An Open-Label Multi-Center Phase II Study of Neoadjuvant Atezolizumab-Based Combination Therapy in Men With Localized Prostate Cancer Prior to Radical Prostatectomy
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 68
- 试验地点
- 2
- 主要终点
- Proportion of subjects who demonstrate a positive response to neoadjuvant atezolizumab and atezolizumab-based combination therapy for each Cohort of the study
研究概览
简要总结
This phase II trial studies how well atezolizumab works alone or in combination with etrumadenant or tocilizumab in treating men with localized prostate cancer before radical prostatectomy. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Androgens can cause the growth of prostate cancer cells. IL-6 is expressed by prostate cancer and within the tumor microenvironment and shown to enhance prostate cancer and disease progression. Treatment with an anti-IL-6 antibody such as tocilizumab may inhibit cancer progression. Giving atezolizumab in combination with etrumadenant or tocilizumab may work better in treating prostate cancer.
详细描述
PRIMARY OBJECTIVES:
I. To determine the impact of atezolizumab-based combination therapy on the composition and function of tumor-infiltrating immune cells (TIICS).
SECONDARY OBJECTIVES:
I. To determine the safety and tolerability of atezolizumab-based combination therapy in localized prostate cancer (PC).
II. To determine the clinical efficacy of atezolizumab-based combination therapy in localized PC.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed adenocarcinoma of the prostate.
- •a. Subjects with small cell or neuroendocrine PC are not eligible.
- •Eligible for radical prostatectomy as determined by urologic oncology surgeon, and subject consents to proceeding with radical prostatectomy.
- •a. Deemed by urologic oncology surgeon to be appropriate for a "window-of-opportunity"study.
- •Only patients with high-risk disease are eligible for the safety lead-in for each cohort. Patients with intermediate-risk disease will be included after interim analyses is complete for the corresponding cohort and the PI has determined that it is safe to do so.
- •Availability of a representative tumor specimen that is suitable for the planned study analyses, as determined by the Principal Investigator.
- •A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 15 slides containing unstained, freshly cut, serial sections should be submitted along with an associated pathology report prior to study treatment. If only 10-14 slides are available, the patient may still be eligible for the study, after Principal Investigator approval has been obtained.
- •If archival tumor tissue is unavailable or is determined to be unsuitable for required testing, tumor tissue must be obtained from a biopsy performed at screening. Refer to Section 6.3 for additional information on tumor specimens collected at screening.
- •Subjects have not received any prior systemic or locally directed therapy for PC (see
排除标准
- •Age >= 18 years
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Requirements for organ and marrow function:
- •Hemoglobin >= 9 g/dL
- •- Participants must not have been transfused within 2 weeks prior to screening to meet this criterion
- •Absolute neutrophil count >= 1,500/microliter (uL) without granulocyte colonystimulating factor support
- •Absolute lymphocyte count >= 500/uL
- •Platelets >= 100,000/uL without transfusion
- •Total bilirubin < 1.5 x institutional upper limit of normal (ULN) (known Gilbert disease: < 3 x ULN)
- •Alkaline phosphatase < 2 x institutional ULN
- •Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase (SGOT)) =< 2 x institutional ULN
- •Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase (SGPT)) =< 2 x institutional ULN
- •International normalized ratio (INR) or activated partial thromboplastin time (aPTT) < 1.5 x institutional ULN for subjects not receiving therapeutic anticoagulation
- •Creatinine clearance >= 30 mL/min (calculated using the Cockcroft-Gault formula)
- •Serum creatinine <=1.6 mg/dL (141 μmol/L) in female patients and ≤1.9 mg/dL (168 μmol/L) in male patients . Patients with serum creatinine values exceeding limits may be eligible for the study if their estimated glomerular filtration rates (GFR) are >30
- •Testosterone level > 150 ng/dL.
- •Contraception: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm as defined below:
- •With female partners of childbearing potential: men must remain abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 4 months after the last dose of study treatment. Men must refrain from donating sperm during the same period
- •With pregnant female partners: men must remain abstinent or use a condom during the treatment period and for 4 months after the last dose of study treatment to avoid exposing the embryo
- •Abstinence: the reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
- •For patients receiving therapeutic anticoagulation: stable anticoagulant regimen > 3 months.
- •Ability to understand a written informed consent document, and the willingness to sign it.
- •Ability to comply with the study protocol, in the investigator's judgment.
- •Exclusion Criteria:
- •Evidence of metastatic disease as determined by standard staging scans.
- •a. Staging scans should be performed per urologic standard of care for patients undergoing radical prostatectomy [per American Urological Association (AUA)/National Comprehensive Cancer Network (NCCN) guidelines].
- •Not a candidate for radical prostatectomy as determined by treating urologic oncology surgeon.
- •Any prior systemic therapy for PC, including antiandrogens, androgen deprivation therapy [gonadotropin-releasing hormone (GnRH) agonist or antagonist], chemotherapy, targeted therapy, immunotherapy, OR radiopharmaceuticals.
- •a. Subjects who are on finasteride or dutasteride must discontinue therapy and undergo a washout period of 6 weeks to become eligible for the study. Screening procedures should begin following the washout period.
- •Prior radiotherapy for PC.
- •Any history of prior malignancy, except:
- •Non-melanoma skin cancer treated with curative intent
- •Carcinoma-in-situ (CIS) treated with curative intent, without evidence of recurrence or disease progression for 3 years
- •Appropriately treated Stage I uterine cancer
- •All other cancer: treated with curative intent and without evidence of disease on standard of care follow-up for 5 years
- •Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren's syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:
- •Subjects with a history of autoimmune-related hypothyroidism who are on thyroid-replacement therapy, with a stable dose > 3 months, are eligible for the study
- •Subjects with controlled type 1 diabetes mellitus who are on an insulin regimen, with a Glycated hemoglobin (hemoglobin A1C) < 7.0 are eligible for the study. All subjects with controlled type 2 diabetes mellitus are eligible for the study
- •Subjects with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded from the study) are eligible for the study provided all of the following conditions are met:
- •Rash covers < 10% of body surface area
- •Disease is well controlled at baseline and requires only low-potency topical steroids
- •No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months
- •History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or any evidence of active, non-infectious pneumonitis requiring corticosteroids.
- •History of prior positive human immunodeficiency virus (HIV) test.
- •Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (chronic or acute).
- •Subjects with a past or resolved HBV infection are eligible for this study.
- •HCV positivity is defined as having a positive HCV antibody test followed by a positive HCV ribonucleic acid (RNA) test at screening; the HCV RNA test will only be performed for subjects who have a positive HCV antibody test.
- •Significant cardiovascular disease, such as New York Heart Association class III or greater cardiac disease, myocardial infarction, or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina.
- •Active chronic obstructive pulmonary disease (COPD) requiring use of home oxygen (O2) or systemic steroid therapy > 10 mg prednisone (or equivalent) daily.
- •Asthma requiring systemic corticosteroids > 10 mg prednisone (or equivalent) daily. Inhaled corticosteroids for the treatment of asthma are permitted.
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研究组 & 干预措施
Cohort C (atezolizumab, tocilizumab)
Participants will receive one (1) cycle of neoadjuvant atezolizumab and one (1) cycle of tocilizumab, 6mg/kg will be administered IV on day 1 of a 14 day IV prior to RP; atezolizumab will be administered in an identical fashion as Cohort A. RP will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.
干预措施: Atezolizumab (Drug)
Cohort B (atezolizumab, etrumadenant)
Participants will receive one (1) cycle of atezolizumab, 1200mg intravenously (IV) over 30-60 minutes on day 1 of a 14 day cycle and etrumadenant will be taken at a dose of 150mg PO, once daily, until 48 hours prior to RP, for at least 12 days. Radical Prostatectomy (RP) will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.
干预措施: Etrumadenant (Drug)
Cohort A (atezolizumab monotherapy)
Participants receive one (1) cycle of atezolizumab, 1200mg intravenously (IV) over 30-60 minutes on day 1 of a 14 day cycle. Radical Prostatectomy (RP) will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.
干预措施: Atezolizumab (Drug)
Cohort C (atezolizumab, tocilizumab)
Participants will receive one (1) cycle of neoadjuvant atezolizumab and one (1) cycle of tocilizumab, 6mg/kg will be administered IV on day 1 of a 14 day IV prior to RP; atezolizumab will be administered in an identical fashion as Cohort A. RP will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.
干预措施: Tocilizumab (Drug)
Cohort B (atezolizumab, etrumadenant)
Participants will receive one (1) cycle of atezolizumab, 1200mg intravenously (IV) over 30-60 minutes on day 1 of a 14 day cycle and etrumadenant will be taken at a dose of 150mg PO, once daily, until 48 hours prior to RP, for at least 12 days. Radical Prostatectomy (RP) will occur 21 days (+/- 7 days) following the final dose of atezolizumab. No further study therapy will be administered following RP.
干预措施: Atezolizumab (Drug)
结局指标
主要结局
Proportion of subjects who demonstrate a positive response to neoadjuvant atezolizumab and atezolizumab-based combination therapy for each Cohort of the study
时间窗: Up to 12 months
A positive response is defined as a ≥40% increase in the number of infiltrating cluster of differentiation 3 (CD3) + T cells between the pre-treatment biopsy at baseline and the post-treatment RP specimen. Thus, a negative response is a \<40% increase. The primary endpoint will include all enrolled subjects who receive at least 1 dose of study treatment and undergo RP. Analysis of the primary endpoint will be performed for each cohort independently
次要结局
- Number of treatment-related of adverse events(Up to 12 months)
- Rate of Minimal residual disease (MRD)(Up to 12 months)
- Prostate specific antigen (PSA) response(Up to 12 months)
- Sum of Pathologic complete response (pCR) and Minimal residual disease (MRD) rate(Up to 12 months)
- Rate of Pathologic complete response (pCR) rate(Up to 12 months)
研究者
David Oh
Assistant Professor
University of California, San Francisco