A Phase II Study of the Anti-PD-1 Antibody Pembrolizumab in Patients With Malignant Mesothelioma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 65
- 试验地点
- 2
- 主要终点
- Ability of PD-L1 to predict response
研究概览
简要总结
This phase II trial studies how well pembrolizumab works in treating patients with malignant mesothelioma, a cancer of the linings around the lungs (pleura) or abdomen (peritoneum). Monoclonal antibodies, such as pembrolizumab, work by blocking a protein called programmed cell death 1 (PD-1) which may stimulate an immune response and kill tumor cells.
详细描述
PRIMARY OBJECTIVES:
I. To determine the objective response rate of patients with malignant mesothelioma treated with pembrolizumab in A) an unselected patient population, as well as B) in a programmed cell death ligand 1 (PD-L1) positive population (should the trial proceed to Part B, and PD-L1 expression correlate with improved efficacy).
II. To determine the optimal threshold for PD-L1 expression using the 22C3 antibody based immunohistochemistry (IHC) assay in correlation to tumor response.
SECONDARY OBJECTIVES:
I. To determine the progression-free survival of patients with malignant mesothelioma in A) an unselected patient population and B) a PD-L1 positive population when treated with pembrolizumab.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically or cytologically confirmed pleural or peritoneal malignant mesothelioma, epithelial, sarcomatoid, or biphasic subtypes
- •Disease progression on or after pemetrexed and cis- or carboplatin
- •ONLY FOR PART B - PD-L1 selection should a PD-L1 expression threshold have been defined in Part A and potentially additional mesothelioma trial data; there will be no PD-L1/biomarker selection for Part A
- •No more than 2 prior lines of cytotoxic therapy, which should have included pemetrexed and a platinum
- •Enrollment of treatment naïve patients who refuse standard chemotherapy or are intolerant may be permissible if reviewed and deemed clinically appropriate by the principal investigator (PI)
- •Be willing and able to provide written informed consent for the trial
- •Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for peritoneal mesothelioma, and modified RECIST for pleural mesothelioma
- •Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion; while 20 unstained slides or a tumor block are preferred, at least 14 unstained slides are requested for analysis; PI approval for a lower number of slides is acceptable
- •Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
- •Absolute neutrophil count (ANC) >= 1,500/mcL
- •Platelets >= 100,000/mcL
- •Hemoglobin >= 9 g/dL
- •Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 50 mL/min for subject with creatinine levels > 1.5 X institutional ULN; creatinine clearance should be calculated per institutional standard
- •Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases
- •International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
- •Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
- •Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- •Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
- •Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
排除标准
- •Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 2 weeks (4 weeks for monoclonal antibodies) of the first dose of treatment
- •Side effects from prior treatment have not resolved to =< grade 1 (or baseline due to previously administered agent/pre-existing conditions)
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- •Has had a prior monoclonal antibody within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
- •Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent
- •Note: Subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study
- •Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
- •Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, or other indolent cancers which either have undergone curative-intent therapy or inactive (i.e. not expected to limit life expectancy or interfere with therapy)
- •Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment
- •Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents; subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule; subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study; subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study
- •Has evidence of interstitial lung disease or active, non-infectious pneumonitis
- •Has an active infection requiring systemic therapy
- •Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
- •Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
- •Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
- •Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- •Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
- •Has received a live vaccine within 30 days prior to the first dose of trial treatment
研究组 & 干预措施
Treatment (pembrolizumab)
Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients may be eligible for up to 1 year of additional pembrolizumab therapy if they progress after stopping pembrolizumab.
干预措施: Pembrolizumab (Biological)
Treatment (pembrolizumab)
Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients may be eligible for up to 1 year of additional pembrolizumab therapy if they progress after stopping pembrolizumab.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (pembrolizumab)
Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Patients may be eligible for up to 1 year of additional pembrolizumab therapy if they progress after stopping pembrolizumab.
干预措施: Pharmacogenomic Study (Other)
结局指标
主要结局
Ability of PD-L1 to predict response
时间窗: Up to 3 years
Based on the results from Part A, the Youden Index methodology will be used to determine the optimal threshold for PD-L1 expression in correlation with tumor response, and if a correlation is identified this threshold will be used for Part B. The overall ability of PD-L1 to predict response will be assessed using the area under the receiver operating characteristic curve (area under the curve). If the area is significantly greater than 0.5, part B will begin using the optimum cutpoint as determined from the Youden index.
次要结局
- Disease control rate (CR + PR + SD)(Up to 3 years)
- Progression free survival (PFS)(Time from enrollment until disease progression or death from any cause, assessed up to 3 years)
- Overall survival (OS)(Up to 3 years)