Inclusion Criteria:

• At least 18 years of age at the time of informed consent
• Have confirmed diagnosis of MPM with the following characteristics:
  • Unresectable disease (defined as the participant not being a candidate for curative surgery)
  • Epithelial type
  • Have an archived tissue sample to be submitted either as a formalin fixed paraffin-embedded (FFPE) tumor block, or 5 to 15 unstained slides
• Have measurable disease at screening by computed tomography (CT) (or magnetic resonance imaging [MRI]) as defined by at least 1 lesion of greater than or equal to 1.5 cm in the longest diameter for a non-lymph node or greater than or equal to 1.5 cm in the short-axis diameter for a lymph node that is serially measurable according to the modified RECIST criteria
• Have other significant medical conditions well-controlled and stable in the opinion of the investigator for at least 30 days prior to day 1
• Have an ECOG Performance Status 0 or 1 at screening
• Have a life expectancy of at least 3 months, as estimated by the investigator
• Have adequate organ reserve as determined by laboratory test results obtained within 2 weeks prior to study day 1 as indicated below
  • Absolute neutrophil count greater than or equal to 1.5 x 109/L
  • Platelet count greater than or equal to 100 x 109/L
  • Hemoglobin greater than or equal to 9 g/dL
  • Serum bilirubin less than or equal to 1.5 x upper limit of normal (ULN)
    • Participants with serum bilirubin abnormalities greater than this specified limit are eligible only if they have known Gilberts disease
  • Aspartate aminotransferase less than or equal to 3 x ULN
  • Alanine aminotransferase less than or equal to 3 x ULN
  • Alkaline phosphatase less than or equal to 3 x ULN
• Have a calculated serum creatinine clearance greater than or equal to 45 mL/min using the Cockcroft-Gault equation
• Participants of childbearing potential must be surgically sterile or consent to use a highly effective method of contraception throughout the study period
• All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing)
• If a participant of childbearing potential is neither surgically sterile nor postmenopausal, highly effective contraceptive measures must start either prior to or at screening and continue throughout the entire study period and for at least 6 months after the last dose of chemotherapy and at least 30 days after the last dose of Test Article (amatuximab or placebo) is administered (whichever is later)
  • A highly effective method of contraception is defined as one that results in a low failure rate (ie, less than 1% per year) when used consistently and correctly. Periodic abstinence, the rhythm method, the withdrawal method, condoms, and diaphragms are not acceptable methods of contraception
• Women of childbearing potential must refrain from egg cell donation for 6 months after the final dose of investigational product
• Male participants must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (ie, not of childbearing potential or practicing highly effective contraception throughout the study period and for 6 months after discontinuation of chemotherapy and for 5 weeks after Test Article (amatuximab or placebo) discontinuation (whichever is later). No sperm donation is allowed during the study period and for 90 days after Test Article discontinuation
• Willing and able to provide written informed consent
• Willing and able to comply with all aspects of the protocol

Exclusion Criteria:

• Have any history of the following
  • Prior systemic therapy or radiotherapy for MPM
    • Local radiotherapy of noncurative intent (ie, for prevention of instrument-tract recurrence and/or symptom control) is permitted
  • Evidence of other active, invasive malignancy requiring treatment within the past 5 years
    • Noninvasive cancer history (such as carcinoma-in-situ [CIS] that has been resected) is allowed
• Currently have mesothelioma of the sarcomatous type, mixed histologic disease, or have malignant peritoneal mesothelioma
• Have confirmed presence of central nervous system metastases
• Active viral hepatitis or active human immunodeficiency virus infection
• Have evidence of any other serious systemic disease, including active bacterial or fungal infection, or any medical condition that, in the opinion of the investigator(s) could affect the participant's safety or interfere with the study assessments
• Clinically significant heart disease (eg, congestive heart failure of New York Heart Association Class 3 or 4, angina not well controlled by medication, or myocardial infarction within 6 months)
• Electrocardiogram (ECG) demonstrating clinically significant arrhythmias 
  • Participants with chronic atrial arrhythmia, ie, atrial fibrillation or paroxysmal supraventricular tachycardia, are eligible
• A clinically significant ECG abnormality, including a marked prolonged QT/QTc interval (eg, a repeated demonstration of a QTc interval of greater than 500 ms)
• Have known intolerance to the Test Article (ie, documented hypersensitivity AE to prior monoclonal antibody therapy, amatuximab or any of its excipients)
• Pregnant and/or lactating females are excluded
  • A negative beta-human chorionic gonadotropin [B-hCG]) is required during screening, and a separate local assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of Test Article
• Have any medical or other condition that in the opinion of the investigator(s) would preclude the participant's participation in a clinical study
• Scheduled for debulking surgery during the study
• Currently enrolled in another clinical study or used any investigational drug or device within 30 days (or 5 x the half-life of the investigational drug/device, whichever is longer) preceding informed consent