Avelumab in Patients With MSS, MSI-H and POLE-mutated Recurrent or Persistent Endometrial Cancer and of Avelumab/Talazoparib in Patients With MSS Recurrent or Persistent Endometrial Cancer

This research study is a Phase II clinical trial. Phase II clinical trials test the
effectiveness of an investigational drug to learn whether the drug works in treating a
specific cancer. "Investigational" means that the drug is still being studied and that
research doctors are trying to find out more about it-such as the safest dose to use, the
side effects it may cause, and if the drug is effective for treating different types of
cancer. It also means that the FDA (the U.S. Food and Drug Administration) has not yet
approved the drug for use in patients, including people with Metastatic Endometrial Cancer.

Avelumab is a drug that may stop cancer cells from growing by enabling the activation of the
immune system. Avelumab blocks an immune inhibiting signal that can impair the ability of the
immune system to attack cancers.

Talazoparib is a drug that stops the activity of a protein (called PARP) that's involved in
repairing damage to the DNA within your cells. When PARP is turned off by Talazoparib in
cancer cells, DNA damage cannot be repaired and leads to the death of the cancer cells.

In this research study, the investigators are looking to see whether Avelumab and Talazoparib
are effective in treating recurrent and Metastatic Endometrial Cancer.

Additionally, the investigators are looking to see if participants whose tumors contain a
particular genetic make-up will have better response to Avelumab or the combination of
Avelumab and Talazoparib.

Inclusion Criteria:

Participants must be classified into one of two cohorts of recurrent or persistent
endometrial cancer of any histology:

The first cohort (MSI/POLE cohort) includes endometrial cancers that are:

--MSI-H as determined by immunohistochemical complete loss of expression (absence of
nuclear immunoreactivity) of at least one of the mismatch repair genes MSH2, MSH6, MLH1 and
PMS2. This test is now done routinely for every newly diagnosed endometrial cancer patient
in most centers in the US.

And/OR:

--POLE-mutated, i.e. endometrial cancers known to harbor mutations in the exonuclease
domain (amino acid residues 268-471) of polymerase e (POLE) as determined by targeted
sequencing or other next generation sequencing assay. Any Clinical Laboratory Improvement
Amendments (CLIA)-approved genomic test documenting mutations in the exonuclease domain of
POLE gene (amino acid residues 268-471) in the tumor will be accepted as proof of presence
of POLE mutations and will lead to classification into this patient cohort.

The second cohort (MSS cohort) includes:

- Endometrial cancers that are MSS as determined by normal immunohistochemical nuclear
expression of all the mismatch repair genes MSH2, MSH6, MLH1 and PMS2. Tumors which
have not been sequenced for POLE mutations (i.e. their POLE mutations status is
unknown) but are MSS, will be included in this cohort.

- All patients must have measurable disease as defined by RECIST 1.1. Measurable
disease is defined as at least one lesion that can be accurately measured in at
least one dimension (longest diameter to be recorded). Each lesion must be >= 10
mm when measured by CT, MRI or caliper measurement by clinical exam; or >= 20 mm
when measured by chest x-ray. Lymph nodes must be > 15 mm in short axis when
measured by CT or MRI.

- Prior Therapy:

- There is no upper limit of prior therapies but patients must have had one prior
chemotherapeutic regimen for management of endometrial carcinoma. Initial treatment
may include chemotherapy, chemotherapy and radiation therapy, and/or
consolidation/maintenance therapy. Any platinum based chemotherapy (single agent
platinum or any platinum doublet) administered in conjunction with primary radiation
as a radio-sensitizer WILL be counted as a systemic chemotherapy regimen. Furthermore,
patients who have only received chemotherapy in the adjuvant setting will be eligible
for the study.

- Prior hormonal therapy is allowed.

- Patients must NOT have received any class of drugs targeted to the PD-1/PD-L1 pathway.

- Patients must NOT have received any prior PARP inhibitor therapy.

- Age of 18 or greater years. Because insufficient dosing or adverse event data are
currently available on the use of Avelumab in participants < 18 years of age,
children are excluded from the study. Endometrial cancer is very rare in the
pediatric population.

- ECOG performance status 0 or 1 (reference Appendix A for ECOG performance status
criteria).

- Availability of a formalin fixed paraffin embedded (FFPE) block of cancer tissue
from the original surgery or biopsy or from a biopsy of recurrent disease.

- Participants must have normal organ and marrow function as defined below:

- absolute neutrophil count >1,500/mcL

- platelets >100,000/mcL

- hemoglobin ≥ 9g/dL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) ≤2.5 × institutional upper limit of normal

- creatinine within normal institutional limits OR

- creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine levels above
institutional normal.

Please note: creatinine clearance (CLCR) should be estimated according to the
Cockcroft-Gault formula as:

CLCR={[(140-age) × weight)]/(72 x SCR)} × 0.85 where CLCR (creatinine clearance) is
measured in mL/min, age is expressed in years, weight in kilograms (kg), and SCR (serum
creatinine) in mg/dL.

NOTE: Patients with moderate renal impairment (defined as an estimated creatinine clearance
of 30-59 mL/min) will receive a reduced starting dose of Talazoparib at 0.75 mg PO QD.

- Participant must not be pregnant or breastfeeding given that avelumab is an agent with
unknown effects in pregnancy and breastfeeding and the potential for teratogenesis.
Females of childbearing potential are defined as those who are not surgically sterile
(i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or
post-menopausal (defined as ≥ 12 months with no menses without an alternative medical
cause). Serum pregnancy test (for females of childbearing potential) negative at
screening.

- The effects of avelumab on the developing human fetus are unknown. For this reason and
because some immunomodulatory agents are known to be teratogenic, women of
child-bearing potential 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. Should a woman become pregnant or suspect she is pregnant while
she or her partner is participating in this study, she should inform her treating
physician immediately.

- Toxicities of prior therapy (excepting alopecia and sensory neuropathy) should be
resolved to < grade 2 per the revised NCI Common Terminology Criteria for Adverse
Events (CTCAE) version 4. All appropriate treatment areas should have access to a copy
of the CTCAE version 4. A copy of the CTCAE version 4 can be downloaded from the CTEP
website at: http://ctep.cancer.gov.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- Participants 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.

- Participants who are receiving any other investigational agents.

- Participants with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

- History of allergic reactions attributed to avelumab or any component in its
formulations, or compounds of similar chemical or biologic composition to avelumab.
Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI CTCAE
v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more
features of partially controlled asthma)

- Participants with a history of treatment with an anti-PD-1, anti-PD-L1, anti-CTLA-4 or
other investigational agents that target immune checkpoint inhibitors.

- Participants with a history of treatment with a PARP inhibitor.

- Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)
related illness, which may compromise the efficacy of immunostimulatory therapy.

- Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV
antibody tested positive)

- Subjects requiring hormone replacement with corticosteroids are eligible if the
steroids are administered only for the purpose of hormonal replacement and at doses ≤
10 mg or 10 mg equivalent prednisone per day

- Active infection requiring systemic therapy.

- Current or prior use of immunosuppressive medication within 7 days prior to enrollment
with the following exceptions to this exclusion criterion:

- Intranasal, inhaled, topical steroids, or local steroid injections (eg,
intra-articular injection);

- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or equivalent;

- Steroids as premedication for hypersensitivity reactions (eg, CT scan
premedication).

- Active autoimmune disease that might deteriorate when receiving an immunostimulatory
agent. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid
disease not requiring immunosuppressive treatment are eligible.

- Prior organ transplantation including allogeneic stem-cell transplantation.

- Persisting Grade >=2 toxicity related to prior therapy; however, Grade 2 sensory
neuropathy is acceptable.

- Severe gastrointestinal conditions such as clinical or radiological evidence of bowel
obstruction within 4 weeks prior to study entry, uncontrolled diarrhea in the last 4
weeks prior to enrollment, or history of inflammatory bowel disease.

- Uncontrolled intercurrent illness including, but not limited to symptomatic congestive
heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements.

- Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart
Association Classification Class II), or serious cardiac arrhythmia requiring
medication.

- Known alcohol or drug abuse.

- Individuals with a history of a different malignancy are ineligible except for the
following circumstances: Individuals with a history of other malignancies are eligible
if they have been disease-free for at least 5 years and are deemed by the investigator
to be at low risk for recurrence of that malignancy. Individuals with the following
cancers are eligible if diagnosed and treated within the past 5 years: breast cancer
in situ, cervical cancer in situ, and basal cell or squamous cell carcinoma of the
skin.

- All other significant diseases (for example, inflammatory bowel disease, uncontrolled
asthma), which, in the opinion of the Investigator, might impair the subject's
tolerance of trial treatment.

- Any psychiatric condition that would prohibit the understanding or rendering of
informed consent

- Vaccination within 4 weeks of the first dose of avelumab and while on trial is
prohibited except for administration of inactivated vaccines.