Primary Outcome Measures
- Response rate [ Time Frame: Up to 4 years after study activation ]
Will be compared between arms.
Secondary Outcome Measures
- Major pathologic response rate [ Time Frame: Up to 3 years ]
The proportion of patients with a pathologic response will be calculated and compared between arms and 95% confidence intervals reported. The chi-square test will be used to compare the rates between arms.
- Completeness of cytoreduction [ Time Frame: Up to 3 years ]
Will be estimated.
- Conversion rate to surgical resection among those not deemed to be surgical candidates [ Time Frame: Up to 3 years ]
Will estimate the conversion rate to surgical resection among those not deemed to be surgical candidates prior to treatment and provide the 95% confidence interval as well.
- Progression-free survival (PFS) [ Time Frame: From study entry to the first of either disease progression or death from any cause, where disease progression will be determined based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, assessed up to 3 years ]
Will be estimated using the Kaplan-Meier method, where the log-rank test will be used to compare the 2 treatment arms.
- Overall survival [ Time Frame: From study entry to death from any cause, assessed up to 3 years ]
Will be estimated using the Kaplan-Meier method, where the log-rank test will be used to compare the 2 treatment arms.
- Incidence of adverse events [ Time Frame: Up to 3 years ]
The maximum grade for each type of adverse event will be summarized using Common Terminology Criteria for Adverse Events version 5.0. The frequency and percentage of grade 3+ adverse events will be compared between the 2 treatment arms. Comparisons between arms will be made by using either the Chi-square or Fisher’s Exact test.
Other Outcome Measures
- Soluble mesothelin-related peptides and megakaryocyte potentiating factor [ Time Frame: Up to 3 years ]
Will be correlated with clinical endpoints including confirmed response, overall survival, PFS, recurrence, and adverse events. Statistical and graphical techniques will be used to explore the relationships between the translational and clinical data. For time-to-event endpoints, will use Cox proportional hazards models, and for confirmed response will use Logistic regression models. In addition, will use the Chi-square or Fisher’s exact tests to test the association between categorical marker data and confirmed response/adverse events.
Inclusion Criteria
- Histologically or cytologically confirmed malignant peritoneal mesothelioma for which there has been no prior treatment. Given the indolent nature of well-differentiated papillary mesothelioma and multicystic mesothelioma, patients with these variants are not eligible for participation
- All slides including performed immunostains from diagnostic tumor tissue together with pathology report for retrospective central pathology review
- Must have measurable disease per RECIST version (v) 1.1
- Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done =< 28 days prior to registration is required
- Age >= 18 years
- Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- Leukocytes >= 2,500/mm^3
- Absolute neutrophil count (ANC) >= 1,500/mm^3
- Platelet count >= 100,000/mm^3
- Creatinine clearance >= 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- Total bilirubin =< 1.5 x upper limit of normal (ULN)
- Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 3.0 x upper limit of normal (ULN)
- Urine protein:creatinine (UPC) ratio < 1, or urine protein: =< 1+
- No prior systemic therapy for peritoneal mesothelioma is allowed. No concurrent radiotherapy is allowed
- No 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 syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions:
- Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study
- Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
- Rash must cover < 10% of body surface area
- Disease is well controlled at baseline and requires only low-potency topical corticosteroids
- 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
- No history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
- No prior allogeneic stem cell or solid organ transplantation
- Central nervous system (CNS) metastases must have been treated with local therapy (surgery, radiation, ablation) with systemic steroids tapered to a physiologic dose (10 mg or prednisone equivalent or less)
- Patients who have received live attenuated vaccines within 30 days of the first dose of trial treatment are eligible at the discretion of the investigator. All seasonal influenza vaccines and vaccines intended to prevent SARS-CoV-2 and coronavirus disease 2019 (COVID-19) are allowed
- No history of inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg)
- No history of hypertensive crisis or hypertensive encephalopathy
- No clinically significant cardiovascular disease, such as cerebrovascular accidents within 6 months prior to randomization, myocardial infarction within 6 months prior to randomization, unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with study treatment
- No clinically significant cardiovascular disease, such as cerebrovascular accidents within 12 months prior to randomization, myocardial infarction within 12 months prior to randomization, unstable angina, New York Heart Association (NYHA) grade II or greater CHF, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with study treatment
- No significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to randomization
- No history of grade >= 4 venous thromboembolism
- No history or evidence upon physical or neurological examination of central nervous system
- No history of grade >= 2 hemoptysis (defined as >= 2.5 mL of bright red blood per episode) within 1 month prior to screening
- No history or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (i.e., in the absence of therapeutic anticoagulation)
- No major surgical procedure or significant traumatic injury within 28 days prior to initiation of study treatment (diagnostic laparoscopy is allowed as part of diagnosing peritoneal mesothelioma)
- No core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to initiation of study treatment
- Placement of a vascular access device should be at least 2 days prior to initiation of study treatment
- No active infection requiring IV antibiotics at the time of initiation of study treatment
- No history of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess, or active GI bleeding within 6 months prior to randomization
- No serious, non-healing wound, active ulcer, or untreated bone fracture
- No other malignancy within 5 years prior to randomization, except for localized cancer in situ, such as basal or squamous cell skin cancer
- Patients with a creatinine clearance between 45 and 79 mL/min should not use ibuprofen or other nonsteroidal anti-inflammatory drug (NSAIDs) for 2 days before, the day of, and 2 days following pemetrexed administration
- No treatment with immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:
- Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) may be eligible for the study
- Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study
