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

Study Overview
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Brief Summary
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This randomized phase II trial studies how well glycosylated recombinant human interleukin-7 (CYT107) after vaccine therapy works in treating patients with castration-resistant prostate cancer that has spread to other areas of the body or has not responded to at least one type of treatment. Biological therapies, such as glycosylated recombinant human interleukin-7, may stimulate the immune system in different ways and stop tumor cells from growing. Vaccines made from white blood cells mixed with tumor proteins may help the body build an effective immune response to kill tumor cells. It is not yet known whether glycosylated recombinant human interleukin-7 works better with or without vaccine therapy in treating prostate cancer.

Detailed Description
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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.

Official Title
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Phase 2 Study of Recombinant Glycosylated Human Interleukin-7 (CYT107) After Completion of Standard Therapy With Sipuleucel-T (Provenge®) in Pts w/ Asymptomatic or Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer(mCRPC)

Conditions
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Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Stage IV Prostate Cancer

Intervention / Treatment
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* Biological: Glycosylated Recombinant Human Interleukin-7
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Cohort I (no therapy)<br>Patients receive no treatment (observation) after completion of standard sipuleucel-T therapy. | |
| Experimental: Cohort II (glycosylated recombinant human interleukin-7)<br>Patients receive glycosylated recombinant human interleukin-7 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. | Biological: Glycosylated Recombinant Human Interleukin-7<br>* Given SC<br>* Other names: Glycosylated rhIL-7;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantification of T-cell Responses to Prostatic Acid Phosphatase Granulocyte-macrophage Colony-stimulating Factor (PAP-GM-CSF), Assessed by Quantification of Interferon Gamma Levels Measured Using Enzyme-linked Immunospot (ELISPOT) | The Mann-Whitney-Wilcoxon (MWW) test will be used as part of the statistical analysis to determine quantification of T-cell responses to prostatic acid phosphatase granulocyte-macrophage colony-stimulating factor (PAP-GM-CSF), as assessed by quantification of interferon gamma levels measured using enzyme-linked immunospot (ELISPOT). The power is roughly equivalent to that based on the t-test. | Day 70 (week 11) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Bystander Antigen Specific Immune Responses, Measured by Interferon Gamma Production in Response to Various Antigens as Quantified by Enzyme-linked Immunospot (ELISPOT) | Bystander antigen specific immune responses will be assessed to other ongoing and nascent antitumor responses (e.g., preferentially expressed antigen in melanoma, cancer/testis antigen 1B and/or tumor protein p53), additional tumor antigens specific to prostate cancer (e.g., prostate specific antigen [PSA] and/or prostate-specific membrane antigen), and memory viral responses (influenza A and cytomegalovirus, Epstein-Barr virus and influenza virus-derived peptides) using the interferon gamma ELISPOT assay. | Baseline to up to week 53 | 
| Change in Circulating Tumor Cells | Enumerated by the approved Veridex assay. | Baseline to up to week 53 | 
| Change in Number of Peripheral Blood Mononuclear Cell (PBMC) Subsets and T Lymphocyte Subsets | The absolute fold change from baseline of CD3+ cells | Week 11 | 
| Change in Prostate Specific Antigen (PSA) Kinetics. | The change in prostate specific antigen (PSA) kinetics will be evaluated according to the recommendations from PSA Working Group (PSAWG). Analysis of PSA doubling time | Baseline to up to week 53 | 
| Change in Vaccine-induced Antigen-specific Antibody Immune Response to Prostatic Acid Phosphatase (PAP) | Will be measured by change in immunoglobulin G (IgG) and immunoglobulin M (IgM) levels quantified by standard enzyme-linked immunosorbent assay (ELISA). Fold change from baseline in week 6 titer | Baseline to up to week 6 | 
| Overall Survival | Number of participants that have survived | Up to 5 years |