Palbociclib After CDK and Endocrine Therapy (PACE)

This research study is a Phase II clinical trial. Phase II clinical trials test the safety
and effectiveness of an investigational intervention to learn whether the intervention works
in treating a specific disease. "Investigational" means that the intervention is being
studied and the researchers are trying to find out more about it— for example, the side
effects it may cause, and the activity of a drug, or combination of drugs, against a cancer.

In this research study, the investigators are evaluating the activity of fulvestrant alone,
fulvestrant and palbociclib, or fulvestrant, palbociclib, and avelumab combined, in
participants with metastatic hormone receptor positive HER2 negative breast cancer that has
previously stopped responding to prior palbociclib and endocrine therapy.

The FDA (the U.S. Food and Drug Administration) has approved both palbociclib and fulvestrant
as treatment options for this disease, however the use of palbociclib has not been studied in
people who have previously been treated with palbociclib. The FDA has not approved avelumab
as a treatment for any disease.

Palbociclib is a drug that may stop cancer cells from growing. Palbociclib blocks activity of
two closely related enzymes (proteins that help chemical reactions in the body occur), called
Cyclin Dependent Kinases 4 and 6 (CDK 4/6). These proteins are part of a pathway, or a
sequence of steps, which is known to promote cancer cell growth. Laboratory testing has shown
that palbociclib may stop the growth of hormone receptor positive breast cancer. Palbociclib
is FDA-approved as therapy for metastatic hormone receptor positive HER2 negative breast
cancer in combination with endocrine therapy in the first line setting, and in combination
with fulvestrant for pre-treated disease. It is not known whether cancers that have grown
despite prior palbociclib treatment are still sensitive to palbociclib.

Endocrine therapy prevents growth of hormone receptor positive breast cancer by blocking
stimulation of cancer cells by estrogen. During this study, the endocrine therapy will be
fulvestrant. Fulvestrant is a drug that is approved by the FDA for treatment of metastatic
hormone receptor positive breast cancer.

The immune system is the body's natural defense against disease. The immune system sends a
type of cells called T cells throughout the body to detect and fight infections and
diseases—including cancers. One way the immune system controls the activity of T cells is
through the PD-1 (programmed cell death protein-1) pathway. However, some cancer cells hide
from T-cell attack by taking control of the PD-1 pathway and this stops T cells from
attacking cancer cells.

Avelumab is an antibody designed to block the PD-1 pathway and helps the immune system in
detecting and fighting cancer cells. An antibody is a protein produced by the body's immune
system when it detects harmful substances. Previous studies show that the administration of
antibodies which block the PD-1 pathway can lead to tumor destruction.

In the laboratory, adding avelumab to fulvestrant and palbociclib appears to improve
effectiveness. It is not known whether this is true in humans

Inclusion Criteria:

- Participants must have histologically confirmed hormone receptor positive (HR+) HER2
negative metastatic or locally recurrent unresectable invasive breast cancer. ER, PR
and HER2 measurements should be performed according to institutional guidelines, in a
CLIA-approved setting. Cut-off values for positive/negative staining should be in
accordance with current ASCO/CAP (American Society of Clinical Oncology/College of
American Pathologists) guidelines.

- Men and pre- and postmenopausal women are eligible. Ongoing monthly GNRH agonist is
required in pre-menopausal women or male participants for at least 4 weeks prior to
study entry.

- Participants must have radiological or objective evidence of progression on an
endocrine and CDK 4/6 inhibitor regimen in the metastatic setting, and/or
relapse/progression during or within 12 months of completion of an endocrine and
CDK4/6 inhibitor regimen in the adjuvant setting.

- Participants must have previously been exposed to CDK4/6 inhibitor therapy in
combination with endocrine therapy. Exposure to any prior CDK4/6 inhibitor,
(including palbociclib, abemaciclib, and ribociclib) is allowed. Patients may
have a line of endocrine therapy after combination endocrine and CDK4/6 inhibitor
exposure.

- Participants must have remained on prior endocrine and CDK4/6 therapy in the
metastatic setting without progression for at least 6 months prior to study
entry.

- It is not mandatory to have a CDK 4/6 inhibitor containing regimen as the most
recent treatment.

- Participants may have 0-1 prior lines of cytotoxic chemotherapy in the metastatic
setting.

- Prior endocrine therapy in the metastatic setting may include any aromatase inhibitor
(AI) or tamoxifen, but may not include prior fulvestrant. In the metastatic setting,
1-2 prior lines of endocrine therapy are allowed.

- Participants may have received radiotherapy for palliative purpose, but must not be
experiencing > grade 1 treatment related toxicities, and must have completed treatment
> 14 days prior to registration.

- Age ≥18 years. Because no dosing or adverse event data are currently available on the
use of study agents in participants <18 years of age, children are excluded from this
study.

- ECOG performance status 0-1 (see Appendix A).

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

- Absolute neutrophil count > 1,500/µL

- Platelets > 100,000/µL

- Hemoglobin > 9g/dL

- Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (participants
with documented Gilbert's disease are allowed total bilirubin up to 1.5X ULN)

- AST (SGOT)/ALT (SGPT) < 2.5 x institutional ULN, or ≤ 5 x ULN for subjects with
documented metastatic disease to the liver.

- Creatinine < institutional ULN or creatinine clearance > 60 mL/min/1.73 m2 for
subjects with creatinine levels above institutional ULN.

- Baseline QTc < 480 ms

- The effects of palbociclib and avelumab on the developing human fetus are unknown. If,
for any reason, a woman should become pregnant or suspect that she is pregnant while
participating in this study, she should inform her treating physician immediately.
Women of childbearing age, women who are made postmenopausal through use of GNRH
agonists, and men must agree to use adequate contraception for the duration of
protocol treatment and for at least 60 days after the last dose of study medication if
the risk of contraception exists.

- Adequate contraception is defined as one highly effective non-hormonal form of
contraception or two effective forms of non-hormonal contraception by the participant
and/or partner.

- Highly Effective Non-Hormonal Contraception

- Methods of birth control which result in a low failure rate (i.e., less than 1% per
year) when used consistently and correctly are considered highly-effective forms of
contraception.

- The following non-hormonal methods of contraception are acceptable:

- True abstinence when this is in line with the preferred and usual lifestyle of
the participant. [Periodic abstinence (e.g., calendar, ovulation, symptothermal
post-ovulation methods) and withdrawal are not acceptable methods of
contraception].

- Male sterilization (with appropriate post-vasectomy documentation of the absence
of sperm in the ejaculate). For female participants, the vasectomized male
partner should be the sole partner.

OR

-Effective Non-Hormonal Contraception

Alternatively two of the following effective forms of contraception may be used instead:

- Placement of non-hormonal intrauterine device (IUD) or intrauterine system (IUS).
Consideration should be given to the type of device being used, as there is higher
failure rates quoted for certain types, e.g., steel or copper wire.

- Condom with spermicidal foam/gel/film/cream/suppository.

- Occlusive cap (diaphragm or cervical/vault caps) with spermicidal
foam/gel/film/cream/suppository.

- The use of barrier contraceptives should always be supplemented with the use of
spermicide. The following should be noted:

- Failure rates indicate that, when used alone, the diaphragm and condom are not highly
effective forms of contraception. Therefore, the use of additional spermicides does
confer additional theoretical contraceptive protection.

- However, spermicides alone are ineffective at preventing pregnancy when the whole
ejaculate is spilled. Therefore, spermicides are not a barrier method of contraception
and should not be used alone.

It should be noted that two forms of effective contraception are required. A double barrier
method is acceptable, which is defined as condom and occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream /suppository.

- Premenopausal women must have a negative serum or urine pregnancy test. Pregnancy
testing does not need to be pursued in female participants who are:

- Age > 60 years; or

- Age < 60 with intact uterus and amenorrhea for 12 consecutive months or more AND
estrogen (estradiol) levels within postmenopausal range; or

- Status-post bilateral oophorectomy, total hysterectomy, or bilateral tubal
ligation.

- Participant must be able to swallow and retain oral medication.

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

Exclusion Criteria:

- Participants who have had endocrine, chemotherapy, and/or biologic therapy within 14
days prior to entering the study or those who have not recovered from any prior
treatment-related toxicities (must recover to no more than grade 1. Alopecia, sensory
neuropathy Grade ≤ 2, or other Grade ≤ 2 toxicity not constituting a safety risk based
on investigator's judgment are acceptable).

- Participants who are receiving concurrent therapy with other investigational agents.

- Rapidly progressive, symptomatic, visceral spread of disease placing participant at
risk of life-threatening complications in the short term.

- Participants with active brain metastases. Stable treated brain metastases are allowed
(this includes participants who have documented radiologic stability at least 4 weeks
after radiotherapy, and do not require systemic steroids for management of symptoms
from CNS metastatic lesions).

- Participants who have discontinued prior palbociclib for toxicity, or have needed more
than one dose or schedule reduction for toxicity from prior palbociclib therapy. If a
participant required a single dose reduction during prior palbociclib therapy and
tolerated it well, for example prior dosing at 100 mg qd 3 weeks on 1 week off
schedule, than that dose may be selected for this trial.

- History of allergic reactions to palbociclib or attributed to compounds of similar
chemical or biologic composition to palbociclib.

- Known prior severe hypersensitivity to investigational product or any component in its
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (NCI CTCAE v4.03 Grade ≥ 3)

- Participants receiving any medications or substances that are strong inhibitors or
inducers of CYP3A isoenzymes are ineligible. Lists including medications and
substances known or with the potential to interact with the CYP3A isoenzymes are
provided in Appendix B, and can also be found within Section 5.4. Because the lists of
these agents are constantly changing, it is important to regularly consult a
frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx;
medical reference texts such as the Physicians' Desk Reference may also provide this
information. As part of the enrollment/informed consent procedures, the participant
will be counseled on the risk of interactions with other agents, and what to do if new
medications need to be prescribed or if the participant is considering a new
over-the-counter medicine or herbal product.

- Current use of drugs listed in Appendix C that are known to prolong the QT interval
(See Appendix C)

- Prior organ transplantation including allogenic stem-cell transplantation

- Current use of immunosuppressive medication, except for the following: a. intranasal,
inhaled, topical steroids, or local steroid injection (e.g., intra-articular
injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone
or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT
scan premedication).

- Uncontrolled intercurrent illness including, but not limited to: ongoing or active
infection requiring systemic therapy, clinically significant cardiovascular disease
including: 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, uncontrolled diabetes mellitus, or
psychiatric illness/social situations that would limit compliance with study
requirements. Ability to comply with study requirements is to be assessed by each
investigator at the time of screening for study participation.

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

- Known history of testing positive for HIV or known acquired immunodeficiency syndrome,
or need to receive combination antiretroviral therapy for HIV

- Known history of immune-mediated conditions including colitis, inflammatory bowel
disease requiring steroid or immunosuppressive therapy, pneumonitis, or pulmonary
fibrosis.

- Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)

- Live vaccination within 4 weeks of the first dose of avelumab

- Pregnant women are excluded from this study because effect of palbociclib and avelumab
on a developing fetus is unknown. Breastfeeding should be discontinued prior to entry
onto the study.

- 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 3 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: ductal
carcinoma in situ of the breast, cervical cancer in situ, and basal cell or squamous
cell carcinoma of the skin