The proposed study will evaluate the safety and feasibility of neoadjuvant nivolumab +/- ipilimumab in resectable MPM. In addition, maintenance nivolumab will be administered for 1 year following completion of standard bi-/tri-modality therapy.

For Arm A 15 patients with resectable MPM will be enrolled and receive preoperative nivolumab, 240mg IV, on Day -42, -28 and Day -14 (+/- two days for each timepoint) prior to planned surgery on Day 0 (to allow for scheduling surgery may take place between Day -3 and Day +10).

Subsequent to full accrual to Arm A, 15 patients with resectable MPM will be enrolled and receive preoperative nivolumab, 3mg/kg IV, on Day -42, -28 and Day -14 (+/- two days for each timepoint) + ipilimumab 1mg/kg IV on Day -42 prior to planned surgery on Day 0 (to allow for scheduling surgery may take place between Day -3 and Day +10).

Inclusion Criteria:

• Men and women ≥ 18 years old

• Primary tumor amenable to safe research biopsy. A tumor biopsy is required for study entry.

• Histology proven epithelial or biphasic MPM

  • Diagnostic core biopsy specimens must be reviewed by faculty pathologist at SKCC, MDACC, or UMGCCC.
  • Either a formalin fixed paraffin block that has been confirmed by a pathologist to contain tumor or a minimum of twenty 5-micron tissue sections (slides) of tumor biopsy sample must be available for biomarker evaluation (study pathologist must review for adequacy of sampling). This can be obtained from archived tissues if adequate, or from a new biopsy as needed.

• Stage I-III and deemed to be potentially surgically resectable as assessed by faculty surgeon at SKCC, MDACC, or UMGCCC

• ECOG performance status 0-1

• Adequate organ function as follows:

  • Leukocytes ≥ 2,000/mm3
  • Absolute neutrophil count (ANC) ≥ 1000/mm3
  • Platelet count ≥ 100,000/mm3
  • Hemoglobin ≥ 9 g/Dl
  • Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥40 mL/min (if using the Cockcroft-Gault formula below):

Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in mg/dL

Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in mg/dL

• Total Bilirubin ≤ 1.5 x institutional ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)

• AST(SGOT), ALT(SGPT), and alkaline phosphatase ≤ 3 times the institutional upper limit of normal

• Subjects must have adequate lung function to permit surgical resection determined by pre-enrollment pulmonary function tests to include DLCO

  • The effects of nivolumab on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation and for up to 23 weeks after the last dose of nivolumab. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Sexually active fertile men must use effective barrier birth control if their partners are WOCBP for up to 31 weeks after the last dose of nivolumab. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within two weeks of registration. Women must not be breastfeeding.
  • Patient understands the study regimen, its requirements, risks and discomforts and is able and willing to sign the informed consent form. Voluntary signed and dated IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines must be obtained before the performance of any protocol related procedures that are not part of normal patient care. Subjects must be competent to report AEs, understand the drug dosing schedule and use of medications to control AEs.

Exclusion Criteria:

• Stage I-III disease but deemed to be unresectable, a poor surgical candidate, or unfit for study therapy as assessed by study investigators
• Pure sarcomatoid histology
• Subjects are excluded if they have an active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Subjects are excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatotoxicity should be used with caution in patients treated with nivolumab-containing regimen.
• Administration of chemotherapy or any other cancer therapy in the pre-operative period.
• Subjects with active concurrent malignancies are excluded i.e. cancers other than MPM (except non-melanoma skin cancers, cervical dysplasia, and in situ cancers of bladder, stomach, breast, colon and cervix).
• Subjects with a history of symptomatic interstitial lung disease.
• Active systemic infection requiring therapy, as well as positive tests for hepatitis B surface antigen or hepatitis C antibody.
• Known positive history or positive test for human immunodeficiency virus or Acquired Immunodeficiency Syndrome (AIDS).
• History of allergy to study drug components.
• Women who are pregnant or nursing.
• Men with female partners (WOCBP) that are unwilling to use contraception
• Prior therapy with an anti-PD1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody (or any other antibody targeting T-cell co-regulatory pathways).
• History of any other condition that may require the initiation of anti-tumor necrosis factor alpha (TNFα) therapies or other immunosuppressant medications during the study
• Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events.
• Prisoners or subjects who are involuntarily incarcerated or compulsorily detained for treatment of either a psychiatric or physical (e.g. infectious disease) illness.