Trial of Sunitinib in Patients With Type B3 Thymoma or Thymic Carcinoma in Second and Further Lines (Style Trial)

Study Overview
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Brief Summary
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Study to investigate response to sunitinib in patients with thymic epithelial tumours who had progressive disease after at least one previous regimen of platinum-based chemotherapy.

Detailed Description
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This trial will be conducted to assess the activity of Sunitinib in patients affected by advanced or recurrent B3 thymoma or thymic carcinoma progressing after at least one line of chemotherapy (including one platinum based regimen). Taking into account the different biology and historically discrepant responses and survival of thymoma and thymic carcinoma, patients will be enrolled with these tumour types in two separate cohorts. Sunitinib will be self orally administered at 50 mg once daily, is 50 mg taken orally once daily, for 4 consecutive weeks, followed by a 2-week rest period (schedule 4/2) to comprise a complete cycle of 6 weeks until tumour progression, unacceptable toxicity or other criteria for discontinuation is met. Sunitinib dose reductions are permitted as per the approved product label for safety reasons. Dose reductions should occur in 12.5 mg decrements. No more than 2 dose reductions are allowed. If more than 2 dose reductions are necessary (ie, reduction to less than 25 mg daily), the subject must be permanently discontinued (Section 7.2.2) Possible dose reductions: Sunitinib at dose of 37,5 mg orally once daily for 4 weeks followed by 2 weeks rest-period in cycles of 6 weeks. Sunitinib at dose of 25 mg orally once daily for 4 weeks followed by 2 weeks rest-period in cycles of 6 weeks

Official Title
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Phase II Trial of Sunitinib in Patients With Type B3 Thymoma or Thymic Carcinoma in Second and Further Lines (Style Trial)

Conditions
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Type B3 Thymoma, Thymic Carcinoma

Intervention / Treatment
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* Drug: Sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated IRB (Independent Review Board)/IEC (Independent Ethics Committee)-approved Informed Consent Histological diagnosis of invasive recurrent or metastatic type B3 thymoma or thymic carcinoma. In case of presence of both histologies it will be classified based on the predominantly part. B2 thymoma with areas of B3 thymoma are eligible. Patients must have had at least one prior platinum-containing chemotherapy regimen. There is no limit to the number of prior chemotherapy regimens or targeted agents received. Progressive disease should have been documented before entry into the study Patients must have measurable disease, defined as at least one lesion that can be accurately measured according with RECIST 1.1 criteria Availability of archival tissue (paraffine block or at least 10 unstained slides) Patients must have recovered from toxicity related to prior therapy to at least grade 1 (defined by v.CTCAE 4.0) Patients must not have had major surgery, radiation therapy, chemotherapy, biologic therapy (including any investigational agents), or hormonal therapy (other than replacement), within 4 weeks prior to entering the study Age > 18 years Life expectancy > 3 months Performance status (ECOG) ≤ 2 Negative pregnancy test (if female in reproductive years) Patients must have adequate organ and marrow function (as defined below). Patients must have returned to baseline or grade 1 from any acute toxicity related to prior therapy: Absolute neutrophil count ≥ 1,500/mm Hemoglobin ≥ 9 g/dL Platelets ≥ 100,000/mm Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) , except for patients affected by Gilbert's syndrome AST(SGOT) (aspartate aminotransferase) /ALT(SGPT) (alanine transaminase) ≤ 3 x institutional ULN (5x if LFT (liver function test) elevations due to liver metastases) Creatinine ≤ 1.5 x institutional ULN Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception before study entry, for all the duration of the study and for at least 8 weeks after the last dose of investigational drug (30 days for an ovarian cycle turnover plus the time required for the active metabolite of sunitinib to undergo five half-lives). Males who are sexually active with WOCBP must agree to follow instructions for method(s) of before study entry, for all the duration of the study and for at least 16 weeks after the last dose of investigational drug (90 days for sperm turnover plus the time required for the active metabolite of sunitinib to undergo five half-lives). Exclusion Criteria: untreated CNS metastases. Patients with treated brain metastases are eligible if they are clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 2 weeks prior to start of treatment, or after surgical resection performed at least 28 days prior to start of treatment. The patient may have no evidence of Grade ≥1 CNS haemorrhage based on pre-treatment Magnetic Resonance Imaging (MRI) or IV contrast CT scan (performed within 28 days before start of treatment) Major surgery, other than diagnostic surgery, within 4 weeks prior to treatment Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy Pregnant or breast feeding women Previous (within the last 5 years) or current malignancies at other sites, except for adequately treated basal cell or squamous cell skin cancer or in situ carcinoma of the cervix uteri Current enrollment in or participation in another therapeutic clinical trial within 4 weeks before treatment start. Patients with uncontrolled or significant cardiovascular disease (AMI within 12 months, unstable angina within 6 months, NYHA (New York Heart Association) Class III, IV Congestive heart failure or left ventricular ejection fraction below local institutional lower limit of normal or below 45%, Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial fibrillation, or prolongation of the Fridericia corrected QT (QTcF) interval defined as > 450 msec for males and > 470 msec for females, where QTcF = QT / 3√RR Poorly controlled hypertension History of cerebrovascular accident including transient ischemic attack within the past 12 months. History of deep vein thrombosis (DVT) unless adequately treated with low molecular weight heparin History of pulmonary embolism within the past 6 months unless stable, asymptomatic, and treated with low molecular weight heparin for at least 6 weeks. Evidence of active bleeding or bleeding susceptibility; or medically significant hemorrhage within prior 30 days. Receiving concomitant CYP3A4 inducers or strong CYP3A4 inhibitors Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sunitinib Known HIV infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sunitinib<br>Sunitinib orally administered at 50 mg once daily for 4 consecutive weeks, followed by a 2-week rest period (schedule 4/2) to comprise a complete cycle of 6 weeks | Drug: Sunitinib<br>* small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor<br>* Other names: Sutent;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Activity of Sunitinib | Best tumour response (Complete Response + Partial Response) | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | The PFS is defined as the time from the date of randomization to the date of documented progressive disease, recurrence or Death (whichever occurs first) | 4 years | 
| Overall Survival (OS) | The OS is defined as the time from the date of randomization to the date of death | 4 years | 
| Duration of activity of sunitinib | Complete Response + Partial Response + Stable Disease | 4 years | 
| Safety and toxicity profile of sunitinib | will be utilized the CTCAE v 4.0 criteria for assessment of toxicity and serious adverse event reporting. | 4 years | 
| Incidence of adverse events (AEs) | Incidence of adverse events (AEs) will be graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0, laboratory values, physical examinations, vital signs. | 4 years |