Amatuximab for High Mesothelin Cancers

Primary Outcome Measures:

• Biodistribution of radiolabelled amatuximab in tumor and nontumor tissues.
• Tumor
• Background ratio of maximum counts

Secondary Outcome Measures:

• CTCAE V.4 events
• Observation of HACA
• PKs
• Antibody uptake vs. IHC mesothelin expression

Intervention Details:

Drug: Amatuximab (MORab-009)

Detailed Description:

Background:

• Amatuximab is a high-affinity monoclonal IgG antibody raised against human mesothelin.
• Mesothelin is a glycosyl-phosphatidyl inositol-linked membrane glycoprotein thought to be involved in tumor metastasis
• Mesothelin is over-expressed in many cancers

Objectives:

-The primary objective is to determine the biodistribution of radiolabeled amatuximab in tumor and nontumor tissues in subjects with mesothelin over-expressing cancers including mesothelioma, pancreatic, ovarian, and non small cell lung cancer.

Eligibility:

• Female or male subjects greater than or equal to 18 years of age;
• Histologically confirmed mesothelin-expressing cancer;
• Transaminases less than or equal to 3 times ULN for mesothelioma, non small cell lung and ovarian cancer;
• Transaminases less than or equal to 5 times ULN for pancreatic cancer with known liver metastasis.

Design:

• This is a single-center, single-dose, open-label, pilot study of amatuximab in approximately 20 subjects with mesothelin expressing tumors.
• Unlabeled amatuximab will be administered at a low dose (50 mg) to saturate any nonspecific binding and shed antigen.
• Within 6 hours after cold antibody infusion, Indium-radiolabeled amatuximab (5 mCi) will be administered.
• Serial SPECT imaging will be performed to determine binding to tumor and nontumortissue.
• Subjects will be observed closely for safety and possible development of anti-amatuximab antibodies.
• Pharmacokinetics of radiolabeled antibody will be determined with imaging over time.

  Eligibility Criteria

Inclusion Criteria:

• Female or male subjects, greater than or equal to 18 years of age.
• Histologically-confirmed diagnosis of pancreatic adenocarcinoma, mesothelioma, mesothelin-positive ovarian cancer, or NSCLC. A new biopsy is not required; the diagnostic biopsy sample will be sufficient. IHC confirmation of mesothelin-positivity is not necessary for pancreatic adenocarcinoma and mesothelioma as nearly 100% of pancreatic adenocarcinomas and mesotheliomas express mesothelin. Mesothelin expression in ovarian cancer and NSCLC will be tested by IHC and any degree of positivity (1+, 2+, or 3+) will be accepted.
• Subjects are required to have measurable disease that has progressed through prior therapy and that includes a non-hepatic lesion for imaging that is greater than or equal to 1.5 cm, as defined by Modified Response Evaluation Criteria in Solid Tumors (RECIST).
• Eastern Cooperative Oncology Group (ECOG) performance status or 0, 1, or 2.
• Female subjects of childbearing potential and all male subjects are required to consent to use a medically acceptable method of contraception throughout the study period and for 30 days after amatuximab administration. A barrier method of contraception is required.
• Laboratory and clinical results within the 2 weeks prior to Day of Infusion as follows:
  • Absolute neutrophil count (ANC): greater than or equal to 1.5 times 10(9)/L
  • Platelet count: greater than or equal to 75 times 10(9)/L
  • Hemoglobin: greater than or equal to 10 g/dL
  • Serum bilirubin: less than or equal to 1.5 mg/dL
  • Aspartate transaminase (AST): less than or equal to 3 x upper limit of normal (ULN) (less than or equal to 5 ULN acceptable for pancreatic patients with known liver metastasis only)
  • Alanine transaminase (ALT) less than or equal to 3 times upper limit of normal (ULN) (less than or equal to 5 ULN acceptable for pancreatic patients with known liver metastasis only)
  • Alkaline Phosphatase less than or equal to 5 times ULN
  • Serum creatinine less than or equal to 1.5 mg/dL
• Subjects are required to be willing and able to provide written informed consent.

Exclusion Criteria:

• Subjects are ineligible to participate in this study if any of the following criteria are met:
  • Known allergy or hypersensitivity to monoclonal antibodies;
  • Prior treatment with amatuximab;
  • Prior treatment with SS1(dsFv)PE38 (SS1P);
  • Known brain metastases;
  • Known prosthetic devices that would prohibit imaging of lesion of interest due to radiographic artifact;
  • Evidence of other active malignancy requiring treatment;
  • Clinically significant heart disease (e.g., congestive heart failure of New York Heart Association Class III or IV, angina not well controlled by medication, or myocardial infarction within 6 months);
  • ECG demonstrating clinically significant arrhythmias. Subjects with chronic atrial arrhythmia, (i.e., atrial fibrillation or paroxysmal supraventricular tachycardia), are eligible;
  • Active serious systemic disease, including active bacterial or fungal infection within 2 weeks before study entry;
  • Active viral hepatitis or symptomatic human immunodeficiency virus (HIV) infection;
  • Treatment within 3 months with immunomodulatory therapy (e.g., interferons, immunoglobulin therapy, Interleukin 1 receptor antagonist (IL-1RA) or systemic corticosteroids). Short-term systemic corticosteroids or topical or intra-articular steroids are acceptable, at the discretion of the Investigator;
  • Chemotherapy, biologic therapy, radiation therapy or immunotherapy within 3 weeks prior to dosing with amatuximab;
  • Breast-feeding, pregnant, or likely to become pregnant during the study.