CYT107 After Vaccine Treatment (Provenge®) in Patients With Metastatic Castration-Resistant Prostate Cancer

PRIMARY OBJECTIVES:

I. To determine whether CYT107 administration increases the vaccine-induced antigen-specific T-cell immune response to the sipuleucel-T fusion protein vaccine construct prostatic acid phosphatase granulocyte-macrophage colony-stimulating factor (PAP-GM-CSF) (PA2024).

SECONDARY OBJECTIVES:

I. To determine whether CYT107 administration increases the vaccine-induced antigen-specific T-cell immune response to PAP.

II. To assess the character of the T-cell immune response to PAP and PA2024. III. To determine whether CYT107 administration increases the vaccine-induced antigen-specific antibody immune responses to PAP and PA2024.

IV. To quantify the effects of CYT107 on T-cell repertoire diversity. V. To assess the effects of CYT107 on the immune competence of patients with advanced prostate cancer.

VI. To assess the clinical efficacy and tolerability of sipuleucel-T plus CYT107 compared with sipuleucel-T alone.

OUTLINE: Patients are randomized to 1 of 2 cohorts.

COHORT I: Patients receive no treatment (observation) after completion of standard sipuleucel-T therapy.

COHORT II: Patients receive glycosylated recombinant human interleukin-7 subcutaneously (SC) every week for 4 weeks (on days 0, 7, 14, and 21) beginning 3-7 days after completion of standard sipuleucel-T therapy. Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 53 weeks. Patients are followed by phone, once a year, after completion of Week 53 for overall survival.

Inclusion criteria

• Asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC)
• Patients must have successfully completed therapy with sipuleucel-T within 3-7 days of planned CYT107 study drug treatment
• Assessable disease with a positive bone scan and/or measurable disease on computed tomography (CT) scan and/or magnetic resonance imaging (MRI) of the abdomen and pelvis
• Prior orchiectomy or must be on ongoing luteinizing hormone-releasing hormone (LHRH) agonist or antagonist (e.g., degarelix) therapy
• No ongoing anti-androgen therapy; patients must be off anti-androgen therapy for at least 30 days
• Patients receiving any other hormonal therapy, including any dose of megestrol acetate (Megace), Proscar (finasteride), any herbal product known to decrease prostate specific antigen (PSA) levels (e.g. saw palmetto, PC-SPES), or any systemic corticosteroid, must discontinue the agent for at least 30 days prior to study treatment
• Absolute neutrophil count (ANC) >= 1500/uL
• Bilirubin < 1.5 x upper limit of normal (ULN)
• Hemoglobin >= 10 g/dL
• Platelets >= 100,000/mcL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
• Creatinine clearance >= 60 mL/min by the Cockcroft-Gault equation
• Testosterone =< 50 ng/dL (documented at any time while on LHRH agonist or antagonists or s/p orchiectomy)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 or a Karnofsky performance status of >= 80%
• Life expectancy of at least 6 months
• Prior local radiation therapy must be completed at least 30 days prior to enrollment and the patient must have recovered from all toxicity
• Prior "systemic" radiopharmaceuticals (strontium, samarium, radium 223 dichloride) must be completed >= 8 weeks prior to enrollment
• Patients must agree to use 2 methods of adequate contraception for the duration of study participation, and for four months after discontinuing therapy
• Ability to understand and the willingness to sign a written informed consent document

Exclusion criteria

• Prior chemotherapy for castration resistant prostate cancer; neoadjuvant chemotherapy and chemotherapy given for hormone sensitive prostate cancer are allowed
• Prior investigational immunotherapy
• Prostate cancer pain requiring regularly scheduled narcotics
• Pathologic long-bone fractures, imminent pathologic long-bone fracture (cortical erosion on radiography > 50%) or spinal cord compression
• Current treatment with systemic steroid therapy (inhaled/topical steroids are acceptable); systemic corticosteroids must be discontinued for at least 30 days prior to first CYT107 injection
• Known central nervous system metastases
• Documented cirrhosis or documented acute hepatitis; Note: a positive hepatitis B serology indicative of previous immunization (i.e., hepatitis B surface antibody [HBsAb] positive and hepatitis B core antibody [HBcAb] negative), or a fully resolved acute hepatitis B virus (HBV) infection is not an exclusion criterion
• History of severe asthma, as defined by prior or current use of systemic corticosteroids for disease control, with the exception of physiological replacement doses of cortisone acetate or equivalent, as defined by a dose of 10 mg or less
• Medical or psychiatric illness that would, in the opinion of the investigator, preclude participation in the study or the ability of patients to provide informed consent for themselves
• Cardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association class III or IV), active angina pectoris, or recent myocardial infarction (within the last 6 months)
• Concurrent or prior malignancy except for the following:

• Adequately treated basal or squamous cell skin cancer
• Adequately treated stage I or II cancer from which the patient is currently in complete remission
• Any other cancer from which the patient has been disease-free for 5 years
• Known human immunodeficiency virus (HIV) or other history of immunodeficiency disorder; HIV-positive patients on combination antiretroviral therapy are ineligible
• Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or medical (e.g. infectious) illness
• Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of CYT107 hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to CYT107
• Patients who have received prior immunosuppressive therapy within 30 days prior to enrollment
• Active (as defined by requiring immunosuppressive therapy) or history of clinically significant autoimmune disease (as defined by previously requiring immunosuppressive therapy)
• Patients who have received hepatotoxic drugs less than 7 days prior to enrollment
• Patients who have received prior biologic agents less than 30 days prior to enrollment
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients who have a history of any hematopoietic malignancy
• History of pulmonary disease such as emphysema or chronic obstructive pulmonary disease (COPD), (forced expiratory volume [FEV] > 60% of predicted for height and age required in patients with prolonged smoking history or symptoms of respiratory dysfunction)