Sunitinib for Advanced Thymus Cancer Following Earlier Treatment

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 (PR+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 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 CTCAE Version 4.0

- 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 VEGFR2, PLGF, IL-4, IL-12, HGF, and b-FGF
(Group 1 only); and circulating tumor cells, endothelial progenitors, and mature apoptotic
endothelial cells (both groups). In Group 2, regulatory T cells (Tregs), exhausted CD8 T
cells, myeloid-derived suppressor cells (MDSCs), and Th1/Th2 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 NCI only.

- INCLUSION CRITERIA:

3.1.1Histological confirmation of thymoma (Group 1 only) orthymic 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 greater than 20 mm with conventional
techniques or as greater than10 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
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 ULN.

- 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) 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
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 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.

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 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, 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 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
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).