Clinical Trials /

Vaccine Therapy and Pembrolizumab in Treating Patients With Hormone-Resistant, Metastatic Prostate Cancer

NCT02499835

Description:

This randomized pilot trial studies vaccine therapy and pembrolizumab in treating patients with prostate cancer that does not respond to treatment with hormones (hormone-resistant) and has spread to other places in the body (metastatic). Vaccines made from deoxyribonucleic acid (DNA), such as pTVG-HP plasmid DNA vaccine, may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as pembrolizumab, may find tumor cells and help kill them. Giving pTVG-HP plasmid DNA vaccine and pembrolizumab may kill more tumor cells.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Vaccine Therapy and Pembrolizumab in Treating Patients With Hormone-Resistant, Metastatic Prostate Cancer
  • Official Title: Pilot Trial of pTVG-HP DNA Vaccine and Pembrolizumab in Patients With Castration-Resistant, Metastatic Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: UW15014
  • SECONDARY ID: 2015-0453
  • SECONDARY ID: NCI-2015-01154
  • SECONDARY ID: P30CA014520
  • NCT ID: NCT02499835

Conditions

  • Hormone-Resistant Prostate Cancer
  • Metastatic Malignant Neoplasm in the Bone
  • Metastatic Malignant Neoplasm in the Soft Tissues
  • Metastatic Prostate Carcinoma
  • Prostate Adenocarcinoma
  • Recurrent Prostate Carcinoma
  • Stage IV Prostate Cancer

Interventions

DrugSynonymsArms
Pembrolizumab1374853-91-4, Immunoglobulin G4, Anti-(Human Programmed Cell Death 1), Lambrolizumab, Keytruda, MK-3475, SCH 900475Arm I (pTVG-HP plasmid DNA vaccine, concurrent pembrolizumab)
pTVG-HP Plasmid DNA VaccineArm I (pTVG-HP plasmid DNA vaccine, concurrent pembrolizumab)

Purpose

This randomized pilot trial studies vaccine therapy and pembrolizumab in treating patients with prostate cancer that does not respond to treatment with hormones (hormone-resistant) and has spread to other places in the body (metastatic). Vaccines made from deoxyribonucleic acid (DNA), such as pTVG-HP plasmid DNA vaccine, may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as pembrolizumab, may find tumor cells and help kill them. Giving pTVG-HP plasmid DNA vaccine and pembrolizumab may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety of pembrolizumab in combination with pTVG-HP (pTVG-HP plasmid DNA
      vaccine) in patients with castration-resistant, metastatic prostate cancer.

      II. To determine the 6-month progression-free survival and median time to radiographic
      progression in patients with castration-resistant metastatic prostate cancer treated with
      pembrolizumab in combination with pTVG-HP.

      III. To evaluate the anti-tumor response rates (objective response rate and prostate specific
      antigen [PSA] response rate, using Prostate Cancer Clinical Trials Working Group 2 [PCWG2]
      criteria) in patients with castration-resistant metastatic prostate cancer treated with
      pembrolizumab in combination with pTVG-HP.

      SECONDARY OBJECTIVES:

      I. To determine whether either treatment sequence, or prostatic acid phosphatase
      (PAP)-specific immune response, is associated with prolonged (6-month) radiographic
      progression-free survival.

      II. To evaluate effects of schedule (concurrent versus delayed administration of
      pembrolizumab) on the magnitude of PAP-specific T-cell responses, programmed death receptor-1
      (PD-1) expression on circulating T cells, and ligands for PD-1 (PD-L1) expression on
      circulating epithelial cells (CEC) and on tumor biopsies.

      III. To determine the median time to radiographic progression using a concurrent
      administration schedule

      TERTIARY OBJECTIVES:

      I. To evaluate effects of treatment on number of circulating tumor cells. II. To evaluate
      PAP-specific antibody responses following treatment with pembrolizumab and pTVG-HP DNA
      vaccine (pTVG-HP plasmid DNA vaccine).

      III. To determine whether either treatment sequence elicits immunologic antigen spread to
      other prostate-associated antigens.

      IV. To determine whether pre-existing or vaccine-induced PD-L1 expression on CEC or tumor
      biopsies is predictive of objective clinical response.

      V. To determine whether treatment elicits expression of other regulatory molecules on
      tumor-specific T cells (e.g. hepatitis A virus cellular receptor 2 [TIM3], B and T lymphocyte
      associated [BTLA], and lymphocyte-activation gene 3 [LAG3]) or tumor cells (e.g. tumor
      necrosis factor receptor superfamily, member 14 [HVEM], phosphatidyl serine, ligands for
      programmed death receptor-2 [PD-2] [PD-L2]).

      VI. To determine whether PD-1-regulated antigen-specific T cells identified by trans vivo
      delayed-type hypersensitivity (DTH) testing can identify patients who develop objective
      clinical responses with PD-1 blockade therapy in combination with pTVG-HP.

      VII. To determine whether changes in lymph nodes and soft tissue tumor lesions are observed
      by fluorothymidine F-18 (FLT) positron emission tomography (PET)/computed tomography (CT)
      after treatment with vaccine with or without pembrolizumab.

      VIII. To determine if PD-1 inhibitor therapy in combination with pTVG-HP will change number
      and activity (SUV) in osteoblastic metastases as measured by NaF PET/CT.

      OUTLINE: Patients are randomized to 1 of 2 treatment arms.

      ARM I: Patients receive pTVG-HP plasmid DNA vaccine intradermally (ID) every other week on
      days 1, 15, 29, 43, 57, and 71 and pembrolizumab intravenously (IV) over 30 minutes every 3
      weeks on days 1, 22, 43, and 64.

      ARM II: Patients receive pTVG-HP plasmid DNA vaccine ID as in Arm I and pembrolizumab IV over
      30 minutes every 3 weeks on days 85, 106, 127, and 148.

      After completion of study treatment, patients are followed up 3, 6, 9, and 12 months and then
      annually for 2 years.

      ARM III: Extended Treatment. Patients received pTVG-HP + Pembrolizumab Extended Treatment

      ARM IV: Extended Treatment. Patients receive pTVG-HP every two weeks, and Pembrolizumab every
      4 weeks
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (pTVG-HP plasmid DNA vaccine, concurrent pembrolizumab)ExperimentalPatients receive pTVG-HP plasmid DNA vaccine ID every other week on days 1, 15, 29, 43, 57, and 71 and pembrolizumab IV over 30 minutes every 3 weeks on days 1, 22, 43, and 64.
  • Pembrolizumab
  • pTVG-HP Plasmid DNA Vaccine
Arm II (pTVG-HP plasmid DNA vaccine, sequential pembrolizumab)ExperimentalPatients receive pTVG-HP plasmid DNA vaccine ID as in Arm I and pembrolizumab IV over 30 minutes every 3 weeks on days 85, 106, 127, and 148.
  • Pembrolizumab
  • pTVG-HP Plasmid DNA Vaccine
Extended Treatment Arm IIIExperimentalpTVG-HP (100 μg) with rhGM-CSF (208 μg) administered intradermally (i.d.) every 3 weeks, for a maximum of 16 doses. Pembrolizumab 2 mg/kg, with a maximum dose of 200 mg, administered intravenously every 3 weeks, for a maximum of 16 doses, beginning on day 1 after the first pTVG-HP vaccination.
  • Pembrolizumab
  • pTVG-HP Plasmid DNA Vaccine
Extended Treatment Arm IVExperimentalpTVG-HP (100 µg) with rhGM-CSF (208 µg) administered intradermally (i.d.) every 2 weeks, for a maximum of 24 doses Pembrolizumab 2 mg/kg, with a maximum dose of 200 mg, administered intravenously every 4 weeks, for a maximum of 12 doses, beginning on day 1 after the first pTVG-HP vaccination
  • Pembrolizumab
  • pTVG-HP Plasmid DNA Vaccine

Eligibility 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 patients must have received (and be receiving) standard of care androgen
                  deprivation treatment (surgical castration versus gonadotropin-releasing hormone
                  [GnRH] analogue or antagonist treatment); subjects receiving GnRH analogue or
                  antagonist must continue this treatment throughout the time on this study

               -  Patients may or may not have been treated previously with a nonsteroidal
                  antiandrogen; for patients previously treated with an antiandrogen, they must be
                  off use of anti-androgen for at least 4 weeks (for flutamide) or 6 weeks (for
                  bicalutamide or nilutamide) prior to registration; moreover, subjects 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

               -  Patients 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 2 (PCWG2) bone
             scan criteria or Response Evaluation Criteria in Solid Tumors (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 fluorine F 18 sodium fluoride [NaF] 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 magnetic resonance imaging [MRI])

          -  Prior treatment with abiraterone or enzalutamide is permitted, but patients must have
             been off prior corticosteroid treatment for at least 3 months

          -  Life expectancy of at least 6 months

          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
             0, 1, or 2

          -  White blood cells (WBC) >= 2000/mm^3

          -  Absolute neutrophil count (ANC) >= 1000/mm^3

          -  Hemoglobin (HgB) >= 9.0 gm/dL

          -  Platelets >= 100,000/mm^3

          -  Creatinine =< 2.0 mg/dL

          -  Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 2.5 x
             institutional upper limit of normal

          -  No known history of human immunodeficiency virus (HIV) 1 and 2, human T-lymphotropic
             virus (HTLV)-1, or active hepatitis B or hepatitis C

          -  Patients 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

          -  Patients must be willing and able (in the opinion of the treating physician) to
             undergo two research biopsies for the investigational component of this trial

          -  Patients must be willing to undergo two leukapheresis procedures for the
             investigational component of this trial

          -  Patients must be willing to undergo FLT PET/CT or NaF PET/CT scans for the
             investigational component of this trial and have no known allergies to FLT or NaF

          -  For those patients who are sexually active, they must be willing to use barrier
             contraceptive methods during the period of treatment on this trial (and for four weeks
             after the last DNA immunization treatment for patients in Arm 1)

          -  Patients 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

          -  Patients 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 patients should not start
             bisphosphonate therapy while on this study; those patients 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; patients receiving opioids must
             receive approval from the principal investigator (PI) for eligibility

          -  Treatment with any of the following medications within 28 days of registration, or
             while on study, is prohibited:

               -  Systemic corticosteroids (at doses over the equivalent of 5 mg prednisone daily)
                  - not permitted within 3 months of registration; inhaled, intranasal or topical
                  corticosteroids are acceptable

               -  Prostate cancer (PC)-SPES

               -  Saw palmetto

               -  Megestrol

               -  Ketoconazole

               -  5-alpha-reductase inhibitors - patients already taking 5-alpha-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 patients
                  are on study

               -  Diethyl stilbestrol

               -  Abiraterone

               -  Enzalutamide

               -  Radium 223 (Xofigo)

               -  Any other hormonal agent or supplement being used with the intent of cancer
                  treatment

          -  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

          -  Major surgery within 4 weeks of registration is prohibited

          -  Prior cytotoxic chemotherapy (for example, but not limited to, docetaxel,
             mitoxantrone, cabazitaxel) within 6 months of registration is prohibited

          -  Patients with a history of life-threatening autoimmune disease

          -  Patients with a history of allergic reactions to filgrastim (GM-CSF) or the tetanus
             vaccine

          -  Patients who have undergone splenectomy

          -  Patients must not have other active malignancies other than non-melanoma skin cancers
             or superficial bladder cancer; subjects with a history of other cancers who have been
             adequately treated and have been recurrence-free for >= 3 years are eligible

          -  Patients with known brain metastases

          -  Any antibiotic therapy or evidence of infection within 1 week of registration

          -  Any other medical intervention or condition, which, in the opinion of the PI or
             treating physician, could compromise patient safety or adherence with the study
             requirements (including biopsies or leukapheresis procedures) over the primary 3-6
             month treatment period

          -  Patients cannot have concurrent enrollment on other phase I, II, or III
             investigational treatment studies

        NOTE: There is no exclusion for prior immune-based therapy. This includes patients
        previously treated on Arms 1 or 2 who are otherwise eligible for treatment on Arm 3 or 4.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events, using the National Cancer Common Terminology Criteria, version 4
Time Frame:Up to 12 months after completion of study treatment
Safety Issue:
Description: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 will be used to compare toxicity rates between study arms.

Secondary Outcome Measures

Measure:PAP-specific immune response
Time Frame:Up to 2 years
Safety Issue:
Description:Number and frequencies of PAP-specific immune responses will be summarized in tabular format for each study arm and both study arms combined. A log-linear model will be used to evaluate whether PAP-specific immune response predicts 6-months progression-free survival rate. Interaction between treatment (pembrolizumab administered sequentially versus delayed) and PAP-specific immune response will be included in the model. Analogously, a Cox proportional hazard regression model will be used to examine the association between PAP-specific immune response and time to radiographic progression.
Measure:PAP-specific T-cell response
Time Frame:Up to 2 years
Safety Issue:
Description:Number and frequencies of PAP-specific T-cell responses will be summarized in tabular format. Fisher's exact test will be used to compare the PAP-specific T-cell response rates between study arms.
Measure:PD-1 expression
Time Frame:Up to day 85
Safety Issue:
Description:PD-1 and PD-L1 expression levels will be summarized in terms of means, standard deviations and ranges for each study arm separately and for both arms combined. A linear regression model or a negative binomial regression model will be utilized to evaluate effects of schedule (concurrent versus delayed administration pembrolizumab) on PD-1 expression on number of circulating T cells, and PD-L1 expression on number of circulating epithelial cells. Choice of the model will be dependent on distribution of outcome variables (number of circulating T-cells and number of circulating epithelial cells).
Measure:PD-L1 expression
Time Frame:Up to day 85
Safety Issue:
Description:PD-1 and PD-L1 expression levels will be summarized in terms of means, standard deviations and ranges for each study arm separately and for both arms combined. A linear regression model or a negative binomial regression model will be utilized to evaluate effects of schedule (concurrent versus delayed administration pembrolizumab) on PD-1 expression on number of circulating T cells, and PD-L1 expression on number of circulating epithelial cells. Choice of the model will be dependent on distribution of outcome variables (number of circulating T-cells and number of circulating epithelial cells).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Wisconsin, Madison

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