Pembrolizumab +/- SD-101 in Hormone-Naïve Oligometastatic Prostate Cancer With RT and iADT
Pembrolizumab +/- SD-101 in Hormone-Naïve Oligometastatic Prostate Cancer With RT and iADT
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.
This randomized phase II trial studies how well androgen deprivation therapy, pembrolizumab,
 and stereotactic body radiation therapy with or without toll-like receptor 9 (TLR9) agonist
 SD-101 in treating patients with prostate cancer and cancer in all oligometastatic sites 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 and cancer in all oligometastatic sites.

 PRIMARY OBJECTIVES

 -  Cohort 1 (No longer recruiting)

 --To assess the safety associated with giving RT and pembrolizumab with or without
 intratumoral SD-101.

 -  Cohort 2

 -  To continue to assess the safety associated with giving RT and pembrolizumab with
 or without intratumoral SD-101.

 -  To assess if the rate of PSA < nadir + 2 ng/mL at 15 months in patients with
 non-castrate levels of testosterone is greater than the historical control in each
 study arm.

 SECONDARY OBJECTIVES

 -  To determine the rate of testosterone-PSA uncoupling in each study arm in cohort 2.
 Testosterone-PSA uncoupling is defined as PSA < 50% baseline and < 20ng/mL for at least
 3 months after testosterone recovers to >150 ng/dL. In patients with metastatic hormone
 sensitive prostate cancer off hormonal therapy, >90% patient are expected to have PSA
 increase to > 50% baseline after 3 months of testosterone recovery.

 -  To estimate time to clinical progression

 -  To estimate progression-free survival (PFS) in each study arm

 EXPLORATORY OBJECTIVE

 -  To assess peripheral and tumor-based biomarkers of response and resistance in both
 cohorts.

 -  To define the treatment-induced effects on circulating immune cells in both cohorts.

 -  To explore remodeling of circulating T cell repertoire in both cohorts.

 -  To explore the concordance of Prostate-Specific Membrane Antigen (PSMA) - Positron
 Emission Tomography (PET) scanning with conventional imaging in oligometastatic prostate
 cancer patients in both cohorts.
Inclusion Criteria:

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

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

 3. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
 Performance Scale.

 4. Histologically documented adenocarcinoma of the prostate

 5. 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 sodium fluoride (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.

 -  Note: Radiographic imaging performed as standard of care prior to obtaining
 informed consent and within 60 days of initiating study treatment may be
 used to assess oligometastatic disease during screening, rather than
 repeating scans. For patients who have started on ADT, they must have had
 imaging prior to initiation of hormonal therapy

 6. 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)

 7. No prior chemotherapy for prostate cancer

 8. Not a candidate for or refuse chemotherapy

 9. No prior prostatectomy or prostatic radiation

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

 11. 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

 12. Consent to undergo mandatory prostatic core biopsies at the time of fiducial marker
 placement and 1-3 weeks after Cycle 1 Day 1 of pembrolizumab.

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

 14. Demonstrate adequate organ function defined as: Adequate Organ Function Laboratory
 Values (Performed within 10 days of treatment initiation):

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

 -  Platelets >=100,000 / mcL

 -  Hemoglobin >=9 g/dL or ≥5.6 mmol/L without transfusion or erythropoietin (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

 -  Aspartate aminotransferase (AST) (SGOT) and alanine aminotransferase (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:

 1. Patients who are not appropriate candidates for prostate or oligometastasis-directed
 SBRT

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

 3. Patients with evidence of liver metastasis are excluded.

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

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

 6. Estrogen containing compounds for > 2 months prior to consenting

 7. 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.

 8. Prior immunotherapy or chemotherapy for prostate cancer

 9. Prior radiation therapy to the prostate

 10. Prior prostatectomy

 11. 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.

 12. 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.

 13. Has a known history of active Bacillus Tuberculosis (TB)

 14. Hypersensitivity to pembrolizumab or any of its excipients.

 15. 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.

 16. 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

 17. 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.

 18. 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.

 19. 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.

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

 21. Has an active infection requiring systemic therapy.

 22. 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.

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

 24. 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.

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

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

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

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