Prostate Cancer
Conditions
Keywords
metastatic castrate-resistant prostate cancer (mCRPC), neuroendocrine prostate cancer (NEPC)
Brief summary
The purpose of this study is to assess the safety and efficacy of avelumab in patients with metastatic neuroendocrine-like prostate cancer. Eligible men will be started on avelumab every 2 weeks and will stay on therapy until progression or intolerable side effects. The central hypothesis is that PD-L1 inhibition with avelumab will be efficacious based on radiographic responses in a subset of men with metastatic neuroendocrine-like prostate cancer and be reasonably well tolerated, meeting criteria for further study in larger phase 2 and 3 trials based on meeting pre-specified efficacy rates and prolonged PFS in some men.
Interventions
DRUGAvelumab
10 mg/kg intravenously every 2 weeks
Sponsors
Andrew J. Armstrong, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Neuroendocrine-like prostate cancer, based on histology OR based on clinical presentation as defined by meeting one of the two below criteria. All subjects must submit their primary tumor or metastatic biopsy pathology specimens to the Duke Cancer Institute where they will be centrally reviewed by Duke Pathology. Central Duke pathologic review is not required for screening but rather for confirmation of histologic subtype. Local pathologic review is sufficient for eligibility determination. 1. Criterion 1: Presence of 1 of 3 histologically proven diagnoses: 1) Primary small cell carcinoma of the prostate, defined by classic histologic features such as small tumor cells with scanty cytoplasm, darkly stained nuclei with homogeneous chromatin pattern. The tumor cells do not form glandular structure but grow as solid sheets with frequent mitotic figures and necrosis; 2) Intermediate atypical carcinoma of the prostate, which has histologic features distinct from small cell carcinoma or adenocarcinoma. The tumor grows as solid sheets or vague glandular structures. The tumor cells have moderate amounts of cytoplasm and centrally located, round and regular nuclei with fine, granular and homogeneous chromatin. Mitosis and necrosis are absent; 3) mixed histology tumors of the prostate, containing both adenocarcinoma and neuroendocrine or small cell components. 2. Criterion 2: Presence of histologically proven adenocarcinoma of the prostate without any sign of neuroendocrine or small cell histology that is radiographically progressing despite castrate levels of testosterone (\<50 ng/mL) with the following poor risk features: i. Prior progression despite therapy with either abiraterone acetate and/or enzalutamide ii. At least one of the following: 1) Liver metastases; 2) Bulky radiographic progression (≥2 cm short axis lymph nodes or ≥1 cm long axis visceral metastases) combined with low serum PSA (\<10ng/mL); 3) High serum LDH (\>1X upper limit of normal). 2. Measurable disease as defined by modified PCWG3 using iRECIST criteria 3. Available tumor tissue for pathologic review and correlative studies. Tumor tissue (localized or metastatic) does not need to be received but rather identified and available (slides and/or blocks) to be sent to Duke. 4. Documented progressive metastatic CRPC based on at least one of the following criteria: 1. PSA progression defined as 25% increase over baseline value with an increase in the absolute value of at least 2.0 ng/mL that is confirmed by another PSA level with a minimum of a 1 week interval and a minimum PSA of 2.0 ng/mL. Note: If confirmed rise is the only indication of progression, a minimal starting value of 1.0 ng/mL is acceptable, unless pure small-cell carcinoma. 2. Soft-tissue progression based on new lesions or growth of existing soft tissue metastases. 3. Progression of bone disease (evaluable disease) or (new bone lesion(s)) by bone scan. 5. Castrate levels of serum total testosterone (\<50 ng/dl) OR ongoing documented ADT unless pure small cell prostate cancer is present. 6. Previous use of radiation to metastatic site(s) at any time prior to enrollment is allowed, provided that this site is not the only measurable disease present or unless that solitary site is progressing following radiation. 7. Patients should have received at least one line of approved chemotherapy and/or hormonal therapy 8. Previous cytotoxic chemotherapy including cisplatin, carboplatin, oxaliplatin, etoposide, docetaxel, cabazitaxel, and gemcitabine is allowed, up to 3 prior regimens. 9. Karnofsky performance status of 70 or higher. 10. Acceptable initial laboratory values within 14 days of Cycle 1 Day 1 according to the below table: ANC ≥ 1500/µl Hemoglobin ≥ 9.0 g/dL(prior transfusion permitted) Platelet count ≥ 100,000/µl Creatinine ≤ 2.0 x the institutional upper limit of normal (ULN) OR creatinine clearance \>30 ml/min Potassium ≥ 3.5 mmol/L (within institutional normal range) Bilirubin ≤ 1.5 x ULN (unless documented Gilbert's disease) SGOT (AST) ≤ 2.5x ULN, or \<5x ULN in patients with documented liver metastases SGPT (ALT) ≤ 2.5x ULN or \<5x ULN in patients with documented liver metastases 11. Age \>18 12. Highly effective contraception for male subjects with childbearing potential throughout the study and for at least 60 days after last avelumab treatment administration if the risk of conception exists. 13. Willing and able to provide written informed consent and HIPAA authorization for the release of personal health information. 14. Life expectancy of over 3 months as determined by treating physician.
Exclusion criteria
1. Prior usage of PD-1 inhibitors, programed-death ligand 1 and/or 2 inhibitors, CTLA-4 inhibitors including but not limited to ipilimumab, nivolumab, avelumab, durvalumab, tremelimumab, and pembrolizumab. 2. Active on-going immunologic or autoimmune disease including but not limited to systemic or cutaneous lupus erythematosus, cutaneous psoriasis, psoriatic arthritis, rheumatoid arthritis, scleroderma, sicca syndrome, polymyalgia rheumatica, polyarteritis nodosa, granulomatous polyangiitis, microscopic polyangiitis, polyarteritis nodosa, temporal arteritis, giant cell arteritis, dermatomyositis, Kawasaki disease. 3. Previous malignancy within 3 years other than non-melanomatous skin cancers or cancers of low malignant potential such as non-invasive urothelial carcinoma. 4. Any other on-going chemotherapeutic, biologic, radiopharmaceutical, or investigational agent currently or within 28 days of Cycle 1 Day 1. 5. Prior use of abiraterone and other hormonal agents used to treat prostate cancer are permitted but abiraterone acetate should be stopped prior to study treatment initiation. 6. Current usage of immunosuppressant medication except for a) intranasal, inhaled, and topical corticosteroids and b) systemic corticosteroids equivalent to ≤ 10 mg/day of prednisone, c) steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication). 7. Prior organ transplantation including allogeneic stem-cell transplants. 8. Active bacterial or viral infections requiring systemic therapy. 9. Current active infections with HIV/AIDS, Hepatitis B, and Hepatitis C requiring treatment. 10. Live virus vaccination within 4 weeks of the first dose of avelumab (inactivated vaccines are allowed). 11. Known prior hypersensitivity to the investigational product or any component formulations, including known severe hypersensitivity reactions to monoclonal antibodies. 12. Clinically significant (i.e. active) cardiovascular disease: cerebral vascular accident (\<6 months prior to enrollment), myocardial infarction (\<6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication. 13. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade \> 1); however, alopecia, sensory neuropathy Grade ≤ 2, Grade 2 anemia, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable. 14. Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Overall Response as Determined by iRECIST | baseline to end of treatment (approximately 6 months) | Overall response rate is determined by radiographic response assessment utilizing modified Prostate Cancer Working Group 3 (PCWG3) using Immune Response Evaluation Criteria In Solid Tumors Criteria (iRECIST 1.1). iRECIST is the modified RECIST 1.1 for immune-based therapeutics, to measure radiographic response rate in men with metastatic prostate cancer. Patients alive who had not progressed as of the last follow-up, had PFS censored at the last follow-up date. There are five categories overall responses: iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions iSD: immune stable disease in the absence of CR or PD iUPD: immune unconfirmed progressive disease when PD is unconfirmed NE: not evaluable |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of PD-L1 Inhibition With Avelumab as Determined by RECIST1.1 | baseline to end of treatment (approximately 6 months) | Overall response rate is determined by radiographic response assessment utilizing Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). Patients alive who had not progressed as of the last follow-up, had PFS censored at the last follow-up date. There are four overall response categories: Complete Response (CR): disappearance of all target and non-target lesions Progressive Disease (PD): 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions Stable Disease (SD): In the absence of CR and PD Unevaluable (NE) |
| Radiographic Progression Free Survival (rPFS) | baseline to end of treatment (approximately 6 months) | Radiographic progression free survival (rPFS) as determined by PCWG3 and RECISTS1.1 criteria. Radiographic progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median rPFS was estimated using a Kaplan-Meier curve. |
| Overall Survival | Up to 23.5 months | Length of patient's life after starting study |
| Toxicity and Safety of PD-L1 Inhibition With Avelumab in Men With Metastatic Neuroendocrine-like Prostate Cancer | 28 days post-treatment (approximately 7 months) | Number of Participants with Adverse Events |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Single Arm-arm Phase II Study of Avelumab Subjects with metastatic neuroendocrine-like prostate cancer will be treated with Avelumab intravenously at a dose of 10 mg/kg every 2 weeks. | 15 |
| Total | 15 |
Baseline characteristics
| Characteristic | Single Arm-arm Phase II Study of Avelumab |
|---|---|
| Age, Continuous | 71 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Karnofsky Performance Status Score | 90 units on a scale |
| Prior PSA | 53.6 ng/ml |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 11 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 9 / 15 |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 9 / 15 |
Outcome results
Primary
Number of Participants With Overall Response as Determined by iRECIST
Overall response rate is determined by radiographic response assessment utilizing modified Prostate Cancer Working Group 3 (PCWG3) using Immune Response Evaluation Criteria In Solid Tumors Criteria (iRECIST 1.1). iRECIST is the modified RECIST 1.1 for immune-based therapeutics, to measure radiographic response rate in men with metastatic prostate cancer. Patients alive who had not progressed as of the last follow-up, had PFS censored at the last follow-up date. There are five categories overall responses: iCR: immune complete response achieved with disappearance of all target lesions iCPD: immune confirmed progressive disease when there is either 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions iSD: immune stable disease in the absence of CR or PD iUPD: immune unconfirmed progressive disease when PD is unconfirmed NE: not evaluable
Time frame: baseline to end of treatment (approximately 6 months)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm-arm Phase II Study of Avelumab | Number of Participants With Overall Response as Determined by iRECIST | iSD: immune stable disease | 3 Participants |
| Single Arm-arm Phase II Study of Avelumab | Number of Participants With Overall Response as Determined by iRECIST | iCR: immune complete response | 1 Participants |
| Single Arm-arm Phase II Study of Avelumab | Number of Participants With Overall Response as Determined by iRECIST | iCPD: immune confirmed progressive disease | 1 Participants |
| Single Arm-arm Phase II Study of Avelumab | Number of Participants With Overall Response as Determined by iRECIST | iUPD: immune unconfirmed progressive disease | 9 Participants |
| Single Arm-arm Phase II Study of Avelumab | Number of Participants With Overall Response as Determined by iRECIST | NE: not evaluable | 1 Participants |
Secondary
Efficacy of PD-L1 Inhibition With Avelumab as Determined by RECIST1.1
Overall response rate is determined by radiographic response assessment utilizing Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). Patients alive who had not progressed as of the last follow-up, had PFS censored at the last follow-up date. There are four overall response categories: Complete Response (CR): disappearance of all target and non-target lesions Progressive Disease (PD): 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions Stable Disease (SD): In the absence of CR and PD Unevaluable (NE)
Time frame: baseline to end of treatment (approximately 6 months)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single Arm-arm Phase II Study of Avelumab | Efficacy of PD-L1 Inhibition With Avelumab as Determined by RECIST1.1 | Complete Response (CR) | 1 Participants |
| Single Arm-arm Phase II Study of Avelumab | Efficacy of PD-L1 Inhibition With Avelumab as Determined by RECIST1.1 | Progressive Disease (PD) | 10 Participants |
| Single Arm-arm Phase II Study of Avelumab | Efficacy of PD-L1 Inhibition With Avelumab as Determined by RECIST1.1 | Stable Disease (SD) | 3 Participants |
| Single Arm-arm Phase II Study of Avelumab | Efficacy of PD-L1 Inhibition With Avelumab as Determined by RECIST1.1 | Unevaluable (NE) | 1 Participants |
Secondary
Overall Survival
Length of patient's life after starting study
Time frame: Up to 23.5 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm-arm Phase II Study of Avelumab | Overall Survival | 7.4 month |
Secondary
Radiographic Progression Free Survival (rPFS)
Radiographic progression free survival (rPFS) as determined by PCWG3 and RECISTS1.1 criteria. Radiographic progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median rPFS was estimated using a Kaplan-Meier curve.
Time frame: baseline to end of treatment (approximately 6 months)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single Arm-arm Phase II Study of Avelumab | Radiographic Progression Free Survival (rPFS) | 1.8 month |
Secondary
Toxicity and Safety of PD-L1 Inhibition With Avelumab in Men With Metastatic Neuroendocrine-like Prostate Cancer
Number of Participants with Adverse Events
Time frame: 28 days post-treatment (approximately 7 months)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm-arm Phase II Study of Avelumab | Toxicity and Safety of PD-L1 Inhibition With Avelumab in Men With Metastatic Neuroendocrine-like Prostate Cancer | 15 Participants |