PRIMARY OBJECTIVE:
I. To determine whether frontline treatment with carboplatin, pemetrexed, bevacizumab and
atezolizumab results in a superior best response rate than carboplatin, pemetrexed and
bevacizumab in patients with peritoneal mesothelioma as determined by (RECIST).
SECONDARY OBJECTIVES:
I. To determine the safety, major pathologic response rates, and completeness of
cytoreduction of patients treated with neoadjuvant carboplatin, pemetrexed, bevacizumab and
atezolizumab or carboplatin, pemetrexed and bevacizumab.
II. To determine the safety of patients treated with palliative carboplatin, pemetrexed,
bevacizumab and atezolizumab or carboplatin, pemetrexed and bevacizumab.
III. To determine whether frontline treatment with carboplatin, pemetrexed, bevacizumab and
atezolizumab results in a superior metabolic response rate than carboplatin, pemetrexed and
bevacizumab as determined by Positron Emission Tomography (PET) Response Criteria in Solid
Tumors.
IV. Explore the value that analysis of secondary computed tomography (CT) findings and
quantitative fludeoxyglucose F-1 (FDG)-PET imaging adds to prognostic information and
response assessment in this disease.
V. Determine the number of patients who were deemed to have unresectable disease who are able
to undergo surgery following treatment with carboplatin, pemetrexed, bevacizumab and
atezolizumab or carboplatin, pemetrexed and bevacizumab due to dramatic response.
VI. To compare the progression-free survival and overall survival between arms. VII. Results
of the primary analysis will be examined for consistency, while taking into account the
stratification factors and/or covariates of baseline quality of life (QOL) and fatigue.
EXPLORATORY OBJECTIVE:
I. To determine whether blood-based biomarkers including our recently described cell-free
chromosomal junctions, soluble mesothelin-related peptides and megakaryocyte potentiating
factor correlate with clinical outcomes data (i.e. overall survival [OS], progression-free
survival [PFS], recurrence, response, etc.).
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive atezolizumab intravenously (IV) over 60 minutes, bevacizumab IV over
30-90 minutes, carboplatin IV over 30 minutes, and pemetrexed IV over 10 minutes on day 1.
Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or
unacceptable toxicity. Within 4-8 weeks, patients undergo cytoreductive surgery and
hyperthermic intraperitoneal chemotherapy (HIPEC). Patients not eligible for surgery may
receive atezolizumab and bevacizumab in the absence of disease progression or unacceptable
toxicity.
ARM II: Patients receive bevacizumab IV over 30-90 minutes, carboplatin IV over 30 minutes,
and pemetrexed IV over 10 minutes on day 1. Treatment repeats every 21 days for up to 4
cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks,
patients undergo cytoreductive surgery and HIPEC. Patients not eligible for surgery may
receive bevacizumab with or without atezolizumab at the discretion of the investigator in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 3
years.
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
