Pembrolizumab and HER2Bi-Armed Activated T Cells in Treating Patients With Metastatic Castration Resistant Prostate Cancer

PRIMARY OBJECTIVES:

I. To estimate the clinical efficacy of 8 infusions of HER2 HER2Bi-armed activated T cells
(BATs) (up to 10^10/infusion) twice per week for 4 weeks in combination with pembrolizumab
once every 3 weeks starting with one dose 3 weeks before the 1st BATs infusion, by assessing
the percentage of patients free of clinical progression at 6 months after registration.

SECONDARY OBJECTIVES:

I. Evaluate phenotype, cytokine profiles and IFN-gamma enzyme-linked immunosorbent spots
(ELISpots), cytotoxicity and antibodies directed at laboratory prostate cancer cell lines for
proof of principle of immune system activation and to correlate with clinical outcomes of
response, progression free survival (PFS), and overall survival (OS).

II. Evaluate the magnitude of change in tumor infiltrating T cells, PD-1 expression, and the
Th1/Th2 ratio in prostate cancer tumor tissue before and after immunotherapy and correlate it
with the clinical outcomes of response, PFS, and OS.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes every 3 weeks. Treatment
repeats every 3 weeks for up to 6 months in the absence of disease progression or
unacceptable toxicity. Beginning at least 1 week after pembrolizumab, patients receive
HER2Bi-armed activated T cells IV over 5-15 minutes 2 times a week for 4 weeks in the absence
of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

- Be willing and able to provide written informed consent/assent for the trial

- Have histologically confirmed prostate adenocarcinoma, with metastases

- Progression by either PSA, Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria for measurable disease or new areas of metastases on bone scan or symptom
progression related to prostate cancer despite castrate levels of testosterone; (level
< 50 ng/ml)

- Be agreeable to continue to maintain castrate levels of testosterone

- At least 2 weeks should have elapsed since any immunosuppressive therapy

- At least 4 weeks since prior chemotherapy for metastatic disease or at least 2 weeks
since prior androgen targeting agents such as ketoconazole, abiraterone, enzalutamide,
etc.

- Discontinue anti-androgens prior to therapy; at least 6 weeks since last dose of
bicalutamide or nilutamide and at least 4 weeks from last dose of flutamide

- Have normal bone marrow, renal and hepatic function as deemed by the treating
physician and approved by the clinical principal investigator (PI) Dr. Vaishampayan

- Not have concurrent anti-cancer therapy

- Not have concurrent immunosuppressive therapy or medical condition likely to cause
immunosuppression

- Have life expectancy > 6 months

- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group
(ECOG)/Zubrod performance scale

- Agree to use an adequate method of contraception starting with the first dose of study
therapy through 120 days after the last dose of study therapy

- Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject

- Within 10 days of treatment initiation: Absolute neutrophil count (ANC) >= 1,500 /mcL

- Within 10 days of treatment initiation: Platelets >= 100,000 / mcL

- Within 10 days of treatment initiation: Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without
transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)

- Within 10 days of treatment initiation: Serum creatinine =< 1.5 X upper limit of
normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration
rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >=
60 mL/min for subject with creatinine levels > 1.5 X institutional ULN

- Within 10 days of treatment initiation: Serum total bilirubin =< 1.5 X ULN OR direct
bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN

- Within 10 days of treatment initiation: Aspartate aminotransferase (AST) (serum
glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum
glutamate pyruvate transaminase [SGPT] =< 2.5 X ULN OR =< 5 X ULN for subjects with
liver metastases

- Within 10 days of treatment initiation: Albumin >= 2.5 mg/dL

- Within 10 days of treatment initiation: International normalized ratio (INR) or
prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy
as long as PT or partial thromboplastin time (PTT) is within therapeutic range of
intended use of anticoagulants

- Within 10 days of treatment initiation: Activated partial thromboplastin time (aPTT)
=< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is
within therapeutic range of intended use of anticoagulants

Exclusion Criteria:

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (> 10 mg
of prednisone daily or equivalent steroid doses) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of trial treatment

- Has a known history of active TB (Bacillus tuberculosis)

- Has hypersensitivity to pembrolizumab or any of its excipients

- Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
day 1 or has not recovered (i.e. =< grade 1 or at baseline) from adverse events due to
agents administered earlier; Note: Subjects with = to this criterion and may qualify for the study

- Has received major surgery, subject must have recovered adequately from the toxicity
and/or complications from the intervention prior to starting therapy

- Has a known additional malignancy that is progressing or requires active treatment;
exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer

- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis; subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least four weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment; this exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs); replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment

- Has known history of, or any evidence of active, non-infectious pneumonitis

- Has an active infection requiring systemic therapy

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject?s
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)

- Has known active hepatitis B (e.g. hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g. hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)

- Has received a live vaccine within 30 days of planned start of study therapy; Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g. Flu-Mist) are live attenuated
vaccines, and are not allowed

- Has history of cardiac or pulmonary impairment either by clinical history or symptoms
or cardiac ejection fraction < 40%