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pTVG-HP DNA Vaccine With or Without pTVG-AR DNA Vaccine and Pembrolizumab in Patients With Castration-Resistant, Metastatic Prostate Cancer

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ClinicalTrials.gov Identifier: NCT04090528
Recruitment Status : Not yet recruiting
First Posted : September 16, 2019
Last Update Posted : October 4, 2019
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Madison Vaccines, Inc
Prostate Cancer Foundation
Information provided by (Responsible Party):
University of Wisconsin, Madison

Brief Summary:
This trial will evaluate the use of one versus two DNA vaccines, delivered concurrently with PD-1 blockade using pembrolizumab followed by treatment with pembrolizumab alone, and delivered over a prolonged period of time (for a maximum of 2 years (32 cycles) or until radiographic progression) on the treatment of castrate-resistant, metastatic prostate cancer. The hypothesis to be tested is that delivering two vaccines with PD-1 blockade will elicit a greater frequency and magnitude of tumor-directed CD8+ T cells, and thereby increase the percentage of patients experiencing objective anti-tumor effect as measured by PSA declines and/or objective radiographic responses. Participants must be 18 years of age or older and can expect to be on treatment for 2 years (32 cycles) and on study for up to 4 years (including 2 years of follow up via phone).

Condition or disease Intervention/treatment Phase
Castration-resistant Prostate Cancer Metastatic Cancer Prostate Cancer Biological: pTVG-HP Biological: pTVG-AR Drug: Pembrolizumab Drug: rhGM-CSF Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 1:1 randomized, open-label, multi-institution phase II trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Trial of pTVG-HP DNA Vaccine With or Without pTVG-AR DNA Vaccine and Pembrolizumab in Patients With Castration-Resistant, Metastatic Prostate Cancer
Estimated Study Start Date : October 2019
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2023


Arm Intervention/treatment
Experimental: Arm 1: One DNA vaccine

100 µg pTVG-HP (with 208 µg rhGM-CSF) administered intradermally (i.d.) days 1, 8 plus 200 mg Pembrolizumab, administered intravenously on day 1 of 21-day cycles (for 8 cycles)

Following cycle 8, subsequent 21-days cycles: Pembrolizumab 200 mg IV day 1 of 21-day cycles

In the event of PSA rise (25% increase over cycle 9 day 1, minimum of 2 ng/ml), and no evidence of radiographic progression, participants will receive 4 additional vaccine booster cycles: 100 µg pTVG-HP (with 208 µg rhGM-CSF) i.d. days 1, 8 + 200 mg pembrolizumab IV day 1 of 21-day cycles x 4 cycles

Biological: pTVG-HP
pTVG-HP is a plasmid DNA, produced in E. coli, that encodes the complementary deoxyribonucleic acid (cDNA) for human prostatic acid phosphatase (PAP).

Drug: Pembrolizumab
Pembrolizumab is a human programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of patients with multiple different types of cancer.
Other Name: Keytruda

Drug: rhGM-CSF
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.
Other Names:
  • Leukine
  • Sargramostim

Experimental: Arm 2: Two DNA vaccines

100 µg pTVG-AR (with 208 µg rhGM-CSF) administered intradermally (i.d.) on days 1, 8 plus 200 mg Pembrolizumab administered intravenously day 1 of 21-day cycles, for cycles 1, 2, 5, and 6 alternating with 100 µg pTVG-HP (with 208 µg rhGM-CSF) administered intradermally (i.d.) on days 1, 8 plus 200 mg Pembrolizumab administered intravenously day 1 of 21-day cycles, for cycles 3, 4, 7, and 8.

Following cycle 8, subsequent 21-days cycles: Pembrolizumab 200 mg IV day 1 of 21-day cycles

In the event of PSA rise (25% increase over cycle 9 day 1, minimum of 2 ng/ml), and no evidence of radiographic progression, participants will receive 4 additional vaccine booster cycles: 100 µg pTVG-AR (with 208 µg rhGM-CSF) i.d days 1, 8 + 200 mg pembrolizumab IV day 1 of q 21-day cycles, for cycles 1 and 2 followed by 100 µg pTVG-HP (with 208 µg rhGM-CSF) i.d. days 1, 8 + 200 mg pembrolizumab IV day 1 in 21-day cycles, for cycles 3 and 4

Biological: pTVG-HP
pTVG-HP is a plasmid DNA, produced in E. coli, that encodes the complementary deoxyribonucleic acid (cDNA) for human prostatic acid phosphatase (PAP).

Biological: pTVG-AR
pTVG-AR is a plasmid DNA

Drug: Pembrolizumab
Pembrolizumab is a human programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of patients with multiple different types of cancer.
Other Name: Keytruda

Drug: rhGM-CSF
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.
Other Names:
  • Leukine
  • Sargramostim




Primary Outcome Measures :
  1. Progression-Free Survival (PFS) [ Time Frame: 6 months ]

    The expected 6-months PFS rate in Arm 1 (pTVG-HP DNA vaccine and Pembrolizumab) in this participant population is 20-30%. It is hypothesized that adding pTVG-AR DNA vaccine (Arm 2) will increase the 6-months PFS rate to at least 55%.

    The 6-month PFS rate will be calculated for each study arm along with the corresponding two-sided 95% confidence interval which will be constructed using the Wilson score method. Participants who withdraw from the study without a progression or death event before the 6-month assessment will be excluded from this analysis. The stratified (by randomization strata) Mantel-Haenszel test will be used to compare the 6-months PFS rates between study arms.



Secondary Outcome Measures :
  1. Overall Objective Response Rate [ Time Frame: up to 2 years ]
    The number of responses will be summarized in tabular format, stratified by study arm. Of note, objective response rate using radiographic criteria will apply only to subjects with RECIST measurable disease (i.e. not subjects with bone-only metastatic disease). Response rates will be calculated for each study arm along with the corresponding two-sided 95% confidence interval which will be constructed using the Wilson score method. The stratified (by randomization strata) Mantel-Haenszel test will be used to compare the overall objective response rates between study arms

  2. Prostate Specific Antigen (PSA) Response Rate [ Time Frame: Up to 2 years ]
    The number of responses will be summarized in tabular format, stratified by study arm. PSA Response Rates will be calculated for each study arm along with the corresponding two-sided 95% confidence interval which will be constructed using the Wilson score method.

  3. Median Radiographic Progression-Free Survival [ Time Frame: up to 2 years ]
    Progression-Free Survival will be analyzed using the Kaplan-Meier method. Median PFS will be calculated for each study arm and reported along with the corresponding 95% confidence intervals will which will constructed using the nonparametric Brookmeyer and Crowley method. The stratified (by randomization strata) log-rank test will be used to compare PFS between study arms.

  4. Median Duration of PSA and Objective Response [ Time Frame: up to 2 years ]
    Duration of PSA and objective response will be analyzed using the Kaplan-Maier method. The median duration of PSA and objective response will be calculated and report along with the corresponding 95% confidence interval which will be constructed using the nonparametric Brookmeyer-Crowley method.

  5. Overall Survival (OS) [ Time Frame: up to 2 years ]
    Overall Survival will be analyzed using the Kaplan-Meier method. OS will be calculated for each study arm and reported along with the corresponding 95% confidence intervals will which will constructed using the nonparametric Brookmeyer and Crowley method. The stratified (by randomization strata) log-rank test will be used to compare OS between study arms.

  6. Antigen-Specific Th1 Immune Response [ Time Frame: up to 2 years ]
    The number and frequencies of antigen-specific Th1 immune responses will be summarized in tabular format for each study arm and both study arms combined. A generalized linear model with a logit link function will be used to evaluate whether antigen-specific Th1 immunity elicited with treatment to either antigen (PAP or AR) is associated with PSA response. The interaction term between treatment arm and antigen-specific Th1 immune will be included in this model.

  7. Safety and Tolerability: Toxicity Rates [ Time Frame: up to 2 years ]
    Participants will be evaluated at each visit by a review of systems based on the most recent version of the NCI common toxicity criteria. Toxicities will be summarized by type and severity in tabular format. Toxicity rates (grade 2, grade 3, grade 4, grade ≥ 2, grade ≥ 3, etc.) will be calculated for each study arm and reported along the corresponding 95% confidence intervals. The 95% confidence intervals will be constructed using the Wilson score method. Fisher's exact test wi be used to compare toxicity rates between study arms.

  8. Safety and Tolerability: Change in Serum Chemistry from Baseline [ Time Frame: up to 2 years ]
    Serum chemistries, including renal function tests, blood counts, liver function tests, and serum amylase, will be evaluated at 6-12 week intervals. Serum chemistry and amylase parameters will be summarized using standard descriptive statistics. Changes from the baseline assessment will be evaluated using a paired t-test.


Other Outcome Measures:
  1. PAP-specific Antibody Response Following Treatment [ Time Frame: up to 2 years ]
    Generalized linear models with a logit link function will be used to evaluate PAP-specific and AR-specific antibody responses following treatment with pembrolizumab and DNA vaccine(s), and to determine whether treatment with either sequence elicits immunologic antigen spread to other prostate associated antigens.

  2. AR-specific Antibody Response Following Treatment [ Time Frame: up to 2 years ]
    Generalized linear models with a logit link function will be used to evaluate PAP-specific and AR-specific antibody responses following treatment with pembrolizumab and DNA vaccine(s), and to determine whether treatment with either sequence elicits immunologic antigen spread to other prostate associated antigens.

  3. Spread of Immunologic Antigens [ Time Frame: up to 2 years ]
    Generalized linear models with a logit link function will be used to determine whether treatment with either sequence elicits immunologic antigen spread to other prostate associated antigens.

  4. Predictive Nature of Pre-existing Antigen-Specific Immunity [ Time Frame: up to 2 years ]
    Logistic regression analysis will be utilized to determine whether pre-existing antigen-specific immunity is predictive of immunological or objective clinical response.

  5. Investigate Cause of Changes in Bone Observed by NaF PET/CT [ Time Frame: up to 2 years ]
    A generalized linear model with subject specific random effects will be used to determine whether early changes in bone observed by NaF PET/CT are associated with immunological or objective clinical response, or pathological changes associated with immune-cell infiltration.

  6. Secondary PSA Response Rate [ Time Frame: up to 2 years ]
    For participants treated in follow-on courses. The stratified (by randomization strata) Mantel-Haenszel test will be used to compare second PSA response rates between study arms.

  7. Change in Gut Microbial Composition [ Time Frame: up to 2 years ]
    Bacterial, viral and archeal species loads identified from the bioinformatics analysis of the microbiome samples will be compared between pre- vs. post-treatment assessment using a paired t-test.

  8. Correlation of gut microbiota to clinical response [ Time Frame: up to 2 years ]
    The false discovery rate will be controlled using the Benjamini-Hochberg False Discovery Rate (FDR) method. Logistic analyses will be conducted to determine whether changes in gut microbiota are associated with clinical response.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed diagnosis of prostate cancer (adenocarcinoma of the prostate)
  • Metastatic disease as evidenced by the presence of soft tissue and/or bone metastases on imaging studies (CT of abdomen/pelvis, bone scintigraphy)
  • Castrate-resistant disease, defined as follows:

    • All participants must have received (and be receiving) standard of care androgen deprivation treatment (surgical castration versus GnRH analogue or antagonist treatment); subjects receiving Gonadotropin-releasing hormone (GnRH) analogue or antagonist must continue this treatment throughout the time on this study.
    • Participants may or may not have been treated previously with a nonsteroidal antiandrogen. For participants previously treated with an antiandrogen, they must be off use of anti-androgen for at least 4 weeks (for flutamide, apalutamide, or enzalutamide) or 6 weeks (for bicalutamide or nilutamide) prior to registration. Moreover, participants who demonstrate an anti-androgen withdrawal response, defined as a > 25% decline in PSA within 4-6 week of stopping a nonsteroidal antiandrogen, are not eligible until the PSA rises above the nadir observed after antiandrogen withdrawal.
    • Participants must have a castrate serum level of testosterone (< 50 ng/dL) within 6 weeks of day 1
  • Progressive disease while receiving androgen deprivation therapy defined by any one of the following as per the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) bone scan criteria or RECIST 1.1 during or after completing last therapy:

    • PSA: At least two consecutive rises in serum PSA, obtained at a minimum of 1-week intervals, with the final value > 2.0 ng/mL.
    • Measurable disease: > 50% increase in the sum of the cross products of all measurable lesions or the development of new measurable lesions. The short axis of a target lymph node must be at least 15 mm by spiral CT to be considered a target lesion
    • Non-measurable (bone) disease: The appearance of two or more new areas of uptake on bone scan (or Sodium Fluoride (NaF) positron emission tomography-computed tomography (PET/CT)) consistent with metastatic disease compared to previous imaging during castration therapy. The increased uptake of pre-existing lesions on bone scan will not be taken to constitute progression, and ambiguous results must be confirmed by other imaging modalities (e.g. X-ray, CT or MRI).
  • Prior treatment with abiraterone or enzalutamide is permitted, but participants must have weaned to a daily corticosteroid dose equivalent of no more than 5 mg prednisone daily for at least 4 weeks prior to day 1.
  • Life expectancy of at least 6 months
  • Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  • Adequate hematologic, renal, liver, and coagulation function as evidenced by the following within 6 weeks of day 1:

    • White Blood Cells (WBC) > 2000 / mm3
    • Absolute Neutrophil Count (ANC) > 1500 / mm3
    • Hemoglobin (HgB) > 9.0 gm/dL
    • Platelets > 100,000 / mm3
    • Creatinine < 1.5 x institutional upper limit of normal (ULN)
    • Total bilirubin < 1.5 x institutional ULN OR direct bilirubin < ULN for participants with total bilirubin levels > 1.5 x ULN
    • Aspartate Aminotransferase (AST),Alanine Aminotransferase (ALT) < 2.5 x institutional upper limit of normal
    • Prothrombin Time (PT) or International Normalized Ratio (INR) < 1.5 x ULN unless participant is receiving anticoagulant therapy and PT is within therapeutic range of intended use of anticoagulant (only required for participants receiving biopsy)
    • Partial Thromboplastin Time (PTT) < 1.5 x ULN unless participant is receiving anticoagulant therapy and a PTT is within therapeutic range of intended use of anticoagulant (only required for participants receiving biopsy)
  • No known history of human immunodeficiency viruses (HIV 1 and 2), Human T-cell leukemia virus type 1 (HTLV-1), or active Hepatitis B or Hepatitis C
  • Participants must be at least 4 weeks from any prior treatments and have recovered (to < Grade 2) from acute toxicity attributed to this prior treatment, unless considered chronic
  • A subset of participants (6 participants per treatment arm) treated at the lead University of Wisconsin (UW) site must be willing and able (in the opinion of the treating physician) to undergo two research biopsies for the investigational component of this trial.
  • A subset of participants (6 participants per treatment arm) treated at the lead UW site must be willing to undergo NaF PET/CT scans for the investigational component of this trial.
  • For those participants who are sexually active, they must be willing to use barrier contraceptive methods, and refrain from donating sperm, during the period of treatment on this trial and for four weeks after the last DNA immunization treatment
  • Participants must be informed of the experimental nature of the study and its potential risks, and must sign an Institutional Review Board (IRB)-approved written informed consent form indicating such an understanding

Exclusion Criteria:

  • Small cell or other variant (non-adenocarcinoma) prostate cancer histology, unless there is evidence that the tumor expresses PAP
  • Participants may not be receiving other investigational agents or be receiving concurrent anticancer therapy other than standard androgen deprivation therapy
  • Concurrent bisphosphonate therapy is not excluded, however participants should not start bisphosphonate therapy while on this study; those participants already receiving bisphosphonate therapy should continue at the same dosing and schedule as prior to study entry
  • Rapidly progressive symptomatic metastatic disease, as defined by the need for increased opioid analgesics within one month of registration for the treatment of pain attributed to a prostate cancer metastatic lesion; participants receiving opioids must receive approval from the PI for eligibility
  • 5. Treatment with any of the following medications within 28 days of day 1, or while on study, is prohibited:

    • Systemic corticosteroids (at doses over the equivalent of 5 mg prednisone daily); inhaled, intranasal or topical corticosteroids are acceptable
    • Prostate Cancer and spes (PC-SPES)
    • Megestrol
    • Ketoconazole
    • 5-α-reductase inhibitors - participants already taking 5-α-reductase inhibitors prior to 28 days prior to registration may stay on these agents throughout the course of therapy, but these should not be started while participants are on study
    • Diethyl stilbesterol
    • Abiraterone
    • Enzalutamide
    • Apalutamide
    • Radium 223 (Xofigo®)
    • Any other hormonal agent or supplement being used with the intent of cancer treatment must be reviewed by the PI for eligibility
  • External beam radiation therapy within 4 weeks of registration is prohibited, or anticipated need for radiation therapy (e.g. imminent pathological fracture or spinal cord compression) within 3 months of registration. Participants must have recovered from all radiation-related toxicities and not have had radiation pneumonitis.
  • Major surgery within 4 weeks of registration is prohibited
  • Prior cytotoxic chemotherapy (for example, but not limited to, docetaxel, mitoxantrone, cabazitaxel) within 3 months of registration is prohibited
  • Prior treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with any agent directed to another T-cell stimulatory or inhibitory receptor (e.g. CTLA-4, OX-40, CD137).
  • Participants with a history of life-threatening autoimmune disease
  • Participants with a history of non-infectious pneumonitis that required corticosteroid treatment, or has current pneumonitis
  • Participants with a history of allergic reactions to GM-CSF or the tetanus vaccine
  • Participants who have undergone splenectomy or who have a diagnosis of immunodeficiency
  • Participants must not have other active malignancies other than non-melanoma skin cancers or superficial (non-muscle-invasive) carcinoma of the bladder. Participants with a history of other cancers who have been adequately treated and have been recurrence-free for > 3 years are eligible.
  • Participants with known brain metastases and/or carcinomatous meningitis
  • Participants who have received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette - Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
  • Any antibiotic therapy within 1 month of day 1, or anticipated need for antibiotic therapy within 1 month of beginning treatment
  • Participants with active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Any other medical intervention or condition, which, in the opinion of the PI or treating physician, could compromise participant safety or adherence with the study requirements (including biopsies), or confound results of the study, over the treatment period.
  • Any known psychiatric or substance abuse disorders that would interfere with cooperation with the requirement of the trial.
  • Participants cannot have concurrent enrollment on other phase I, II, or III investigational treatment studies.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04090528


Contacts
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Contact: Cancer Connect 800-622-8922 skotila@wisc.edu

Locations
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United States, Missouri
Washington University Siteman Cancer Center Not yet recruiting
Saint Louis, Missouri, United States, 63110
United States, Wisconsin
University of Wisconsin Carbone Cancer Center Not yet recruiting
Madison, Wisconsin, United States, 53705
Principal Investigator: Christos Kyriakopoulos, MD         
Sponsors and Collaborators
University of Wisconsin, Madison
Merck Sharp & Dohme Corp.
Madison Vaccines, Inc
Prostate Cancer Foundation
Investigators
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Principal Investigator: Douglas McNeel, MD, PhD University of Wisconsin, Madison

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Responsible Party: University of Wisconsin, Madison
ClinicalTrials.gov Identifier: NCT04090528     History of Changes
Other Study ID Numbers: UW18037
2018-0938 ( Other Identifier: Institutional Review Board )
SMPH/MEDICINE/HEM-ONC ( Other Identifier: UW Madison )
A534260 ( Other Identifier: UW Madison )
First Posted: September 16, 2019    Key Record Dates
Last Update Posted: October 4, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Wisconsin, Madison:
immunotherapy
prostate cancer
vaccine
DNA vaccine
pTVG-HP
pTVG-AR
androgen receptor
prostatic acid phosphatase
pembrolizumab
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Genital Diseases, Male
Prostatic Diseases
Pembrolizumab
Vaccines
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents