Docetaxel and PROSTVAC for Metastatic Castration-Sensitive Prostate Cancer

Background:

- A phase III trial demonstrated that combining docetaxel and androgen deprivation therapy
(ADT) significantly improved survival (57.6 vs 44.0 months (HR=0.56, (0.44-0.70), p
<0.0001) for men with metastatic castration sensitive prostate cancer (mCSPC).

- PROSTVAC (developed by the National Cancer Institute [NCI] and licensed to Bavarian
Nordic Immunotherapeutics, Mountain View, CA) is a therapeutic cancer vaccine for
prostate cancer.

- Preclinical and clinical studies support the potential synergy in the combination of
docetaxel and PROSTVAC. The potential to combine docetaxel with vaccine in mCSPC could
improve upon the survival advantage that has been previously seen.

Objectives:

Primary

-To determine if PROSTVAC combined with docetaxel is able to induce greater antigen spreading
(i.e. a broader immune response) with greater associated response score compared to docetaxel
alone after 19 weeks.

Key Eligibility Criteria:

- Must have castrate sensitive prostate cancer (rising PSA and testosterone over 100) or
is within 134 days of starting ADT (Arm A or B) or within 28 days of start ADT (Arm C)

- Histopathological confirmation of prostate cancer

- Patients must have metastatic disease

- Patients must have a performance status of 0 to 2 according to the ECOG criteria

- Patients must have adequate bone marrow, hepatic, and renal function

Design

- This is a randomized trial of ADT followed by simultaneous docetaxel 75 mg/m(2) q3 weeks
x 6 cycles + PROSTVAC q3 weeks x 6 cycles versus ADT followed by sequential docetaxel 75
mg/m(2) q3 weeks x 6 cycles followed by PROSTVAC q3 weeks x 6 cycles in men with newly
diagnosed mCSPC.

- Patients who have not started ADT or who have been on ADT 28 days or fewer will be
assigned to treatment with PROSTVAC for 4 - 6 injections followed by docetaxel 75 mg/m2
q3 weeks x 6 cycles.

- INCLUSION CRITERIA:

- Documented histopathological confirmation of prostate cancer-from a CLIA certified
laboratory.

- Patients must have metastatic disease, defined as at least one lesion on bone scan or
at least one lesion that are measurable per RECIST 1.1. (Patients who have metastatic
disease by these criteria prior to ADT, but then have changes after ADT that diminish
the size of these lesions or changes on bone scan are still eligible.)

- Patients must have a performance status of 0 to 2 according to the ECOG criteria

- Patients must have adequate bone marrow, hepatic, and renal function with:

- ANC greater than or equal to 1500/microL, without CSF support

- Platelets greater than or equal to 100,000/microL

- AST(SGOT) less than or equal to 2.5 times upper limit of normal (ULN);

- ALT(SGPT) less than or equal to 2.5 times upper limit of normal (ULN);

- Total serum bilirubin less than or equal to 1.5 times upper limit of normal
(ULN), OR in patients with Gilbert s syndrome, a total bilirubin less than or
equal to 3.0)

- Serum albumin greater than or equal to 2.8 g/dL

- Lipase < 2.0 times the upper limit of normal and no radiologic or clinical
evidence of pancreatitis

- Creatinine less than or equal to 1.5 times institutional upper limits of normal

OR

Creatinine clearance of greater than or equal to 50 ml/min/1.73 m(2) for patients with
creatinine levels above institutional normal by 24-hour urine.

- Willing to travel to the NIH for follow-up visits

- 18 years of age or older.

- Able to understand and sign informed consent.

- May have had up to 24 months of ADT (testosterone suppression therapy in the
nonmetastatic setting) and are at least 12 months removed from treatment

- Men treated or enrolled on this protocol must also agree to use adequate
contraception, prior to the study, for the duration of study participation, and 4
months after completion. Sexually active subjects and their female partners must agree
to use medically accepted barrier methods of contraception (e.g., male or female
condom) during the course of the study and for 4 months after the last dose of study
drug(s), even if oral contraceptives are also used. All subjects of reproductive
potential must also agree to use both a barrier method and a second method of birth
control during the course on the study and for 4 months after the last dose of study
drug(s). Should a woman become pregnant or suspect she is pregnant while her partner
is participating in this study, she should inform her treating physician immediately.

- Must have started ADT for metastatic disease within 134 days (for Arm A and B) or
within 28 days (for Arm C).

EXCLUSION CRITERIA:

- Immunocompromised status due to:

- Human immunodeficiency virus (HIV) positivity.

- Active autoimmune diseases such as Addison s disease, Hashimoto s thyroiditis,
systemic lupus erythematosus, Sj(SqrRoot)(Delta)gren syndrome, scleroderma,
myasthenia gravis, Goodpasture syndrome or active Grave s disease. Patients with
a history of autoimmunity that has not required systemic immunosuppressive
therapy or does not threaten vital organ function including CNS, heart, lungs,
kidneys, skin, and GI tract will be allowed.

- Other immunodeficiency diseases

- Chronic administration (defined as daily or every other day for continued use > 14
days) of corticosteroids deemed systemic by investigator within 28 days before the
first planned dose of PROSTVAC. Use of inhaled steroids, nasal sprays, and topical
creams for small body areas is allowed.

- Evidence of rising PSA on ADT

- Serious intercurrent medical illness that, in the judgment of the investigator, would
interfere with patient s ability to carry out the treatment program.

- Other medications used for urinary symptoms including 5-alpha reductase inhibitors
(finasteride and dutasteride) and alternative medications known to alter PSA (e.g.
phytoestrogens and saw palmetto)

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to poxviral vaccines (e.g., vaccinia vaccine)

- Known allergy to eggs, egg products, aminoglycoside antibiotics (for example,
gentamicin or tobramycin).

- History of atopic dermatitis or active skin condition (acute, chronic, exfoliative)
that disrupts the epidermis

- Previous serious adverse reactions to smallpox vaccination

- Unable to avoid close contact or household contact with the following high-risk
individuals for three weeks after the Day 1 vaccination: (a) children less than or
equal to 3 years of age, (b) pregnant or nursing women, (c) individuals with prior or
concurrent extensive eczema or other eczemoid skin disorders, or (d) immunocompromised
individuals, such as those with HIV.

- Receipt of an investigational agent within 28 days (or 60 days for an antibody-based
therapy) before the first planned dose of study drugs.

- Patients who test positive for HBV or HCV

- Uncontrolled hypertension (SBP>170/ DBP>105)

- Patients who have had prior chemotherapy for prostate cancer.

- The subject has had evidence within 2 years of the start of study treatment of another
malignancy which required systemic treatment (with the exception of nonmelanoma skin
cancers or carcinoma in situ of the bladder).

- The subject has active brain metastases or epidural disease.

- Patients with greater than or equal to grade 2 peripheral neuropathy at baseline.

- Patients with history of splenectomy