A Phase II Study of Sunitinib in Patients With Advanced Relapsed or Refractory Thymoma or Thymic Carcinoma With at Least One Prior Line of Platinum-Based Systemic Chemotherapy
- INCLUSION CRITERIA:
3.1.1 Histological confirmation of thymoma or thymic carcinoma by the pathology
department/CCR/NCI or the pathology department of participating institutions.
3.1.2 At least one prior line of platinum-based chemotherapy or patient must have refused
cytotoxic chemotherapy. Progressive disease must be documented prior to study entry.
3.1.3 Patients must not have received chemotherapy, radiation therapy, or undergone major
surgery within 4 weeks prior to enrollment.
3.1.4 Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
nonnodal lesions and short axis for nodal lesions) as > 20 mm with conventional techniques
or as > 10 mm with spiral CT scan, MRI, or calipers by clinical exam.
3.1.5 Age greater than or equal to 18 years.
3.1.6 ECOG performance status less than or equal to 2 (Karnofsky > 50 percent)
3.1.7 Life expectancy of greater than 3 months.
3.1.8 Patients must have normal organ and marrow function as defined below:
- hemoglobin greater than or equal to 9 g/dL
- leukocytes greater than or equal to 3,000/mcL
- absolute neutrophil count greater than or equal to 1,500/mcL
- platelets greater than or equal to 100,000/mcL
- total bilirubin within normal institutional limits
- serum calcium less than or equal to 12.0 mg/dL
- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
- creatinine within normal institutional limits
- creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with
creatinine levels above institutional normal.
- If subjects have liver metastases, both ALT and AST must be less than or equal to 5
- Patients must have QTc < 500 msec
3.1.9 PT or INR, and APTT less than or equal to 1.5 times upper limit of normal (ULN),
unless the abnormality can be explained by the presence of lupus anticoagulant or if these
values are in the therapeutic range for a patient on low molecular weight heparin.
3.1.10 The following groups of patients are eligible provided they have New York Heart
Association Class II (NYHA; see Appendix B) cardiac function on baseline ECHO/MUGA:
- those with a history of Class II heart failure who are asymptomatic on treatment
- those with prior anthracycline exposure
- those who have received central thoracic radiation that included the heart in the
3.1.11 Patients must have blood pressure (BP) no greater than 140 mmHg (systolic) and 90
mmHg (diastolic) for eligibility. Initiation or adjustment of BP medication is permitted
prior to study entry provided that the average of three BP readings at a visit prior to
enrollment is less than 140/90 mmHg.
3.1.12 The effects of sunitinib on the developing human fetus at the recommended
therapeutic dose are unknown. For this reason and because anti-angiogenic agents are known
to be teratogenic, women of childbearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to study
entry and for the duration of study participation. All women of childbearing potential
must have a negative pregnancy test prior to receiving sunitinib. Should a woman
become pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately. Men treated or enrolled on this protocol must
also agree to use adequate contraception prior to the study, for the duration of study
participation, and 4 months after completion of sunitinib administration.
3.1.13 Ability to understand and willingness to sign a written informed consent document.
3.2.1 Patients with tumor amenable to potentially curative therapy.
3.2.2 Prior treatment within the past 6 months with sunitinib, sorafenib, bevacizumab or
other multikinase inhibitors targeting any of the following: vascular endothelial growth
factors 1-3 (VEGF1-3), FMS-like tyrosine kinase 3 (FLT3), stem cell growth factor (c-KIT),
platelet-derived growth factors-alpha and -beta (PDGF-alpha,-beta), colony-stimulating
factor 1 (CSF1), and the RET' receptor for glial-derived neurotrophic factors.
3.2.3 Patients with symptomatic brain metastases will be excluded from trial secondary to
poor prognosis. However, patients who have had treatment for their brain metastasis and
whose brain disease has remained stable for 3 months without steroid therapy may be
3.2.4 Patients with evidence of severe or uncontrolled systemic disease, or any concurrent
condition, which could compromise participation in the study, including, but not limited
to, active or uncontrolled infection, immune deficiencies, uncontrolled HBV and/or HCV
infection unless sustained virologic response to HCV therapy, uncontrolled
diabetes,serious non-healing ulcer, wound or bone fracture, history of intra-abdominal
abscess, abdominal fistula or gastrointestinal perforation within 28 days of treatment,
pulmonary embolism in the past 12 months, uncontrolled hypertension, myocardial
infarction, cardiac arrhythmia, stable/unstable angina, symptomatic congestive heart
failure, or coronary/peripheral artery bypass graft or stenting within 12 months prior to
study entry, Class III or IV heart failure as defined by the NYHA functional
classification system,stroke/cerebrovascular accident or transient ischemic attack within
the past 12 months or psychiatric illness/social situations which would jeopardize
compliance with the protocol.
3.2.5 History of a previous invasive malignancy within the last 5 years, except adequately
treated non-melanoma skin cancer, papillary carcinoma of the thyroid or carcinoma in situ
of the uterine cervix.
3.2.6 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered
from adverse events due to agents administered more than 4 weeks earlier.
3.2.7 Patients who are receiving any other investigational agents.
3.2.8 History of allergic reactions attributed to compounds of similar chemical or
biologic composition to sunitinib. Patients receiving any medications or substances that
are strong inhibitors or inducers of CYP3A4 are ineligible. (A list of potent CYP3A4
inducers or inhibitors can be found in Section 5.2.) An exception will be made for
patients who are on ritonavir-based highly active antiretroviral therapy, in which case
the starting dose of sunitinib will be modified as indicated in Sections 5.1.1 and 5.2.12.
Every effort should be made to switch patients taking such agents or substances to other
medications. A comprehensive list of medications and substances known or with the
potential to alter the pharmacokinetics of sunitinib through CYP3A4 is provided.
3.2.9 Pregnant women are excluded from this study because sunitinib angiogenesis inhibitor
with the potential for teratogenic or abortifacient effects. Because there is an unknown
but potential risk for adverse events in nursing infants secondary to treatment of the
mother with sunitinib breastfeeding should be discontinued if the mother is treated with
3.2.10 Patients who require therapeutic doses of Coumadin derivative anticoagulants such
as warfarin are excluded. Low molecular weight heparin is permitted, provided the
patient's PT/INR is less than or equal to 1.5. Coumadin doses of up to 2 mg daily are
permitted for prophylaxis of thrombosis.
3.2.11 Patients with a pre-existing thyroid abnormality who are unable to maintain thyroid
function in the normal range with medication are ineligible.
3.2.12 Patients with any condition (e.g., gastrointestinal tract disease resulting in an
inability to take oral medication or a requirement for IV alimentation, prior surgical
procedures affecting absorption, or active peptic ulcer disease) that impairs their
ability to swallow and retain sunitinib tablets are excluded.
3.2.13 Patients with QTc prolongation (defined as a QTc interval equal to or greater than
500 msec) or other significant ECG abnormalities are excluded.
3.2.14 Patients with poorly controlled hypertension (systolic blood pressure of 140 mmHg
or higher or diastolic blood pressure of 91 mmHg or higher) are ineligible.
3.2.15 Patients who require use of therapeutic doses of coumarin derivative anticoagulants
such as warfarin are excluded, although doses of up to 2 mg daily are permitted for
prophylaxis of thrombosis. Note: Low molecular weight heparin is permitted provided the
patient's PT INR is less than or equal to 1.5.
3.2.16 Patients with HIV infection are eligible provided their CD4 count is greater than
or equal to the institutional LLN ( greater than or equal to 334 cells/uL).