Durvalumab (MEDI4736) in Hypermutated Metastatic Castration-Resistant Prostate Cancer
Overview
- Phase
- Phase 2
- Intervention
- Not specified
- Conditions
- Castration Levels of Testosterone
- Sponsor
- University of Washington
- Locations
- 1
- Primary Endpoint
- Response rate to durvalumab defined according to modified RECIST 1.1 criteria or a reduction in PSA level >= 50%
- Status
- Withdrawn
- Last Updated
- 8 years ago
Overview
Brief Summary
This phase II trial studies how well durvalumab works in treating patients with prostate cancer that is resistant to hormones and has spread to other places in the body. Monoclonal antibodies, such as durvalumab, may interfere with the ability of tumor cells to grow and spread.
Detailed Description
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.
Investigators
Eligibility Criteria
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)
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
Outcomes
Primary Outcomes
Response rate to durvalumab defined according to modified RECIST 1.1 criteria or a reduction in PSA level >= 50%
Time Frame: Up to 3 years
Will be calculated as the percentage with 95% confidence interval (CI) of the total number of subjects that achieved a response.
Secondary Outcomes
- PSA PFS(From the start of treatment until PSA progression, assessed up to 3 years)
- PSA response rate as defined per the PCWG3 criteria(Up to 3 years)
- Incidence of adverse events according to NCI-CTCAE version 4.0(Up to 3 years)
- Overall survival(From the start of treatment until death from any cause, assessed up to 3 years)
- Radiographic PFS(From the start of treatment until disease progression, clinical progression, or death, whichever occurs first, assessed up to 3 years)
- Radiographic response rate defined as CR or PR using RECIST 1.1(Up to 3 years)