Condition

• Peritoneal Malignant Mesothelioma

Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

Inclusion Criteria:

- Physicians should consider whether any of the following may render the patient
inappropriate for this protocol:

- Psychiatric illness which would prevent the patient from giving informed
consent

- Medical conditions such as uncontrolled infection, uncontrolled diabetes
mellitus or cardiac disease which, in the opinion of the treating physician,
would make this protocol unreasonably hazardous for the patient

- Human immunodeficiency virus (HIV)-infected patients on effective
anti-retroviral therapy with undetectable viral load within 6 months are
eligible for this trial

- For patients with evidence of chronic hepatitis B virus (HBV) infection,
the HBV viral load must be undetectable on suppressive therapy, if
indicated

- Patients with a history of hepatitis C virus (HCV) infection must have
been treated and cured. For patients with HCV infection who are currently
on treatment, they are eligible if they have an undetectable HCV viral
load

- Patients with a "currently active" second malignancy other than non-melanoma
skin cancers or cervical carcinoma in situ. Patients are not considered to have
a "currently active" malignancy if they have completed therapy and are free of
disease for >= 3 years

- In addition:

- Women and men of reproductive potential should agree to use an appropriate
method of birth control throughout their participation in this study due to the
teratogenic potential of the therapy utilized in this trial. Appropriate
methods of birth control include abstinence, oral contraceptives, implantable
hormonal contraceptives or double barrier method (diaphragm plus condom)

- A female of childbearing potential is a sexually mature female who: 1) has
not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been
naturally postmenopausal for at least 12 consecutive months (i.e., has had
menses at any time in the preceding 12 consecutive months)

- 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

- 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 12 months prior to randomization, myocardial infarction within 12 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 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 disease (e.g. seizures) unrelated to cancer unless adequately treated with
standard medical therapy

- 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

Recruiting Locations

Study Contact

Detailed Description

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 Response Evaluation Criteria in Solid Tumors (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-18 (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 30-60 minutes, bevacizumab IV over 30-90 minutes, carboplatin IV over 30 minutes, and pemetrexed IV over 10 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients then undergo cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Patients not eligible for surgery may receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1 of each maintenance therapy cycle. Treatment repeats every 21 days 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 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 4-8 weeks, patients then undergo cytoreductive surgery and HIPEC. Patients not eligible for surgery may receive bevacizumab IV over 30-90 minutes with or without atezolizumab IV over 30-60 minutes on day 1 of each maintenance therapy cycle at the discretion of the investigator. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT scan, PET scan, and collection of blood and tissue samples throughout the study. After completion of study treatment, patients are followed up every 6 months for up to 3 years.