Combination Immunotherapy in Biochemically Recurrent Prostate Cancer
Combination Immunotherapy in Biochemically Recurrent Prostate Cancer
Background:

 Some people with prostate cancer have a rise in prostate-specific antigen (PSA). This can
 happen even after treatments like radiation and surgery. Androgen deprivation therapy (ADT)
 drugs and close monitoring are one standard way to treat this group of people. Another way is
 to monitor people and their PSA values over time. Researchers want to see if a combination of
 new drugs can help these people.

 Objective:

 To see if the combination treatment of PROSTVAC, CV301, and MSB0011359C (M7824) can induce an
 anti-tumor attack in people with biochemically recurrent prostate cancer.

 Eligibility:

 People ages 18 and older with certain kinds of prostate cancer

 Design:

 Participants will be screened with

 -  Medical history

 -  Physical exam

 -  Blood and urine tests

 -  A scan of the neck, chest, abdomen, and pelvis

 -  A bone scan

 A sample of tissue that was already taken will be tested. This will confirm the diagnosis,
 stage, and disease status.

 Some participants will have close monitoring with four monthly PSA checks.

 All participants will get two study drugs as shots under the skin. They will get the third
 drug in a vein. They will get the drugs over at least 7 months. Their vital signs will be
 checked before they get the drugs and for up to 1 hour after.

 Participants will have frequent study visits. They will have physical exams, urine and blood
 tests, and scans.

 Participants will return to the clinic about 4 weeks after they stop taking the study drugs.
 They will have a medical history, physical exam, and blood tests. They may also have
 long-term follow-up visits.
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

 -  Two-arm, non-randomized 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 greater than or equal to 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).

 -  Patients who have received a red cell transfusion within 2 weeks prior to
 enrollment.

 -  Individual tumor lesion(s) in the liver or chest which are 10 cm or larger.

 -  In the opinion of the investigator the risk of bleeding outweighs the potential
 benefit with M7824. Note: patients with a history of bleeding diathesis or recent
 (within 3 months) clinically significant bleeding events are also excluded.