Combination Immunotherapy in Biochemically Recurrent Prostate Cancer

Background

- Androgen deprivation therapy (ADT) and surveillance are treatment options for prostate
cancer patients with biochemical progression after localized therapy (biochemically
recurrent prostate cancer). The primary goal in these patients is to prevent morbidity
from their cancer that results from disease progression and metastatic disease on
conventional imaging.

- ADT can lower the PSA in these patients, but because of its substantial side effect
profile and ambiguous long term impact, it is generally deferred by most patients until
there is a rapid escalation in their PSA.

- Immunotherapy presents an alternative option for these patients that is especially
attractive because it is not associated with substantial toxicity. Also, since
immunotherapy can have lasting effects after treatment due to a sustained activated
immune response, patients will not be required to take these treatments indefinitely to
potentially benefit clinically.

- Current and previous clinical trials have demonstrated that single agent immunotherapy
can impact PSA in patients in this population.

- The focus of this study is to determine if combination immunotherapy with immune-cell
mobilizing vaccines can initiate an immune response in the first 4 months that is then
augmented by an immune checkpoint inhibitor in the following 3 months.

- In addition to PSA responses (the primary metric in this population), safety, changes in
immune responses, and PSA kinetics will also be evaluated.

Objective

Primary Objectives:

- Safety Lead-In: To evaluate the safety and tolerability of combination immunotherapy in
patients with castration-resistant prostate cancer

- Biochemical Recurrence: To determine if the combination immunotherapy can induce a 30%
decline in PSA in 28% of patients with biochemically recurrent prostate cancer.

Key Eligibility Criteria (for biochemical recurrence):

- Histologically confirmed adenocarcinoma of the prostate

- Patients with negative CT Scan and Tc-99m Bone Scan

- Patients with a PSA over 0.8 ng/ml for patients following radical prostatectomy or for
patients following definitive radiation therapy: a rise in PSA of greater than or equal
to 2 ng/mL above the nadir

- Patients with a PSA doubling time of 5-15 months

- No history of active autoimmune disease or history of organ compromising autoimmune
disease

- ECOG 0-1

- Safety lead-in cohort will evaluate 6 patients with castration resistant prostate cancer

Design

- Single arm study

- Accrual goal is a total of 31 evaluable patients; 6 in an initial safety cohort and 25
to evaluate response

- Patients from an on-going study (NCT02649439) with nearly identical eligibility can
serve as a contemporary control for secondary endpoints

- Following the safety lead-in, all patients will be enrolled and undergo a surveillance
period during which 4 consecutive monthly PSA values will be captured by the NIH labs.

- After surveillance period, patients will be treated with 2 vaccines concurrently,
Prostvac and CV301, during months 1-4. For months 5-7, MSB0011359C [an anti-PD-L1
antibody (avelumab) with TGFbeta-Trap molecule] will be added to the regimen.

- Patients will be monitored for on-treatment and post-treatment PSA, immune and imaging
responses.

- INCLUSION CRITERIA:

- Histopathological documentation of prostate cancer confirmed in either the Laboratory
of Pathology at the National Institutes of Health (NIH) Clinical Center, or Walter
Reed National Military Medical Center prior to enrollment. If no pathologic specimen
is available, patients may enroll with a pathologist s report showing a histologic
diagnosis of prostate cancer and a clinical course consistent with the disease.

- Recovery to baseline from acute toxicity related to prior therapy, including surgery
and radiation. (28 days removed from last systemic therapy, 14 days removed from last
radiation therapy).

- Hepatic function eligibility parameters (within 16 days before starting therapy):

--Bilirubin less than or equal to 1.5 mg/dL (OR in patients with Gilbert s syndrome, a
total bilirubin less than or equal to 3.0), AST and ALT less than or equal to 2.5
times upper limit of normal.

- Adequate renal function defined by an estimated creatinine clearance > 50 mL/min
according to the Cockcroft-Gault formula or by measure of creatinine clearance from 24
hour urine collection.

- No other active malignancies within the past 36 months (with the exception of
nonmelanoma skin cancers or carcinoma in situ of the bladder) or life-threatening
illnesses.

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

- 18 years of age or older.

- Able to understand and sign informed consent.

- The effects Prostvac, CV301 and MSB0011359C on the developing human fetus are unknown.
For this reason, men must agree to use highly effective contraception (that is,
methods with a failure rate of less than 1% per year) prior to study entry, for the
duration of study therapy and at least four months after the last treatment
administration. 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.

- Additional Inclusion Criteria Specific to Safety Lead-In Cohort

- Castrate testosterone level (<50ng/dl or 1.7nmol /L)

- Progressive disease at study entry defined as one or more of the following
criteria occurring in the setting of castrate levels of testosterone:

- Radiographic progression defined as any new or enlarging bone lesions or
growing lymph node disease, consistent with prostate cancer

OR

- PSA progression defined by sequence of rising values separated by >1 week (2 separate
increasing values over a minimum of 2ng/ml (PCWG2 PSA eligibility criteria). If
patients had been on flutamide, PSA progression is documented 4 weeks or more after
withdrawal. For patients on bicalutamide or nilutamide disease progression is
documented 6 or more weeks after withdrawal.

--Patients must agree to continuation of androgen deprivation therapy (ADT) with a
gonadotropin-releasing hormone agonist/antagonist or bilateral orchiectomy

- ECOG performance status of 0-2 (Karnofsky >80%).

- Hematological eligibility parameters (within 16 days before starting therapy):

- Granulocyte count greater than or equal to 1000/mm^3

- Platelet count greater than or equal to 100 000/mm^3

- Hgb greater than or equal to 9 g/dL

Additional Inclusion Criteria Specific to Biochemical Recurrence Cohort

- Biochemical progression defined as follows:

- For patients following definitive radiation therapy: a rise in PSA of greater
than or equal to 2 ng/mL above the nadir (per RTOG-ASTRO consensus criteria)

- For patients following radical prostatectomy: rising PSA after surgical procedure
(patients must have a PSA greater than or equal to 0.8 ng/mL)

- Patients must have a rising PSA as confirmed by 3 values a minimum of 1 week apart
over at least a 1 month period of time.

- Patients must have a PSA doubling time of 5-15 months.

- ECOG performance status of 0-1 (Karnofsky > 80%).

- Negative CT scan/MRI and bone scan for metastatic prostate cancer.

- Baseline testosterone greater than or equal to 100 ng/dl.

- PSA less than or equal to 30 ng/mL.

- Hematological eligibility parameters (within 16 days before starting therapy):

- Granulocyte count greater than or equal to 1000/mm3

- Platelet count greater than or equal to 100 000/mm3

- Hgb greater than or equal to 10 g/dL

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, Sjogren 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.

- Patients with diabetes type I, vitiligo, or alopecia are allowed.

- Other immunodeficiency diseases

- Splenectomy

- Receipt of any organ transplantation, including allogeneic stem-cell
transplantation, but with the exception of transplants that do not require
immunosuppression (e.g. corneal transplant, hair transplant).

- Chronic administration (defined as daily or every other day for continued use >
14 days) of systemic corticosteroids within 28 days before the first planned dose
of investigational therapy. Use of corticosteroids with minimal systemic
absorption (e.g. inhaled steroids, nasal sprays, and topical agents) is allowed.

- 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 prior chemotherapy (chemotherapy allowed for lead-in cohort in
castration resistant disease.)

- History of prior immunotherapy within the last 3 years (immunotherapy allowed for
lead-in cohort in castration resistant disease.)

- Receipt of an investigational agent within 28 days (or 56 days for an
antibody-based therapy) before the first planned dose of study drugs.

- Major surgery within 4 weeks prior to enrollment

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

- Previous serious adverse reactions to smallpox vaccination

- History of allergic reactions attributed to monoclonal antibodies (grade 3)

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

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

- History of grade greater than or equal to 2 radiation proctitis

- 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.

- Patients who test positive for HBV or HCV

- Clinically significant cardiovascular/cerebrovascular disease as follows:
cerebral vascular accident/stroke (< 6 months prior to the first planned dose of
study drugs), myocardial infarction (< 6 months prior to the first planned dose
of study drugs), unstable angina, congestive heart failure (New York Heart
Association Classification Class greater than or equal to II), serious cardiac
arrhythmia, or uncontrolled hypertension (SBP>170/DBP>105).