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 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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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.
- 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
- 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
- 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
- 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.