PRIMARY OBJECTIVES:
I. Determine the response rate to durvalumab in metastatic castration-resistant prostate
cancer (mCRPC) patients with microsatellite instability (MSI), where response rate is defined
either according to modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria or a reduction in prostate specific antigen (PSA) level of >= 50%.
SECONDARY OBJECTIVES:
I. Determine the percent of mCRPC patients with MSI achieving a radiographic response per
modified RECIST 1.1 criteria following treatment with durvalumab.
II. Determine the percent of mCRPC patients with MSI achieving a reduction in PSA level of >=
50% following treatment with durvalumab.
III. Determine the radiographic progression free survival (PFS) in hypermutated mCRPC
patients with MSI treated with durvalumab using modified RECIST 1.1 criteria for soft tissue
metastases and Prostate Cancer Working Group 3 (PCWG3) criteria for bone metastases.
IV. Determine the PSA PFS rate according to PCWG3 criteria in hypermutated mCRPC patients
with MSI treated with durvalumab.
V. Determine the time to response in hypermutated mCRPC patients with MSI treated with
durvalumab using modified RECIST 1.1 criteria.
VI. Determine the overall survival in hypermutated mCRPC patients with MSI treated with
durvalumab.
VII. Determine the change in PSA doubling time 12-weeks after the initiation of durvalumab.
VIII. Track pain as assessed by the Brief Pain Inventory during the course of treatment with
durvalumab.
IX. Assess the incidence and severity of adverse events according to the National Cancer
Institute - Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
TERTIARY OBJECTIVES:
I. Determine mismatch repair gene mutational status and mutational load (by UWOncoPlex).
II. Determine mismatch repair gene mutational status, mutational load and microsatellite
stability from circulating tumor cells (CTCs) and/or cell-free tumor DNA (ctDNA).
III. PD-L1 expression by immunohistochemistry (IHC) and transcript profiling (e.g.
quantitative real-time polymerase chain reaction [qRT-PCR]).
IV. Determine the relative location of T-cells within the tumor microenvironment (i.e. stroma
vs. tumor edge) using CD3/CD8 IHC.
V. Evaluate for tumor specific T-cell responses in blood and within the tumor
microenvironment using next generation sequencing assays.
OUTLINE:
Patients receive durvalumab intravenously (IV) over 60 minutes on day 1. Courses repeat every
4 weeks for up to 12 months in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days, at 2, 3, 4, 6, 8,
and 10 months, and then every 6 months.
Inclusion Criteria:
- Patient must have evidence of castration resistant prostate cancer as evidenced by a
confirmed rising PSA (per Prostate Cancer Working Group 3 [PCWG3] criteria) and a
castrate serum testosterone level (i.e. =< 50 mg/dL); if a subject also received an
anti-androgen, he must first progress through antiandrogen withdrawal prior to being
eligible; the minimum timeframe to document failure of anti-androgen withdrawal will
be four weeks
- Patients must have received at least one of the approved products known to improve the
overall survival of patients with metastatic castration resistant prostate cancer
(i.e. abiraterone, enzalutamide, sipuleucel-t, radium-223, docetaxel or cabazitaxel)
- Microsatellite instability as determined by MSI-plus assay
- Ability to understand and the willingness to sign a written informed consent
- Written informed consent and any locally-required authorization (e.g., Health
Insurance Portability and Accountability Act [HIPAA] authorization) obtained from the
subject prior to performing any protocol-related procedures, including screening
evaluations
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Life expectancy of >= 4 months
- Hemoglobin >= 9.0 g/dL Note: patient may receive blood transfusion to achieve a
hemoglobin >= 9.1 g/dL; however, hemoglobin must be stable at or above 9 g/dL two
weeks prior to dosing
- Absolute neutrophil count (ANC) >= 1.5 x 10^9 /L (>= 1500 per mm^3)
- Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN); this will not
apply to subjects with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or
hepatic pathology), who will be allowed only in consultation with their physician and
the study principal investigator (PI)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal unless liver metastases are present, in
which case it must be =< 5 x ULN
- Serum creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula or by
24-hour urine collection for determination of creatinine clearance
- Subject is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up
- Body weight > 30 kg
Exclusion Criteria:
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site)
- Previous enrollment in the present study
- Participation in another clinical study with an investigational product during the
last 14 days
- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab
- History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease >= 5
years before the first dose of study drug and of low potential risk for
recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of disease (e.g., cervical
cancer in situ)
- Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, other investigational agent) =< 28 days prior to the first dose of study
drug (if sufficient wash-out time has not occurred due to the schedule or
pharmacokinetics [PK] properties of an agent, a longer wash-out period may be
required)
- Major surgical procedure (as defined by the local/lead site PI) within 28 days prior
to the first dose of investigational product (IP); Note: local surgery of isolated
lesions for palliative intent is acceptable
- Ongoing systemic therapy (other than a luteinizing hormone-releasing hormone agonists
[LHRH] agonist/antagonist) for prostate cancer including, but not limited to:
- CYP-17 inhibitors (e.g. ketoconazole, abiraterone)
- Antiandrogens (e.g. bicalutamide, nilutamide)
- Second generation antiandrogens (e.g. ARN-509)
- Immunotherapy (e.g. sipuleucel-T)
- Chemotherapy (e.g. docetaxel, cabazitaxel)
- Radiopharmaceutical therapy (e.g. radium-223, strontium-89, samarium- 153)
- QT interval corrected for heart rate using Fridericia's formula (QTcF) >= 70 ms; any
clinically significant abnormalities detected, require triplicate electrocardiography
(ECG) results and a mean QT interval corrected for heart rate using Fridericia's
formula (QTcF) >= 470 ms calculated from 3 ECGs
- Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid (steroids as pre-med for hypersensitivity
reactions eg. computed tomography (CT) scan premedication is acceptable)
- Any unresolved toxicity (> CTCAE grade 2) from previous anti-cancer therapy; subjects
with irreversible toxicity that is not reasonably expected to be exacerbated by the
investigational product may be included (e.g., hearing loss, peripherally neuropathy)
- Any prior grade >= 3 immune-related adverse event (irAE) while receiving any previous
immunotherapy agent, or any unresolved irAE > grade 1
- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc]); the following are exceptions to this
criterion:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
- Patients with celiac disease controlled by diet alone
- History of primary immunodeficiency
- History of allogeneic organ transplant
- History of hypersensitivity to durvalumab or any excipient
- Uncontrolled intercurrent illness including, but not limited to, symptomatic
congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac
arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses, or
psychiatric illness/social situations that would limit compliance with study
requirements or compromise the ability of the subject to give written informed consent
- Active infection including tuberculosis (TB), hepatitis B, hepatitis C, or human
immunodeficiency virus. Note: TB testing will be at the discretion of the treating
physician and should be in line with local practice
- History of leptomeningeal carcinomatosis
- Receipt of live attenuated vaccination within 30 days prior to study entry or within
30 days of receiving durvalumab
- Patients of reproductive potential who are not employing an effective method of birth
control; male patients of reproductive potential who are not willing to employ
effective birth control from screening to 90 days after the last dose of durvalumab
monotherapy, whichever is the longer time period
- Any condition that, in the opinion of the local/lead site PI, would interfere with
evaluation of study treatment or interpretation of patient safety or study results
- Brain metastases or spinal cord compression unless asymptomatic or treated and stable
off steroids and anti-convulsants for at least 14 days prior to study treatment start;
patients with suspected brain metastases at screening should have a CT/magnetic
resonance imaging (MRI) of the brain prior to study entry
- Subjects with uncontrolled seizure
