Clinical Trials /

Pembrolizumab in Combination With Intratumoral SD-101 Therapy

NCT03007732

Description:

This is a non-comparative open-label multicenter Phase 2 clinical trial combining stereotactic body radiation therapy (SBRT) and pembrolizumab with or without intratumoral SD-101 in patients with newly diagnosed hormone-naive oligometastatic prostate cancer.

Related Conditions:
  • Prostate Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab in Combination With Intratumoral SD-101 Therapy
  • Official Title: Phase 2 Trial Pembrolizumab or Pembrolizumab in Combination With Intratumoral SD-101 Therapy in Patients With Hormone-Naïve Oligometastatic Prostate Cancer Receiving Definitive Prostatic Radiation and Intermittent Androgen Deprivation Therapy

Clinical Trial IDs

  • ORG STUDY ID: 16703
  • SECONDARY ID: NCI-2017-01340
  • NCT ID: NCT03007732

Conditions

  • Prostatic Neoplasms

Interventions

DrugSynonymsArms
PembrolizumabMK-3475, KeytrudaArm 1
SD-101Toll-like receptor 9Arm 2
Leuprolide acetateIntermittent androgen deprivation therapyArm 1
Abiraterone AcetateIntermittent androgen deprivation therapyArm 1
PrednisoneIntermittent androgen deprivation therapyArm 1

Purpose

This is a non-comparative open-label multicenter Phase 2 clinical trial combining stereotactic body radiation therapy (SBRT) and pembrolizumab with or without intratumoral SD-101 in patients with newly diagnosed hormone-naive oligometastatic prostate cancer.

Detailed Description

      This randomized phase II trial studies how well androgen deprivation therapy, pembrolizumab,
      and stereotactic body radiation therapy with or without TLR9 agonist SD-101 in treating
      patients with prostate cancer that has spread to other places in the body. Androgen can cause
      the growth of tumor cells. Androgen deprivation therapy, such as leuprolide acetate,
      prednisone, and abiraterone acetate may lessen the amount of androgen made by the body.
      Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells
      to grow and spread. Stereotactic body radiation therapy is a specialized radiation therapy
      that sends x-rays directly to the tumor using smaller doses over several days and may cause
      less damage to normal tissue. Colony-stimulating factors, such as TLR9 agonist SD-101, may
      increase the production of blood cells. It is not yet known whether giving androgen
      deprivation therapy, pembrolizumab, and stereotactic body radiation therapy with or without
      TLR9 agonist SD-101 may work better in treating patients with prostate cancer.
    

Trial Arms

NameTypeDescriptionInterventions
Arm 1ExperimentalPatients receive ADT including leuprolide acetate IM at baseline and then every 3 months for 3 doses, prednisone PO daily for 12 months, and abiraterone acetate PO daily for 12 months in the absence of disease progression or unacceptable toxicity. Patients are then randomized into 1 of 2 arms. Patients receive pembrolizumab IV over 30 minutes on day 1. Patients also undergo (Stereotactic Body Radiation Therapy) SBRT QOD over 10-14 days. Treatment with pembrolizumab repeats every 21 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
  • Leuprolide acetate
  • Abiraterone Acetate
  • Prednisone
Arm 2ExperimentalPatients receive ADT including leuprolide acetate IM at baseline and then every 3 months for 3 doses, prednisone PO daily for 12 months, and abiraterone acetate PO daily for 12 months in the absence of disease progression or unacceptable toxicity. Patients are then randomized into 1 of 2 arms. Patients receive TLR9 agonist SD-101 intratumorally 1-2 weeks before Cycle 1, Day 1 and 21 days later after the first dose. Patients also receive pembrolizumab IV over 30 minutes on day 1 and undergo (Stereotactic Body Radiation Therapy) SBRT QOD over 10-14 days. Treatment with pembrolizumab repeats every 21 days for up to 13 courses in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
  • SD-101
  • Leuprolide acetate
  • Abiraterone Acetate
  • Prednisone

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to provide written informed consent/assent for the trial.

          -  Be >=18 years of age on day of signing informed consent.

          -  Have a performance status of 0 or 1 on the ECOG Performance Scale.

          -  Histologically documented adenocarcinoma of the prostate

          -  Oligometastatic disease. In order to be eligible, the patient must have a total of <4
             metastatic bone and/or metastatic lymph node sites based on bone and/or soft tissue
             lesions as defined by any of the following:

               1. Bone metastases will be defined by bone imaging. If the patient has technetium
                  bone scan, and/or NaF PET performed, either study may be used for documenting
                  metastases; both scans do not need to show the number of metastases required for
                  study entry. For patients undergoing PSMA PET, only PSMA avid lesions that are
                  consistent with metastasis will be counted as a site of metastasis.

               2. Distant metastatic lymph node disease. A lymph node ≥1 cm in shortest dimension
                  will be noted as involved with disease. Distant metastatic lymph nodes will be
                  determined as any lymph nodes outside the confines of the true pelvis. For
                  patients undergoing PSMA PET, only PSMA avid lesions that are consistent with
                  metastasis will be counted as a site of metastasis.

               3. Any other soft tissue lesion deemed by the physician to be consistent with
                  distant metastatic disease. For patients undergoing PSMA PET, only PSMA avid
                  lesions that have a CT or MRI correlate consistent with metastasis will be
                  counted as a site of metastasis.

          -  Treatment naïve, defined as less than 2 months of standard of care ADT (e.g. GnRH
             agonist or antagonist with or without antiandrogen, including abiraterone) for
             metastatic hormone-sensitive prostate cancer prior to enrollment (at the time of
             consent)

          -  No prior chemotherapy for prostate cancer

          -  Not a candidate for or refuse chemotherapy

          -  No prior prostatectomy or prostatic radiation

          -  PSA >2 ng/mL at baseline or prior to initiation of hormonal therapy

          -  Baseline testosterone >150 ng/dL if patient has not initiated hormonal therapy, for
             those patients who have already initiated hormonal therapy, baseline testosterone is
             not required

          -  Available archival tumor tissue for correlative studies. Submission of archival TRUS
             prostate biopsy tissue is required if available, in the form of representative
             formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred)
             or at least 15 slides, with an associated pathology report. If archival prostate
             tissue are unavailable or cannot be obtained, a repeat TRUS prostate biopsy is not
             required for eligibility.

          -  Consent to undergo a mandatory baseline biopsy of a metastatic tumor, if clinically
             feasible and safe to perform. Acceptable samples include core needle biopsies of bone
             or lymph node. At least three cores should be obtained. A fine needle aspirate is not
             acceptable. Subjects have the option of consenting to a repeat biopsy at time of
             progression.

          -  Consent to undergo mandatory prostatic core biopsies at the time of fiducial marker
             placement and 21 days (+/- 7 days) after with or without SD-101 therapy, depending on
             study arm.

          -  The effects of pembrolizumab on the developing human fetus is unknown. Men treated or
             enrolled on this protocol must agree to use adequate contraception prior to the first
             dose of study therapy, for the duration of the study participation, and for 120 days
             after the last dose of study therapy.

          -  Subjects should agree to use an adequate method of contraception prior to the first
             dose of study therapy through 120 days after the last dose of study therapy.

          -  Their partners should also be encouraged to use proper method of contraception.

          -  Demonstrate adequate organ function as defined in Table 1, all screening labs should
             be performed within 10 days of treatment initiation.

        Adequate Organ Function Laboratory Values (Performed within 10 days of treatment
        initiation):

          -  Absolute neutrophil count (ANC) ≥1,500 /mcL

          -  Platelets ≥100,000 / mcL

          -  Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days
             of assessment)

          -  Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used
             in place of creatinine or CrCl) ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for
             subject with creatinine levels > 1.5 X institutional ULN. Creatinine clearance should
             be calculated per institutional standard

          -  Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total
             bilirubin levels > 1.5 ULN

          -  AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases

          -  Albumin >2.5 mg/dL

          -  International Normalized Ratio (INR) or Prothrombin Time (PT)

          -  Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
             of anticoagulants ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long
             as PT or PTT is within therapeutic range of intended use of anticoagulants

          -  Creatinine clearance should be calculated per institutional standard.

        Exclusion Criteria:

          -  Patients who are not appropriate candidates for prostate SBRT.

          -  Patients with neuroendocrine or small cell features are not eligible.

          -  Patients with evidence of liver metastasis are excluded.

          -  GnRH agonists or GnRH antagonists (e.g., leuprorelin, degarelix) for > 2 months prior
             to consenting

          -  Antiandrogens (e.g., bicalutamide, flutamide, nilutamide, abiraterone, enzalutamide)
             for > 2 months prior to consenting. Patients on 5-alpha reductase inhibitors are
             allowed on study.

          -  Estrogen containing compounds for > 2 months prior to consenting

          -  PC-SPES or PC-x products. Other herbal therapies or supplements will be considered by
             the Principle Investigator on a case-by-case basis based on their potential for
             hormonal or anti-cancer therapies.

          -  Prior immunotherapy or chemotherapy for prostate cancer

          -  Prior radiation therapy to the prostate

          -  Prior prostatectomy

          -  Is currently participating and receiving study therapy or has participated in a study
             of an investigational agent and received study therapy or used an investigational
             device within 4 weeks of the first dose of treatment.

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of systemic immunosuppressive therapy within 7 days prior to the first dose
             of trial treatment, with the exception of steroids for adrenal insufficiency in which
             case prednisone <10mg/day or its equivalent is allowed.

          -  Has a known history of active TB (Bacillus Tuberculosis)

          -  Hypersensitivity to pembrolizumab or any of its excipients.

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
             due to agents administered more than 4 weeks earlier.

          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at
             baseline) from adverse events due to a previously administered agent.

          -  Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may
             qualify for the study.

          -  Note: If subject received major surgery, they must have recovered adequately from the
             toxicity and/or complications from the intervention prior to starting

          -  Has a known additional malignancy that is progressing or requires active treatment.
             Exceptions include carcinoid, basal cell carcinoma of the skin or squamous cell
             carcinoma of the skin that has undergone potentially curative therapy or in situ
             cervical cancer.

          -  Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least four weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroid treatment for at least 14 days prior to the first dose of study treatment.
             This exception does not include carcinomatous meningitis which is excluded regardless
             of clinical stability.

          -  Has 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 (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

          -  Has known history of, or any evidence of active, non-infectious pneumonitis.

          -  Has an active infection requiring systemic therapy.

          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

          -  Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

          -  Expecting to father children within the projected duration of the trial, starting with
             the pre-screening or screening visit through 120 days after the last dose of trial
             treatment.

          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

          -  Has received a live vaccine within 30 days of planned start of study therapy.

          -  Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines
             and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
             attenuated vaccines, and are not allowed within 30 days.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change Rate of PSA < nadir + 2 ng/mL
Time Frame:Change from the start of treatment, 15 months, and 24 months
Safety Issue:
Description:To determine the rate of PSA < nadir + 2 ng/mL at 15 and 24 months in patients with non-castrate levels of testosterone in each study arm.

Secondary Outcome Measures

Measure:Rate of testosterone-PSA uncoupling
Time Frame:24 months
Safety Issue:
Description:To determine the rate of testosterone-PSA uncoupling (section 4.2.3.1) in each study arm.
Measure:Time to clinical progression
Time Frame:24 months
Safety Issue:
Description:To estimate time to clinical progression in each study arm.
Measure:Number of participants with treatment-related adverse events as assessed by CTCAE (Common Terminology Criteria for Adverse Events) 4.0
Time Frame:24 months
Safety Issue:
Description:Assess the safety associated with giving RT (radiation therapy) and pembrolizumab with or without intratumoral SD-101, based on number of participants with treatment-related adverse events as assessed by CTCAE (Common Terminology Criteria for Adverse Events) 4.0
Measure:Progression-free survival (PFS)
Time Frame:24 months
Safety Issue:
Description:To estimate progression-free survival (PFS) in each study arm.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Lawrence Fong

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