BACKGROUND:
Platinum-based chemotherapy is the standard of care for advanced unresectable thymoma and thymic carcinoma. However over 50% of these patients may fail initial therapy and therefore require second-line therapy. New therapeutic options are needed for patients who have disease progression on or after platinum-containing therapy. Results obtained from protocol 12-C-0118 so far have shown impressive clinical activity of sunitinib in patients with recurrent thymic carcinoma with an objective response rate of 23% and disease control rate of 91% which is unprecedented for this histology. Treatment at a dose of 50 mg once daily for four weeks followed by 2 weeks off was poorly tolerated. Twenty five out of 41 patients needed dose reductions due to development of intolerable adverse events.
OBJECTIVES:
Primary objective:
- To evaluate the objective response rate (Partial Response (PR)+Complete Response (CR) for sunitinib in patients with relapsed or refractory thymoma or thymic carcinoma
MAIN ELIGIBILITY:
* Patients with histologically confirmed thymoma (Group 1 only) or thymic carcinoma who have previously been treated with at least one platinum-containing chemotherapy regimen with progressive disease prior to study entry
* Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
* Adequate renal, hepatic and hematopoietic function
* No major surgery, radiotherapy, chemotherapy or biologic therapy within 28 days of sunitinib
DESIGN:
* In the first group (Group 1), sunitinib will be administered orally using a continuous schedule at 50 mg per day for 4 weeks with 2 weeks off to constitute a 6-week cycle (Schedule 4/2) until disease progression or development of intolerable side-effects.
* In the second group (Group 2), sunitinib will be administered orally using a continuous schedule at 50 mg per day for 2 weeks with 1 week off to constitute a 3-week cycle (Schedule 2/1) until disease progression or development of intolerable side-effects.
* Toxicity will be assessed every cycle by Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0
* Tumor response assessments by RECIST 1.1 criteria will be performed every cycle for Group 1 and every other cycle for Group 2 (every 6 weeks) for patients receiving treatment for less than one year, and every two cycles for Group 1 and every four cycles for Group 2 (every 12 weeks) for patients who have been receiving treatment one year or longer.
* Exploratory studies include evaluation of serum vascular endothelial growth factor (VEGF), placental growth factor (PlGF), interleukin 4 (IL-4), interleukin 12 (IL-12), hepatocyte growth factor (HGF), and basic fibroblast growth factor (bFGF) (Group 1 only); and circulating tumor cells, endothelial progenitors, and mature apoptotic endothelial cells (both groups). In Group 2, regulatory T cells (Tregs), exhausted cluster of differentiation 8 (CD8) T cells, myeloid-derived suppressor cells (MDSCs), and Type 1 T helper (Th1)/Type 2 T helper (Th1) T cell populations will also be evaluated. Where tumor samples are available, intra-tumoral immune infiltrate will be assessed (both groups). Exploratory studies apply to National Cancer Institute (NCI) only.
- Inclusion Criteria::
3.1.1 Histological confirmation of thymoma (Group 1 only) or thymic carcinoma by the
pathology department/Center for Cancer Research (CCR)/national Cancer Institute (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, per Response Evaluation Criteria in Solid
Tumors (RECIST) 1.1
3.1.5 Age greater than or equal to 18 years.
3.1.6 Eastern Cooperative Oncology Group (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 1,200/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
- Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase
(SGOT)/alanine transaminase (ALT)/serum glutamic-pyruvic transaminase (SGPT) less than
or equal to 2.5 times institutional upper limit of normal
- creatinine within normal institutional limits
OR
- 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
times upper limit of normal (ULN).
- Patients must have corrected QT Interval (QTc) < 500 msec
3.1.9 Prothrombin time (PT) or international normalized ratio (INR), and partial
thromboplastin time test (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) cardiac function on baseline echocardiogram (ECHO)/multi-gated
acquisition scan (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
radiotherapy port.
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 Absence of brain metastases as confirmed by imaging of the brain by magnetic
resonance imaging (MRI) or computed tomography (CT) brain with contrast performed at
baseline screening
3.1.13 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.
3.1.14 Ability to understand and willingness to sign a written informed consent document.
Exclusion Criteria::
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
enrolled.
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 hepatitis B virus
(HBV) and/or hepatitis C virus (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, history of 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 cytochrome P450 3A4 (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
sunitinib.
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
prothrombin time (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 intravenous (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 electrocardiogram (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 human immunodeficiency virus (HIV) infection are eligible provided
their cluster of differentiation 4 (CD4) count is greater than or equal to the
institutional lower limit of normal (LLN) ( greater than or equal to 334 cells/uL).
Other Respiratory and Intrathoracic Organs