Ipilimumab and Nivolumab in the Treatment of Malignant Pleural Mesothelioma (INITIATE)

Inclusion Criteria:

• Signed informed consent form
• Age ≥ 18 years
• WHO-ECOG performance status 0 or 1
• Able to comply with the study protocol, in the investigator's judgment
• Patients with histologically confirmed diagnosis of the recurrence of MPM. Any pleural MPM subtype is permitted for inclusion in the study
• Progressive disease after at least one prior systemic treatment with a platinum-based doublet (both cisplatin and carboplatin are allowed) for unresectable MPM. All prior cytotoxic toxicities must have resolved to grade ≤ 1 prior to registration
• Measurable disease on CT scan, according to modified RECIST Criteria for Mesothelioma (Byrne MJ, 2004)
• Life expectancy ≥ 12 weeks

• Adequate hematologic and organ function, defined by the following laboratory results, obtained within 14 days prior to the first study treatment:

  • Absolute neutrophil count (ANC) ≥ 1500 cells/µL (without granulocyte colony-stimulating factor support within 2 weeks prior to Cycle 1, Day 1)
  • WBC count ≥ 3000 cells/µL
  • Lymphocyte count ≥ 250 cells/µL
  • Platelet count ≥ 100.000/µL (without transfusion within 2 weeks prior to Cycle 1, Day 1)
  • Hemoglobin ≥ 5.6 mmol/L
  • Serum albumin ≥ 25 gr/L
  • AST, ALT and alkaline phosphatase ≤ 2.5 x ULN, with the following exceptions: patients with documented liver or bone metastases: alkaline phosphatase ≤ 5 x ULN
  • Serum bilirubin ≤ 1.5 x ULN Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled
  • INR and aPTT ≤ 1.5 x ULN Patients receiving therapeutic anticoagulation should be on a stable dose Creatinine clearance ≥ 45 mL/min Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration or Modification of Diet in Renal Disease formulae may be used; 24-hour urine collection is not required
• Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus) and men with partners of childbearing potential, must agree to use adequate contraception (double barrier birth control) for the whole duration of study treatment and for 3 months after the last dose of therapy
• Women of childbearing potential must have a negative serum or urine pregnancy test within 48 hours prior the first dose of treatment

Exclusion Criteria:

• Medical or psychological impediment to comply with the protocol
• Patients with only peritoneal MPM
• Prior malignancy except adequately treated basal cell or squamous cell skin cancer, superficial or in-situ cancer of the bladder or other cancer for which the patient has been disease-free for at least five years
• Concomitant participation in another clinical trial (by the investigator's judgment)
• Uncontrolled pleural/peritoneal effusion, pericardial effusion or ascites requiring recurrent drainage procedures (once monthly or more frequently)
• Uncontrolled tumor-related pain Patients requiring pain medication must be on a stable regimen at study entry. Symptomatic lesions amenable to palliative radiotherapy should be treated prior to enrolment.
• Previous treatment with any checkpoint inhibitor
• Pregnant or lactating women
• Patients with brain metastases
• History of or active autoimmune disease (e.g. pneumonitis; rheumatoid arthritis; severe form of psoriasis; uncontrolled type I diabetes or hypothyroidism)
• History of idiopathic pulmonary fibrosis (including pneumonitis) or unresolved drug-induced pneumonitis, organizing pneumonia, or active pneumonitis on screening chest CT scan
• History of relevant gastrointestinal disease, including, but not limited to, Crohn's disease, ulcerative colitis, recurrent diverticulitis
• Prior allogenic bone marrow transplantation or prior solid organ transplantation
• History of HIV
• Patients with history of HBV infection are eligible if serological profile is compatible with past/resolved infection (defined as negative HBsAg test and positive antibody to HBV core antigen [anti-HBc] antibody test) and HBsAg test and HBV-DNA are both negative prior to Cycle 1, Day 1
• Patients with history of HCV infection must be screened for HCV-RNA PCR test prior to Cycle 1, Day 1, and are eligible if the test turns negative
• Other serious concomitant disease, including:

Active tuberculosis Severe infections within 4 weeks prior to Cycle 1, Day 1 Significant cardiovascular disease (NYHA class III or IV), myocardial infarction within the previous 6 months, unstable angina, or unstable arrhythmias Significant pulmonary (asthma or COPD) or hepatic disease or other illness considered by the investigator to constitute an unwarranted high risk for investigational treatment

• Major surgical procedures within 28 days prior to Cycle 1, Day 1
• Concurrent medications Treatment with systemic immunosuppressive medications, including but not limited to prednisone (with specific exceptions; see below), cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1.

The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed.

The use of systemic prednisone at the dosage of 10 mg/day or lower (or equivalent) is allowed.

• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1