Atezolizumab, Pemetrexed Disodium, Cisplatin, and Surgery With or Without Radiation Therapy in Treating Patients With Stage I-III Pleural Malignant Mesothelioma

Primary Outcome Measures

• Modified Response Evaluation Criteria in Solid Tumors (RECIST) progression free survival [ Time Frame: From date of registration to date of first documentation of progression, assessed up to 3 years ] Will be assessed by modified RECIST 1.1. Will be evaluated using the method of Kaplan-Meier. Confidence intervals around the median will be calculated using the Brookmeyer-Crowley method, confidence intervals around landmark time points will use the Greenwood formula for standard errors.
• Overall survival [ Time Frame: From date of initial registration to date of death due to any cause, assessed up to 3 years ] Will be evaluated using the method of Kaplan-Meier. Confidence intervals around the median will be calculated using the Brookmeyer-Crowley method, confidence intervals around landmark time points will use the Greenwood formula for standard errors.
• Progression free survival [ Time Frame: From date of registration to date of first documentation of progression, assessed up to 3 years ] Will be assessed by Response Evaluation Criteria in Solid Tumors 1.1. Will be evaluated using the method of Kaplan-Meier. Confidence intervals around the median will be calculated using the Brookmeyer-Crowley method, confidence intervals around landmark time points will use the Greenwood formula for standard errors.

Eligibility

Inclusion Criteria

STEP 1: NEOADJUVANT

Patient must have malignant pleural mesothelioma which is deemed resectable (stages I-III; stage IV is excluded) and must be planning to undergo pleurectomy decortication (P/D) or extrapleural pneumonectomy (EPP); patients with T4 disease are not eligible

Patient must have epithelioid or biphasic histology (sarcomatoid histology is excluded); histologic diagnosis and typing of mesothelioma will require at least a core needle biopsy or surgical biopsy of the pleura via thoracoscopy and small thoracotomy; cytology only will not be regarded as sufficient for the diagnosis

Patient must have computed tomography (CT) chest/abdomen/pelvis with contrast or fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/CT scan performed within 28 days prior to step 1 registration

Patients must have measurable disease documented by CT or magnetic resonance imaging (MRI); the CT from a combined PET/CT may be used to document only non-measurable disease unless it is of diagnostic quality; measurable disease must be assessed within 28 days prior to step 1 registration; pleural effusions, ascites and laboratory parameters are not acceptable as the only evidence of disease; non-measurable disease must be assessed within 42 days prior to step 1 registration; all disease must be assessed and documented on the RECIST 1.1 and modified RECIST baseline tumor assessment form

Patient will undergo extended surgical staging which includes mediastinoscopy or endobronchial ultrasound; at minimum, samples should be obtained from the mediastinal stations 4R, 7 (subcarinal), and 4L; this surgical staging must be performed within 42 days prior to step 1 registration; patient must be T1-3 and N0-N2 (single station).

Patient must undergo video-assisted thoracoscopic surgery and diagnostic laparoscopy within 28 days prior to step 1 registration; patients must undergo the diagnostic laparoscopy to rule out peritoneal disease spread

Patient must not have had prior immunotherapy or chemotherapy for malignant pleural mesothelioma

Patient must have Zubrod performance status 0 or 1 documented within 28 days prior to step 1 registration

Patient must have electrocardiography (ECG) and audiogram performed within 28 days prior to step 1 registration

Patient must have not had any major surgery or radiation within 28 days prior to step 1 registration

Patients must not have any anticancer therapy or investigational agent within 28 days prior to step 1 registration

Patients must not have any anticancer therapy or investigational agent within 28 days prior to step 1 registration

Patient must have complete metabolic panel, urinalysis, thyroid-stimulating hormone (TSH), free T4, coagulation testing performed within 28 days prior to step 1 registration

Absolute neutrophil count (ANC) >= 1,500/mcl documented within 28 days prior to step 1 registration

Hemoglobin >= 9 g/dl documented within 28 days prior to step 1 registration

Platelets >= 100 k documented within 28 days prior to step 1 registration

Creatinine =< 1.5 x upper limit of normal (ULN) documented within 28 days prior to step 1 registration

Creatinine clearance >= 45 ml/min documented within 28 days prior to step 1 registration

Total bilirubin =< 1.5 x upper limit of normal (ULN) within 28 days prior to step 1 registration

Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN within 28 days prior to step 1 registration

No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for three years

Patients must not be pregnant or nursing; patients must be willing to take a pregnancy test within 28 days prior to step 1 registration; women/men of reproductive potential must have agreed to use an effective contraceptive method; a woman is considered to be of “reproductive potential” if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, “effective contraception” also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures.

The patient must NOT have a history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins

The patient must NOT have a known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation

Patients must not have severe infections within 28 days prior to step 1 registration, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.

Patients must not have active autoimmune disease that has required systemic treatment in past two years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; autoimmune diseases include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, Bell’s palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis; this protocol includes an immunotherapy agent which can precipitate known autoimmune diseases

Patients must not have undergone prior allogeneic bone marrow transplantation or prior solid organ transplantation.

Patient must not have active tuberculosis

Patient must not have history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis; this protocol includes an immunotherapy agent which can precipitate known pneumonitis

Patients must not have active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C; patients with past hepatitis B virus (HBV) infection or resolved hepatitis B virus (HBV) infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible; patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA

The patient must NOT have a known positive test for human immunodeficiency virus (HIV); patients do not need to be screened for HIV; patients with HIV are excluded

Patients must not have significant cardiovascular disease, such as New York Heart Association cardiac disease (class II or greater), myocardial infarction within the 3 months initiation of treatment, unstable arrhythmias, or unstable angina given the higher risks associated with surgical resection

Patient must be willing to have blood and tissue specimens submitted for PD-L1, Immune Nanostring, and immunofluorescence testing

Patients must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

STEP 2: SURGERY

Patient must have consultation with a surgeon prior to step 2 registration; the surgeon must confirm that the patient’s disease is resectable by pleurectomy decortication (P/D) or extrapleural pneumonectomy (EPP) and that the patient is an appropriate candidate for the surgical procedures

Patients must have a CT of chest/abdomen/pelvis with contrast or FDG-PET/CT scan within 28 days prior to step 2 registration; patients must not have evidence of progression per RECIST 1.1 or modified RECIST for pleural tumors

Patients planning to receive EPP must also be evaluated for appropriateness of radiation therapy (RT) by a radiation oncologist within 14 days prior to step 2 registration

Pulmonary function tests, including spirometry, lung volumes, and diffusion capacity are required for all patients and must be obtained within 28 days prior to step 2 registration

Patients must have a Zubrod performance status of 0-1 documented within 28 days prior to step 2 registration

Postoperative predicted forced expiratory volume (FEV) > 35% prior to surgery

Postoperative predicted carbon monoxide diffusing capability (DLCO) > 35% prior to surgery

Oxygen consumption (VO2) max > 15 ml/kg/min prior to surgery

Preoperative ejection fraction (EF) at least >= 45%, no evidence of pulmonary hypertension on preoperative echocardiogram, no evidence of moderate to severe valvular of coronary artery disease

Patient must have received at least two cycles of triplet neoadjuvant therapy (all three drugs) during step 1

Patient must be enrolled no less than 21 days and no more than 90 days after following the end of their final cycle of neoadjuvant chemotherapy of step 1

Patients must be willing to submit 3-4 blocks and peripheral blood at time of resection for translational medicine and banking purposes

STEP 3: MAINTENANCE

Patient must have received either P/D or EPP and must have recovered from all effects of surgery with adequate wound healing; patient must be enrolled within 56 days of surgery (or 28 days after discontinuing RT)

Patient must have adequate organ function

Patient must have a CT of chest/abdomen/pelvis with contrast or FDG-PET/CT scan within 28 days prior to step 3 registration; patient must not have evidence of progression per RECIST 1.1 or modified RECIST for pleural tumors

Patient may have discontinued RT early due to toxicity or other reasons

Patients must have a Zubrod performance status of 0-1 documented within 28 days prior to step 3 registration

ANC > 1,500/mcl within 28 days documented prior to step 3 registration

Hemoglobin > 9 g/dl documented within 28 days prior to step 3 registration

Platelets > 100,000/mcl documented within 28 days prior to step 3 registration

Creatinine < 1.5 x ULN documented within 28 days prior to step 3 registration

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