Provenge Followed by Docetaxel in Castration-Resistant Prostate Cancer

Castration-resistant prostate cancer (CRPC) develops serial treatment resistance and is
considered incurable. It is a largely indolent disease, which would give the body time to
mount an effective immune response. CRPC is therefore potentially well suited for vaccine
therapy.

Sipuleucel-T (Provenge), is an FDA-approved cancer vaccine therapy manufactured by culturing
an individual's own freshly isolated peripheral blood mononuclear cells (PBMCs), including
antigen-presenting cells (APCs) and T cells, with a fusion protein (PA-2024) composed of
prostatic acid phosphatase (PAP) linked to granulocyte macrophage-colony stimulating factor
(GM-CSF). A course of therapy consists of three doses of Provenge administered at 2-week
intervals.

Docetaxel is an antineoplastic agent belonging to the taxoid family. The FDA-approved course
of therapy for prostate cancer consists of 75 mg/m2 docetaxel given intravenously as a 1-hour
infusion every 21 days on Day 1.

This is an open-label phase II study in taxane-naïve patients with metastatic CRPC of
Provenge followed by docetaxel. Adult (age >18 years) men with pathologically-confirmed
adenocarcinoma of the prostate with clinical or radiologic evidence of metastatic disease
that has progressed despite treatment with anti-androgens, inhibitors of adrenal-produced
androgens (abiraterone), or androgen receptor inhibitors (enzalutamide), and who, prior to
study entry are candidates to receive Standard of Care chemotherapy (e.g.,
docetaxel/prednisone) or immunotherapy (Provenge), will be enrolled in this study.

This study will recruit a total of 32 patients with metastatic CRPC. Patients will receive
Provenge followed by 6 cycles of docetaxel. Treatment will be administered on an outpatient
basis. Patients must meet one of the following prognostic criteria:

- PSA doubling time >6 months

- ≤3 bone lesions (only if they meet PSA doubling time criteria)

- >3 but ≤10 bone lesions (only if they meet PSA doubling time criteria)

- Nodal disease only

The primary objective of this study is to characterize the immunological biomarkers during
therapy and correlate the immunological biomarkers with clinical outcome. The strategy aims
to determine whether cytokine production and T cell infiltration of tumor cells could favor
regression using a combination of vaccine plus chemotherapy. Tissue endpoints will include
biopsies prior to vaccine therapy and chemotherapy and at the end of therapy. Prostate cancer
tissue infiltrates will be studied for expression of CD3, CD4, CD8, CD25/FOX3P, CD56, CTLA-4,
PD-1, and Ki67. Additional immunological endpoints will be secondary antigen spread and
various cytokine biomarkers.

Inclusion Criteria:

- Male 18 years and older.

- Pathologic confirmation of prostate adenocarcinoma.

- Asymptomatic or minimally symptomatic disease.

- Presence of skeletal or visceral/nodal metastasis confirmed by MRI, scintigraphy, or
CT scan

- Disease progression as indicated by:

- PSA increase indicated by two consecutive higher values over baseline at
assessments performed at least 7 days apart from each other in the previous 28
days with the absolute value ≥5 ng/ml; OR

- Progression of measurable lymph nodes (≥15 mm) measureable per RECIST v1.1
criteria; OR

- New bone lesions appearing on imaging compared with a prior bone scan. (Bone scan
to be performed at screening or within the previous 28 days.)

- Maintenance of castrate conditions: Patients who have not had a surgical orchiectomy
must continue with hormone therapy (GnRH/LHRH agonists or antagonists) to maintain
levels of serum testosterone of <50 ng/dl.

- Patient is clinically immunocompetent. Clinical immunocompetence will be assumed
unless a subject has been diagnosed as being immunosuppressed, is receiving oral
steroids (nasal sprays and inhalers are permitted), or is receiving immunosuppressive
therapy following transplant, in which case they will be excluded.

- Peripheral neuropathy grade ≤1.

- Laboratory criteria:

- Adequate bone marrow function:

1. White blood cells ≥4000/mm3

2. Absolute neutrophil count ≥1500/mm3

3. Absolute lymphocyte count ≥500/µl

4. Hemoglobin ≥10 g/dl

5. Platelet count ≥100,000/mm3

- Total bilirubin within normal limits (benign hereditary hyperbilirubinemias,
e.g., Gilbert's syndrome, are permitted)

- Renal function creatinine ≤1.5 x ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be
within normal range.

- Life expectancy of at least 6 months based on Investigators' judgment

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- At least 4 weeks after surgery or radiotherapy

- If patients have been receiving bisphosphonate or denosumab, they can continue either
medication.

- Sufficient washout period from previous anti-androgen and hormonal therapies (PSA
regression verification required after casodex withdrawal during the 6-week washout
period).

- Patient is willing and available to attend clinic visits at least every 2 weeks.

- Signed, informed consent, including patient's ability to comprehend its contents

Exclusion Criteria:

- Patient's disease burden is greater than the prognostic criteria defined earlier,
including the presence of visceral or bone metastases.

- Patient has "currently active" second malignancy, other than non-melanoma skin cancer.
Patients are not considered to have a "currently active" malignancy if they have
completed therapy >5 years previously and have no known evidence of residual or
recurrent disease.

- Current symptomatic cord compression requiring surgery or radiation therapy

- Prior chemotherapy for prostate cancer

- Patient is using supplements or complementary medicines/botanicals. Patients should
review the label with their doctor prior to enrolment. The following exceptions are
permitted at screening and during the course of the study.

- Conventional multivitamin supplements

- Selenium

- Lycopene

- Soy supplements

- Vitamin E

- Fish oil supplements

- Vitamin D

- Glucosamine supplements

- Age-related eye disease vitamins

- Ginkgo biloba

- Patient co-morbidities:

- HIV positive

- Acute hepatitis B (HBV) or active hepatitis C (HCV)

- Clinical and laboratory evidence of active bacterial, viral, or fungal infection
requiring systemic treatment

- Clinically significant cardiovascular disease including

1. Symptomatic congestive heart failure

2. Unstable angina pectoris

3. Serious cardiac arrhythmia requiring medication

4. Uncontrolled hypertension >150/100mm Hg (if controlled with medication this
is not an exclusion).

5. Hypotension

6. Myocardial infarct or ventricular arrhythmia or stroke within a 6-month
period prior to inclusion, ejection fraction (EF) <40%, or serious cardiac
conduction system disorders

7. Patient is exhibiting evidence of symptomatic congestive heart failure,
pulmonary embolus, vascular thrombosis, transient ischemic attack,
cerebrovascular accident, unstable angina, myocardial infarction or active
ischemia if a pacemaker is not present on electrocardiogram (ECG). An ECG
must be performed at screening unless the subject has measurable disease in
which case an ECG taken prior to screening but within 28 days of start of
treatment will be accepted.

- Pleural and pericardial effusion of any CTCAE grade

- Rheumatoid disease (asymptomatic subjects with controlled and rarely flaring
rheumatoid arthritis are also excluded)

- Peripheral neuropathy having a CTCAE grade ≥2

- History of malignant disease (with the exception of non-melanoma skin tumors) in
the preceding 5 years

- Active autoimmune disease requiring treatment (except non-insulin-dependent
diabetes mellitus)

- History of severe forms of primary immune deficiencies

- History of anaphylaxis or other serious reactions following vaccination

- Uncontrolled co-morbidities including psychiatric or social conditions which, in
the Investigator's opinion, would prevent participation in the trial

- Patient has had major surgery or radiation therapy completed < 4 weeks prior to
screening.

- Patient has had prior exposure to the radiopharmaceuticals radium 223, strontium, or
samarium within 8 weeks prior to screening.

- Patient is receiving concurrent chemotherapy, immunotherapy, radiotherapy, or
investigational agents.

- Patient has cerebral metastases (known from previous investigations or clinically
detectable).

- Patient has serum testosterone >50 ng/dl.

- Systemic corticosteroids at doses >40 mg hydrocortisone daily or equivalent for any
reason other than (a) prescribed as replacement therapy in the case of adrenal
insufficiency or (b) oral dexamethasone administration used in combination with
docetaxel.

- Patient has in the opinion of the physician a serious or uncontrolled intercurrent
infection or non-malignant medical illness which is uncontrolled.

- Systemic immunosuppressive therapy for any reason.

- Treatment with anti-androgens, inhibitors of adrenal-produced androgens (abiraterone),
androgen receptor inhibitors (enzalutamide), or other hormonal tumor-focused treatment
performed on the day of screening or within the previous 4 weeks, including any dose
of megestrol acetate, finasteride, any herbal product known to decrease PSA levels
(e.g., saw palmetto and PC-SPES), or any systemic corticosteroid must discontinue the
agent for at least 4 weeks prior to screening. Progressive disease (as defined above)
must be documented after discontinuation of the therapy.

- Refusal to sign the informed consent.

- Participation in a clinical trial using experimental therapy within the last 60 days.