A Phase II Evaluation of Afatinibin Patients With Persistent or Recurrent HER2-positive Uterine Serous Carcinoma

Exploratory/correlative objectives: To systematically evaluate HER2/neu
expression/amplification using standardized scoring criteria for both breast and gastric
cancer and correlate clinical response in uterine serous carcinoma patients with HER2/neu
scoring results. To correlate objective response rate, PFS and overall survival with the
presence/absence of phosphatidyl inositol 3-kinase catalytic subunit and F-box/WD
repeat-containing protein mutations by standard Sanger sequencing, and presence/absence of
Cyclin E2 overexpression by IHC in endometrial cancer patients overexpressing HER2/neu
treated with Afatinib. To study HER2/neu extracellular domain circulating levels in the
plasma of uterine serous carcinoma patients overexpressing HER2/neu before and during
Afatinib treatment to elucidate whether changes in HER2/neu extracellular domain would
predict response to Afatinib and to determine peripheral blood natural killer cell numbers
and activity in HER2/neu+ uterine serous carcinoma patients before and during Afatinib
treatment to assess the possible therapeutic contributions of immune mechanisms of action of
Afatinib.

Inclusion Criteria:

- Patients must have persistent or recurrent histologically confirmed uterine serous
carcinoma, harbor a tumor HER2/neu+ based upon IHC staining score of 3+ or 2+ with
confirmed gene amplification by FISH.

- Have measurable disease.

- Have at least one target lesion to be used to assess response as defined by RECIST
v1.1.

- After undergoing surgery may be optimally or sub optimally debulked, with measurable
recurrent disease of any previous substage.

- Diagnosis histologically confirmed by a gynecologic pathologist as containing >10%
uterine papillary serous adenocarcinoma in the specimen.

- Have adequate bone marrow function.

- WBC greater than or equal to 3,000/ul, platelets greater than or equal to 75,000/ul,
granulocytes greater than or equal to 1500/ul., creatinine less than or equal to 2.0
mg/kl, bilirubin < 1.5 X laboratory normal, SGOT/SGPT <3 X laboratory normal.

- Have an ECOG performance status of 0 or 1.

- Have signed an approved consent.

- Have recovered from effects of recent surgery, radiotherapy or chemotherapy. Should be
free of significant infection.

- Patients with recurrent disease may have received multiple prior chemotherapies for
treatment of their uterine cancer.

- May have received prior trastuzumab therapy alone or in combination with chemotherapy
with 2 week washout period required between trastuzumab treatment and first dose of
Afatanib.

- Patients of childbearing potential must have a negative serum pregnancy test within 7
days prior to the study entry and be practicing an effective form of contraception.

- Must be 18 years of age.

Exclusion Criteria:

- Patients with a history of other invasive malignancies, with the exception of
non-melanoma skin cancers are excluded if there is any evidence of other malignancy
being present within the last five years. Patients are also excluded if their previous
cancer treatment contraindicates this protocol.

- Patients who have a significant history of cardiac disease, uncontrolled hypertension,
unstable angina, uncontrolled congestive heart failure, or uncontrolled arrhythmias
within 6 months of registration. Patients with any unstable medical issue, active
treatment for symptomatic pulmonary embolism, CVA, renal or hepatic insufficiency,
active infection/sepsis requiring IV antibiotics, known brain/leptomengial involvement
of the disease, active neurological disease, dementia.

- Patients who have received prior therapy with any irreversible human epidermal growth
factor receptor tyrosine kinase inhibitor.

- Patients who have an uncontrolled seizure disorder or active neurological disease.
Patients known to be seropositive for HIV and active hepatitis, even if liver function
studies are in the eligible range. Known hemorrhagic diathesis or active bleeding
disorder.