pTVG-HP and Nivolumab in Patients With Non-Metastatic PSA-Recurrent Prostate Cancer

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety of an investigational DNA vaccine, pTVG-HP, a plasmid DNA encoding human prostatic acid phosphatase (PAP), in combination with nivolumab, and the efficacy of this combination in decreasing serum Prostate-Specific Antigen (PSA) in patients with non-metastatic, non-castrate prostate cancer (clinical stage D0/M0).

Official Title
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Phase II Trial of a DNA Vaccine Encoding Prostatic Acid Phosphatase (pTVG-HP) and Nivolumab in Patients With Non-Metastatic, PSA-Recurrent Prostate Cancer

Conditions
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Prostate Cancer

Intervention / Treatment
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* Biological: pTVG-HP
* Drug: Nivolumab
* Drug: GM-CSF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be at least 18 years of age with a histologic diagnosis of adenocarcinoma of the prostate Patients must have undergone radical prostatectomy Patients must have completed local therapy by surgery and any adjuvant/salvage radiation therapy at least 3 months prior to entry, with removal or ablation of all visible disease, including seminal vesical and/or local lymph node involvement. Patients must have biochemically recurrent, non-metastatic (by CT and bone scan) clinical stage D0/M0 disease defined by the following: Patients must have evidence of detectable serum PSA with at least 4 serum PSA measurements available, from the same clinical laboratory, at least two weeks apart up to one year, and the final serum PSA value must be > 2.0 ng/mL. PSA doubling time, calculated from most recent 4 serum PSA values (collected up to one year prior to enrollment, at least 2 weeks apart, and all from the same clinical laboratory), must be a positive number (i.e. evidence of PSA rise over time). PSA doubling time will be calculated using the Memorial Sloan-Kettering Cancer Center nomogram (http://www.mskcc.org/applications/nomograms/prostate/PsaDoublingTime.aspx). Patients must not have definitive evidence of metastases as determined by CT of the abdomen/pelvis and bone scintigraphy (bone scan). Note: patients with lesions detectable by highly sensitive methods (e.g. NaF PET imaging or PSMA PET imaging) will be considered eligible as long as these lesions do not meet size criteria on CT imaging (visceral lesions suspicious for metastases or lymph node > 15 mm in short axis) and/or are not independently observed on bone scan Patients with a prior history of a second malignancy are eligible provided they have been treated with curative intent and have been free of disease greater than three years. There will be no exclusion for patients with a history of basal cell carcinoma, squamous cell skin cancer, superficial bladder cancer, or other in situ carcinoma that has been adequately treated. Patients who are sexually active must use a reliable form of contraception while on study and for 4 weeks after the last immunization. ECOG performance score < 2 and life expectancy of at least 12 months. Patients must have normal hematologic, renal and liver function as defined by: WBC > 3000/mm3, hematocrit > 30%, platelet count > 100,000/mm3, serum creatinine < 1.5 mg/dl or a calculated creatinine clearance > 60 cc/min, AST or ALT < 3.0x ULN, and serum bilirubin < 2.0 mg/dl(except participants with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL), within 4 weeks prior to first immunization. Patients must be informed of the experimental nature of the study and its potential risks and must sign an IRB-approved written informed consent form indicating such an understanding. Willingness to provide blood samples for immune studies, per study calendar, up to one year after study, even if off study treatment. Exclusion Criteria: Small cell or other variant prostate cancer histology Patients cannot have evidence of immunosuppression or have been treated with immunosuppressive therapy, such as chemotherapy or chronic treatment dose corticosteroids (greater than the equivalent of 10 mg prednisone per day), within 3 months of the first vaccination. Seropositive for HIV, hepatitis B (HBV) or hepatitis C (HCV) per patient history due to the immunosuppressive features of these diseases. Prior treatment with an LHRH agonist or nonsteroidal antiandrogen, except in the following circumstances: Neoadjuvant/adjuvant androgen deprivation therapy administered with radiation therapy or at the time of prostatectomy is acceptable, provided that there was no evidence of PSA progression while on treatment. In this situation, patients must not have received more than 24 months of androgen deprivation treatment. Other treatment with androgen deprivation therapy is prohibited. Serum testosterone at screening < 50 ng/dL. Patients must not be concurrently taking other medications or supplements with known hormonal effects, including PC-SPES, megestrol acetate, finasteride, ketoconazole, estradiol, or Saw Palmetto. All other medications with possible anticancer effects must be discussed with the PI prior to study entry. Patients previously treated with herbal supplements as described in 5.B.6 or other potential or experimental therapies for prostate cancer must have discontinued these treatments and completed at least a 4 week washout prior to beginning treatment. Patients must not have evidence of bone metastases or lymph node involvement as determined by bone scan or CT scan of the abdomen and pelvis within 4 weeks of study registration. Note: Advanced imaging modalities (such as NaF-PET/CT, choline PET/CT, fluciclovine, or PSMA PET scans) will NOT be used to determine evidence of metastases for eligibility purposes or for defining disease progression. Patients must not have been treated with a prior DNA vaccine therapy for prostate cancer. Patients must not have known psychological or sociological conditions, addictive disorders or family problems, which would preclude compliance with the protocol. Patients must not have known allergic reactions to GM-CSF. Patients with unstable or severe intercurrent medical conditions or laboratory abnormalities that would impart, in the judgment of the PI, excess risk associated with study participation or study agent administration. Patients cannot have concurrent enrollment on other phase I, II, or III investigational therapeutic treatment studies.

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
Intervention Model: Single Group Assignment
Interventional Model Description: Single-arm, single-institution, two-stage phase II trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Group<br>Nivolumab 240 mg IV every two weeks x 6 beginning day 1, then every four weeks x 9 beginning week 12 pTVG-HP (100 µg) administered intradermally (i.d.) every two weeks x 6 beginning day 1, then every four weeks x 9 beginning week 12 rhGM-CSF (208 µg) administered intradermally (i.d.) every two weeks x 4 beginning week 4, then every four weeks x 9 beginning week 12 NOTE: Only administered to patients for whom serum PSA obtained week 4 > serum PSA obtained at day 1. | Biological: pTVG-HP<br>* Plasmid DNA vaccine encoding Prostatic Acid Phosphatase (PAP)<br>Drug: Nivolumab<br>* Nivolumab is a human programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of patients with multiple different types of cancer.<br>* Other names: Opdivo;Drug: GM-CSF<br>* Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth factor that supports the survival, clonal expansion and differentiation of hematopoietic progenitor cells including dendritic antigen presenting cells.<br>* Other names: Sargramostim;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Adverse Events Grade 3 or Higher | Subjects will be evaluated at each visit by a review of systems based on the most recent version of the NCI common toxicity criteria. Safety and Tolerability of this intervention is defined as following: a toxicity rate p0 of at most 15% of Grade ≥ 3 toxicity events (CTCAE v.4.0) will be considered as acceptable while a toxicity rate p1=35% or more will be considered as unacceptably high. See Adverse Events Section for full summary of data. | up to 48 weeks | 
| Prostate-Specific Antigen (PSA) Complete Response (CR) Rate | A PSA CR will be defined as the percentage of participants with a serum PSA <0.2 ng/mL and confirmatory PSA <0.2 ng/mL at least 4 weeks later, as per Prostate Cancer Working Group 2 (PCWG2) recommendations. To qualify as a PSA CR, there must be no evidence of radiographic progression. | up to 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Metastasis-free Survival Rate | The 2-year metastasis-free survival will be determined by investigator review of radiographic studies (CT/MRI and bone scintigraphy) performed 2 years after study initiation in subjects who have not already met criteria for radiographic progression. | Up to 2 years | 
| Median Radiographic Progression-free Survival | All participants will undergo radiographic imaging prior to treatment and at 6-month intervals (or as clinically required). The appearance of lesions consistent with metastatic disease will be used to define radiographic progression. | Up to 2 years | 
| PSA Doubling Time | Post-treatment doubling time will be calculated from: 1) All PSA values obtained from the same clinical laboratory using the same PSA assay beginning with the PSA value at day 1 (week 0) and continuing until the end-of study (or month 24) value (PSADT 0-24). 2) All PSA values obtained from the same clinical laboratory using the same PSA assay beginning with the PSA value at day 85 (month 3) to the day 253 (month 9) value (PSADT 3-9). | Up to 2 years | 
| PSA Response Rate (</= 50% of Baseline) | The percentage of participants with PSA values less than or equal to their baseline value after 2 year. | Up to 2 years | 
| Number of Participants Receiving GM-CSF as an Adjuvant After Week 4 | GM-CSF is used as an adjuvant if the PSA at week 4 is higher than baseline. | up to week 4 |