrón
Principal Investigator: Antonio López Pousa Fundació Institut de Recerca de l'Hospital de la Santa Creu i Sant Pau
Principal Investigator: Roberto Diaz de Beveridge Hospital Universitario La Fe
Principal Investigator: Javier Martínez Trufero Hospital Universitario Miguel Servet
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Grupo Espanol de Investigacion en Sarcomas
ClinicalTrials.gov Identifier: NCT03277924    
Other Study ID Numbers: GEIS-52
First Posted: September 11, 2017    Key Record Dates
Last Update Posted: March 26, 2020
Last Verified: March 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Grupo Espanol de Investigacion en Sarcomas:
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
Additional relevant MeSH terms:
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Sarcoma
Osteosarcoma
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Nivolumab
Sunitinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action