Anetumab Ravtansine in Treating Patients with Mesothelin Positive, Locally Advanced, or Metastatic Pancreatic Cancer That Cannot Be Removed by Surgery

Inclusion Criteria

• PRE-SCREENING: Written informed consent for prescreening
• PRE-SCREENING: Unresectable locally advanced or metastatic pancreatic cancer, confirmed by histology
• PRE-SCREENING: At least one but not more than two prior chemotherapy regimens with progression or documented intolerance (neoadjuvant or adjuvant chemotherapy would not be counted as a line of therapy; if prior radiation, measurable lesion outside radiation portal)
• PRE-SCREENING: Availability of archival or fresh tissue for testing of mesothelin expression level * Note: archival tissue is preferred and fresh biopsy should only be obtained if no archival tissue is available and if in the investigator’s judgement, there is no additional risk for the patient’s safety; patients with a sarcomatoid histology are not expected to have mesothelin overexpression and should not enter prescreening
• PRE-SCREENING: Life expectancy of at least 3 months
• PRE-SCREENING: No prior treatment with anetumab ravtansine (or any other mesothelin-based therapy)
• FULL STUDY INCLUSION CRITERIA: Written informed consent for full study
• FULL STUDY INCLUSION CRITERIA: Histological documentation of overexpressing mesothelin at the moderate (2+) or stronger (3+) level in at least 30% of tumor cells as determined by immunohistochemistry (IHC)
• FULL STUDY INCLUSION CRITERIA: Unresectable locally advanced or metastatic pancreatic cancer
• FULL STUDY INCLUSION CRITERIA: At least one but not more than two prior chemotherapy regimens with progression or documented intolerance (neoadjuvant or adjuvant chemotherapy would not be counted as a line of therapy; if prior radiation, measurable lesion outside radiation portal)
• FULL STUDY INCLUSION CRITERIA: Patients must have at least 1 measurable lesion according to RECIST version (v) 1.1
• FULL STUDY INCLUSION CRITERIA: Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
• FULL STUDY INCLUSION CRITERIA: Life expectancy of at least 3 months
• FULL STUDY INCLUSION CRITERIA: Total bilirubin =< 1.5 x the upper limit of normal (ULN); documented Gilbert syndrome is allowed if total bilirubin is mildly elevated (< 6 mg/dL) (conducted within 7 days before starting study treatment)
• FULL STUDY INCLUSION CRITERIA: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x ULN (=< 5 x ULN for patients with liver involvement of their cancer) (conducted within 7 days before starting study treatment)
• FULL STUDY INCLUSION CRITERIA: Alkaline phosphatase (ALP) limit =< 2.5 x ULN (=< 5 x ULN for patients with liver involvement of their cancer) (conducted within 7 days before starting study treatment)
• FULL STUDY INCLUSION CRITERIA: Extent of baseline tumor burden will not interfere with causal assessment of treatment-emergent hepatotoxicity, at the investigator’s discretion (conducted within 7 days before starting study treatment)
• FULL STUDY INCLUSION CRITERIA: Amylase and lipase =< 1.5 x ULN (conducted within 7 days before starting study treatment)
• FULL STUDY INCLUSION CRITERIA: Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 according to the Modification of Diet in Renal Disease (MDRD) abbreviated formula (conducted within 7 days before starting study treatment)
• FULL STUDY INCLUSION CRITERIA: International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN (Common Terminology Criteria for Adverse Events [CTCAE] grade =< 1) (conducted within 7 days before starting study treatment) * Note: patients on stable dose of anti-coagulation therapy will be allowed to participate if they have no sign of bleeding or clotting and INR / PT and partial thromboplastin time (PTT) / activated (a)PTT test results are compatible with the acceptable benefit-risk ratio at the investigator’s discretion
• FULL STUDY INCLUSION CRITERIA: Partial thromboplastin time (PTT) or activated PTT (aPTT) =< 1.5 x ULN (CTCAE grade =< 1) (conducted within 7 days before starting study treatment) * Note: patients on stable dose of anti-coagulation therapy will be allowed to participate if they have no sign of bleeding or clotting and INR / PT and PTT / aPTT test results are compatible with the acceptable benefit-risk ratio at the investigator’s discretion
• FULL STUDY INCLUSION CRITERIA: Platelet count >= 75,000/mm^3, without platelet transfusion within 3 weeks before the start of study treatment (conducted within 7 days before starting study treatment)
• FULL STUDY INCLUSION CRITERIA: Hemoglobin (Hb) >= 8 g/dL (conducted within 7 days before starting study treatment) * Note: patients receiving chronic low-dose erythropoietin for chronic renal failure are allowed provided no dose adjustment is undertaken within 6 weeks before signing consent for full study and until safety follow-up visit and provided that they fulfill conditions of eligibility criteria
• FULL STUDY INCLUSION CRITERIA: Absolute neutrophil count (ANC) >= 1000/mm^3 (conducted within 7 days before starting study treatment)
• FULL STUDY INCLUSION CRITERIA: Left ventricular ejection fraction (LVEF) >= 50% or the lower limit of normal (LLN) according to local institution ranges of normality (conducted within 7 days before starting study treatment)

Exclusion Criteria

• Previous assignment to treatment during this study; patients permanently withdrawn from study participation will not be allowed to re-enter the study
• Previous (within 5 drug half-lives - if drug half-life in subjects is known - or 28 days, whichever is shorter, before the start of study treatment) or concomitant participation in another clinical study with investigational medicinal product(s) (IMP[s])
• Patients with corneal epitheliopathy or any eye disorder that may predispose the patients to this condition at the discretion of the investigator
• Previous or concurrent cancer that is distinct in primary site or histology within 5 years; exceptions: curatively treated * Cervical cancer in situ * Non-melanoma skin cancer * Superficial bladder tumors (non-invasive tumor [Ta], carcinoma in situ [Tis] and tumor invades lamina propria [T1])
• Major surgery, open biopsy or significant traumatic injury within 28 days before the start of study treatment
• Pregnant or breast-feeding patients; women of childbearing potential (WOCBP) must have a serum pregnancy test performed a maximum of 7 days before the start of study treatment, and a negative result must be documented before the start of study treatment
• Pre-existing cardiac conditions as outlined below: * Congestive heart failure >= New York Heart Association (NYHA) class 2 * Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months); myocardial infarction less than 6 months before the start of study treatment * Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
• Clinically significant uncontrolled hypertension (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management)
• Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or venous pulmonary embolism within 6 months before the start of study treatment; venous thrombotic events such as deep vein thrombosis within 3 months before the start of study treatment
• Ongoing or active infection (bacterial, fungal, or viral) of National Cancer Institute (NCI)-CTCAE version 4.03 grade > 2
• Known history of human immunodeficiency virus (HIV) infection
• Known history of chronic hepatitis B or C
• Patients with seizure disorder requiring medication
• Symptomatic brain metastases or meningeal tumors or other uncontrolled metastases in the central nervous system (CNS) unless the patient * Is > 6 months from definitive therapy, * Has a negative imaging study within 4 weeks before study entry (informed consent form [ICF] signature for full study) and * Is clinically stable with respect to the tumor at the time of study entry
• History of organ allograft, stem cells or bone marrow transplant
• Patients with evidence or history of bleeding diathesis; any hemorrhage or bleeding event >= CTCAE grade 3 within 4 weeks before the start of study treatment
• Non-healing wound, ulcer, or bone fracture
• Renal failure requiring peritoneal dialysis or hemodialysis
• Known hypersensitivity to anetumab ravtansine, study drug classes or excipients in the formulation
• Any illness or medical conditions that are unstable or could jeopardize the safety of the patient and his/her compliance in the study
• Unresolved toxicity higher than NCI-CTCAE version 4.03 grade 1 attributed to any prior therapy/procedure excluding anemia or neuropathy grade 2 and alopecia of any grade
• Any prohibited prior or concomitant therapy