Androgen Deprivation Therapy, Pembrolizumab, and Stereotactic Body Radiation Therapy with or without TLR9 Agonist SD-101 in Treating Patients with Metastatic 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. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and 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
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (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: * Bone metastases will be defined by bone imaging; if the patient has technetium bone scan, and/or F-18 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 * 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 are consistent with metastasis will be counted as a site of metastasis * 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 computed tomography (CT) or magnetic resonance imaging (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 an abdomen and pelvic CT or MRI prior to initiation of hormonal therapy
- Treatment naive, defined as less than 2 months of standard of care ADT (e.g. gonadotrophin releasing hormone [GNRH] agonist or antagonist with or without antiandrogen, including abiraterone) for metastatic hormone-sensitive prostate cancer prior to enrollment (at 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
- 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
- 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
- Absolute neutrophil count (ANC) >= 1,500/mcL (performed within 10 days of treatment initiation)
- Platelets >= 100,000/mcL (performed within 10 days of treatment initiation)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (performed within 10 days of treatment initiation)
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (performed within 10 days of treatment initiation) * 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 (performed within 10 days of treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (performed within 10 days of treatment initiation)
- Albumin >= 2.5 mg/dL (performed within 10 days of treatment initiation)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial prothrombin time (PTT) is within therapeutic range of intended use of anticoagulants (performed within 10 days of treatment initiation)
- 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 (performed within 10 days of treatment initiation)
- 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
- 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 enrollment
- PCSPES or PCx 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 anticancer 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 =< 10 mg/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 therapy
- 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 steroids for at least 14 days prior to trial 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, noninfectious 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., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [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., FluMist) are live attenuated vaccines, and are not allowed within 30 days
Locations & Contacts
Contact: Lawrence Fong
Trial Objectives and Outline
I. To determine the rate of prostate specific antigen (PSA) < nadir + 2 ng/mL at 15 and 24 months in patients with non-castrate levels of testosterone in each study arm.
I. To determine the rate of testosterone-PSA uncoupling in each study arm.
II. To estimate time to clinical progression in each arm.
III. To assess the safety associated with giving radiotherapy (RT) and pembrolizumab with or without intratumoral TLR9 agonist SD-101 (SD-101).
IV. To estimate progression-free survival (PFS) in each study arm.
I. To assess peripheral and tumor-based biomarkers of response and resistance.
II. To define the treatment-induced effects on circulating immune cells.
III. To explore the remodeling of circulating T cell repertoire.
IV. To explore the concordance of PSMA-positron emission tomography (PET) scanning with conventional imaging in oligometastatic prostate cancer patients.
Patients receive androgen deprivation therapy (ADT) including leuprolide acetate intramuscularly (IM) at baseline and then every 3 months for 3 doses, prednisone orally (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.
ARM I: Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Patients also undergo stereotactic body radiation therapy (SBRT) every other day (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.
ARM II: Patients receive TLR9 agonist SD-101 intratumorally 1-2 weeks before cycle 1 day 1 and 21 days later. Patients also receive pembrolizumab IV over 30 minutes on day 1 and undergo 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.
After completion of study treatment, patients are followed up every 12 weeks for up to 3 years.
Trial Phase & Type
UCSF Medical Center-Mount Zion
Secondary IDs NCI-2017-01340, 16-18989
Clinicaltrials.gov ID NCT03007732