| Eligibility |
Inclusion Criteria:
Patients must meet the following criteria for study entry:
1. Documentation of Disease:
- Progressive castration-resistant metastatic prostate cancer with pathologically
confirmed adenocarcinoma of the prostate without small cell features.
2. Patients must have Measurable or Non-measurable disease per Prostate Cancer Working
Group 2 (PCWG2) response criteria (RECIST criteria will only apply to soft tissue
lesions
- Measurable Disease
- For extra-nodal lesions to be considered measurable, they must be = 10 mm in
one dimension, using spiral CT.
- For lymph nodes to be considered measureable (i.e., target or evaluable lesions),
they must be = 20 mm in at least one dimension, using spiral CT.
- Non-measurable Disease
- All other lesions, including small lesions (longest diameter < 20 mm with
conventional techniques or < 10 mm with spiral CT scan) and truly
non-measurable lesions.
- Lesions that are considered non-measurable include bone lesions (only).
3. Asymptomatic or mildly symptomatic metastatic CRPC defined as pain that is relieved by
acetaminophen or a non-steroidal anti-inflammatory
- Asymptomatic: Score of 0-1 on BPI-SF Question #3 (worst pain in last 24 hours)
- Mildly symptomatic: Score of 2-3 on BPI-SF Question #3
4. Progressive disease:
Patients must have progressive disease at study entry defined as one or more of the
following three criteria that occurred while the patient was on androgen deprivation
therapy. For patients enrolling on the basis of soft tissue or bone progression, the
baseline scan must show progression relative to a comparison scan. If the comparison
scan is not available, the baseline scan report must reference the previous scan to
document progression.
- PSA progression defined by a minimum of two rising PSA levels with an interval of
= 1 week between each determination. Patients who received an anti-androgen must
have progression documented by a minimum of two rising PSA levels with an
interval of = 1 week between each determination such that at least the second of
these rises is > 4 weeks since last flutamide or > 6 weeks since last
bicalutamide or nilutamide. The PSA value at the screening should be > 2 µg/L (2
ng/mL)
- Soft tissue disease progression is defined as at least a 20% increase in the sum
of the diameters of target lesions, taking as reference the smallest sum on study
(this includes the baseline sum if that is the smallest on study). In addition to
the relative increase of 20%, the sum must also demonstrate an absolute increase
of at least 5 mm. (Note: the appearance of one or more new non-osseous lesions is
also considered progression). Clinical lesions will only be considered measurable
when they are superficial (e.g., skin nodules, palpable lymph nodes) and at least
10 mm in diameter as assessed using calipers (e.g., skin nodules). Per PCWG2:
Extranodal lesions need to be = 10 mm in one dimension, using spiral CT. However,
lymph nodes need to be = 20 mm in at least one dimension to be considered new.
- Bone disease progression is defined by PCWG2 as two or more new lesions on bone
scan
5. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin
blocks (blocks are preferred) or at least 10 unstained slides, with an associated
pathology report, for central testing of tumor PD-L1 expression
- Tumor tissue should be of good quality based on total and viable tumor content.
Fine needle aspiration, brushing, cell pellet from pleural effusion, bone
metastases, and lavage samples are not acceptable. For core-needle biopsy
specimens, at least three cores should be submitted for evaluation.
- Patients who do not have tissue specimens meeting eligibility requirements may
undergo a biopsy during the screening period. Acceptable samples include core
needle biopsies for deep tumor tissue (minimum of three cores) or excisional,
incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal
lesions.
- Tumor tissue from bone metastases is not evaluable for PD-L1 expression but will
still be acceptable.
6. Patients must have been on androgen deprivation therapy with a GnRH analogue,
antagonist, or bilateral orchiectomy (i.e., surgical or medical castration) for at
least 3 months prior to study entry and maintain castrate levels of serum testosterone
= 50 ng/dL throughout study participation unless intolerant.
7. Adequate hematologic and end organ function, defined by the following laboratory
results:
- ANC = 1500 cells/uL
- WBC counts = 2500/uL
- Lymphocyte count = 300/uL
- Platelet count = 100,000/uL;
- Hemoglobin = 9.0 g/dL
- Total bilirubin = 1.5 x upper limit of normal (ULN) with the following exception:
- Patients with known Gilbert disease who have serum bilirubin level = 3 xULN
may be enrolled.
- AST/ALT = 2.5 × institutional upper limit of normal
- For patients with documented bone metastases, AST can be = 2.5x ULN if the
investigator can provide evidence of no underlying liver dysfunction and
thus, it is likely that the AST is originating from bone source.
- Alkaline phosphatase = 2.5 x ULN Patients with documented bone metastases:
alkaline phosphatase = 5 x ULN
- Serum creatinine = 1.5 x ULN or creatinine clearance =50 mL/min on the basis of
the Cockcroft-Gault glomerular filtration rate estimation:
- (140- age) x (weight in kg) x (0.85 if female) 72 x (serum creatinine in
mg/dL)
- INR and aPTT =1.5 x ULN - This applies only to patients who do not receive
therapeutic anticoagulation; patients receiving therapeutic anticoagulation (such
as low-molecular-weight heparin or warfarin) should be on a stable dose
8. No clinically significant cardiovascular disease including:
- MI within 6 months
- Uncontrolled angina within 3 months
- CHF with NYHA class 3 or 4, or patients with NYHA class 3 or 4 in the past,
unless a screening echo or MUGA performed within three months demonstrates an
EF>45%
- History of clinically significant ventricular arrhythmias (e.g., ventricular
tachycardia, ventricular fibrillation, Torsades de pointes)
- History of Mobitz II second degree or third degree heart block without a
permanent pacemaker in place
- Hypotension (systolic BP <86 mmHg) or bradycardia (<50 bpm) at screening
- Uncontrolled hypertension (systolic BP >170 mmHg or diastolic BP >105 mmHg at
screening)
9. For male patients with partners of childbearing potential, agreement (by patient
and/or partner) to use highly effective form(s) of contraception (i.e., one that
results in a low failure rate [<1% per year] when used consistently and correctly) and
to continue its use for 6 months after the last dose of atezolizumab
10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
11. Life expectancy of greater than 6 months
12. Ability and willingness to comply with the requirements of the study protocol
13. Age = 18 years
14. Signed Informed Consent Form (ICF)
Exclusion Criteria:
Patients who meet any of the following criteria will be excluded from study entry.
1. Any approved or investigational anticancer therapy, including chemotherapy, hormonal
therapy, or radiotherapy, within 4 weeks prior to initiation of study treatment.
- Palliative radiotherapy for bone metastases = 4 weeks prior to Cycle 1, Day 1 is
allowed
2. Treatment for prostate cancer with any of the following:
- Herbal products that may decrease PSA levels within 4 weeks prior to enrollment
- Use of systemic steroids greater than the equivalent of 10 mg of
prednisone/prednisolone per day within 4 weeks prior to administration of first
dose.
- Prior use of ketoconazole for within 7 days of administration of first dose.
3. AEs from prior anticancer therapy that have not resolved to Grade = 1 except for
alopecia
4. Bisphosphonate therapy for symptomatic hypercalcemia
- Use of bisphosphonate therapy for bone metastasis is allowed.
5. The prior or concurrent use of a RANKL inhibitor denosumab
6. Planned palliative procedures for alleviation of bone pain such as radiation therapy
or surgery
7. Structurally unstable bone lesions suggesting impending fracture
8. Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease;
- Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible.
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV RNA.
9. Patients with acute leukemias, accelerated/blast phase chronic myelogenous leukemia,
chronic lymphocytic leukemia, Burkitt lymphoma, plasma cell leukemia, or non-secretory
myeloma
10. Known primary central nervous system (CNS) malignancy or symptomatic CNS metastases
will be excluded from this clinical trial because of their poor prognosis and because
they often develop progressive neurologic dysfunction or seizures that would confound
the evaluation of neurologic and other adverse events. (NOTE: patients with treated
epidural disease and patients with asymptomatic untreated CNS disease may be enrolled,
provided all of the following criteria are met:
- Evaluable or measurable disease outside the CNS
- No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 10 mm
of the optic apparatus (optic nerves and chiasm)
- No history of intracranial hemorrhage or spinal cord hemorrhage
- No ongoing requirement for dexamethasone for CNS disease; patients on a stable
dose of anticonvulsants are permitted.
- No neurosurgical resection or brain biopsy within 28 days prior to Cycle 1, Day 1
Patients with asymptomatic treated CNS metastases may be enrolled, provided all the
criteria listed above are met as well as the following:
- Radiographic demonstration of improvement upon the completion of CNS directed
therapy and no evidence of interim progression between the completion of
CNS-directed therapy and the screening radiographic study
- No stereotactic radiation or whole-brain radiation within 28 days prior to Cycle
1, Day 1
- Screening CNS radiographic study =4 weeks from completion of radiotherapy and = 2
weeks from discontinuation of corticosteroids
11. Patients with known liver visceral metastasis
12. Patients with bulky lymphadenopathy (i.e., > 5 cm)
13. Known hypersensitivity to Chinese hamster ovary cell products or other recombinant
human antibodies
14. Inability to comply with study and follow-up procedures
15. History or risk of autoimmune disease, including but not limited to systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis
associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's
syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune
thyroid disease, vasculitis, or glomerulonephritis
- Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
replacement hormone may be eligible.
- Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may
be eligible.
16. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced),
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing
pneumonia, etc.), or evidence of active pneumonitis on screening chest computed
tomography (CT) scan
o History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
17. Any other diseases, metabolic dysfunction, physical examination finding, or clinical
laboratory finding giving reasonable suspicion of a disease or condition that
contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications
18. History of HIV infection
19. Active tuberculosis
20. Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited to
hospitalization for complications of infection, bacteremia, or severe pneumonia
21. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 and/or Received
oral or IV antibiotics within 2 weeks prior to Cycle 1, Day 1
o Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract
infection or chronic obstructive pulmonary disease) are eligible.
22. Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of
need for a major surgical procedure during the course of the study
23. Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or
anticipation that such a live, attenuated vaccine will be required during the study
24. Influenza vaccination should be given during influenza season only (approximately
October to March). Patients must not receive live, attenuated influenza vaccine (e.g.,
FluMist®) within 4 weeks prior to Cycle 1, Day 1 or within 90 days after last dose of
atezolizumab.
25. Prior malignancies except for adequately treated benign basal cell carcinoma or other
effectively treated malignancy that has been in remission for more than 3 years and is
considered to be cured
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