Genetically Engineered Lymphocytes in Treating Patients with Metastatic Cancer or Cancer That Cannot Be Removed by Surgery Receiving Chemotherapy and Aldesleukin

Inclusion Criteria

• Metastatic or unresectable measurable cancers that express mesothelin; as in other protocols conducted by Dr. Hassan in the National Cancer Institute (NCI), epithelial mesotheliomas and pancreatic cancers do not need to be assessed for mesothelin expression since all of these tumors have been shown to express mesothelin; other metastatic or unresectable cancers must be shown to expresses mesothelin as assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) or immunohistochemistry on tumor tissue; bi-phasic mesotheliomas must express mesothelin on greater than 50% of the cells in the epithelial component; diagnosis will be confirmed by the Laboratory of Pathology, NCI
• Patients must have previously received at least one systemic standard care (or effective salvage chemotherapy regimens) for metastatic or unresectable disease, if known to be effective for that disease, and have been either non-responders (progressive disease) or have recurred
• Willing to sign a durable power of attorney
• Able to understand and sign the informed consent document
• Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1
• Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment
• Serology: * Seronegative for human immunodeficiency virus (HIV) antibody * Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody; if hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be hepatitis C virus (HCV) ribonucleic acid (RNA) negative
• Women of child-bearing potential must have a negative pregnancy test
• Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim
• White blood cells (WBC) (> 3000/mm^3)
• Platelet count greater than 100,000/mm^3
• Hemoglobin greater than 8.0 g/dl
• Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or equal to 2.5 times the upper limit of normal
• Serum creatinine less than or equal to 1.6 mg/dl
• Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert’s syndrome who must have a total bilirubin less than 3.0 mg/dl
• More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients’ toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo) * Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less
• Subject’s must be co-enrolled in protocol 03-C-0277

Exclusion Criteria

• Patients with sarcomatoid mesothelioma as mesothelin is not expressed in this type of mesothelioma
• Women of child-bearing potential who are pregnant or breastfeeding
• Patients with known brain metastases
• Patients receiving full dose anticoagulative therapy
• Active systemic infections (e.g.: requiring anti-infective treatment), coagulation disorders or any other major medical illnesses
• Any form of primary immunodeficiency (such as severe combined immunodeficiency disease)
• Concurrent opportunistic infections
• Patients with diabetic retinopathy
• Concurrent systemic steroid therapy
• History of severe immediate hypersensitivity reaction to any of the agents used in this study
• History of coronary revascularization or ischemic symptoms
• Documented left ventricular ejection fraction (LVEF) of less than or equal to 45% tested in patients with: * Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block, chest pain, or ischemic heart disease * Age >= 65 years old
• Documented forced expiratory volume in 1 second (FEV1) less than or equal to 60% predicted tested in patients with: * A prolonged history of cigarette smoking (20 packs [pk]/year of smoking within the past 2 years) * Symptoms of respiratory dysfunction
• Patients who are receiving any other investigational agents

PRIMARY OBJECTIVES:

I. To evaluate the safety of the administration of anti-mesothelin chimeric antigen receptor (CAR) engineered peripheral blood lymphocytes in patients receiving the non- myeloablative conditioning regimen, and aldesleukin.

II. Determine if the administration of anti-mesothelin CAR engineered peripheral blood lymphocytes and aldesleukin to patients following a nonmyeloablative but lymphoid depleting preparative regimen will result in clinical tumor regression in patients with metastatic or unresectable cancer that expresses mesothelin.

SECONDARY OBJECTIVES:

I. Determine the in vivo survival of CAR gene-engineered cells.

OUTLINE: This is a phase I, dose-escalation study of mesothelin-specific chimeric antigen receptor-engineered peripheral blood lymphocytes followed by a phase II study.

PREPARATIVE REGIMEN: Patients receive cyclophosphamide intravenously (IV) over 1 hour on days -7 and -6 and fludarabine phosphate IV over 30 minutes on days -7 to -3.

CELL INFUSION AND ALDESLEUKIN ADMINISTRATION: Patients receive mesothelin-specific chimeric antigen receptor-engineered peripheral blood lymphocytes IV over 20-30 minutes on day 0 and aldesleukin IV over 15 minutes every 8 hours for up to 15 doses.

After completion of study treatment, patients are followed up at 4-6 weeks, annually for 5 years, and then periodically for 10 years.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
NCI - Center for Cancer Research

Principal Investigator
Steven A. Rosenberg

• Primary ID 12-C-0111
• Secondary IDs NCI-2013-01516, P11928, 120111, 1112-1139, RD-12-I-02
• Clinicaltrials.gov ID NCT01583686