Lymphodepletion with Adoptive Cell Therapy and High-Dose IL-2 for the Treatment of Metastatic Soft Tissue Sarcoma in Young Adult Patients

Status: complete

This phase I trial studies the side effects of adoptively transferred tumor-specific T cells and high-dose aldesleukin (IL-2) and to see how well they work in treating patients with soft tissue sarcoma that has spread to other parts of the body (metastatic). Fludarabine and cyclophosphamide are two types of chemotherapy drugs used in lymphodepletion. The purpose of lymphodepletion in this study is to temporarily reduce the number of normal lymphocytes circulating in the body before tumor infiltrating lymphocytes are infused. This is so that there will be more “space” for the lymphocytes that will be infused in the veins. Tumor-infiltrating lymphocytes involve the use of special immune cells called T-cells. A T-cell is a type of lymphocyte, or white blood cell. Lymphocytes protect the body from viral infections, help other cells fight bacterial and fungal infections, produce antibodies, fight cancers, and coordinate the activities of other cells in the immune system. These special immune T-cells are taken from a sample of tumor tissue that is surgically removed, then multiplied in a laboratory, and infused back into the patient. IL-2 may help the body's response to treatment on the immune system.

Inclusion Criteria

STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Provision of signed and dated informed consent form
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Stated willingness to comply with all study procedures and availability for the duration of the study
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Patients must have metastatic, high-grade soft tissue sarcoma, all subtypes will be eligible
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Residual measurable disease after resection of target lesion(s) for TIL growth
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 to 1. ECOG performance status of 0 to 1 will be inferred if the patient’s level of energy is >= 50% of baseline.
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Patients must have progressed on at least one prior standard of care treatment regimen for metastatic disease
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: A negative pregnancy test (urine or serum) must be documented at screening for women of childbearing potential
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: A multigated acquisition (MUGA) scan (ejection fraction > 50% is required) =< 6 months prior to lymphodepletion
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Pulmonary function tests should be completed =< 6 months prior to lymphodepletion and forced expiratory volume (FEV1) > 65% or forced expiratory volume (FVC) > 65% of predicted are required
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Creatinine of =< 1.7 gm/dL
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Total bilirubin =< 2.0 mg/dL, except in patients with Gilbert’s syndrome who must have a total bilirubin less than 3.0 mg/dL
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of less than 3 x institutional upper limit of normal
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Hemoglobin of 8 gm/dL or more
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: White blood cells of 3000 per mm^3
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Total granulocytes of 1000 per mm^3 or more
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Platelets of 100 000 per mm^3 or more
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Patients must have a positive screening Epstein-Barr virus (EBV) antibody titre on screening test
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Patients that had previously grown sterile, validated TILs under good manufacturing practices (GMP) conditions meeting the above criteria are eligible using the previously established TIL product stored in the Cell Therapies Core facility for up to 2 years after harvesting
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: All laboratory and imaging studies must be completed and satisfactory within 30 days of signing the consent document
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Patients must have adequate TILs available
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Patients of both sexes must practice birth control for 4 months after receiving the preparative regimen
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), the patient agrees to continue to use a method of contraception throughout the study and for 90 days after your last treatment such as: barrier (i.e. condom, diaphragm), hormonal, intrauterine device (IUD), or sponge plus spermicide
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: For women who have menstruated within the past 12 months and have not had a surgical procedure to accomplish sterilization, pregnancy testing (urine or serum) will be performed within 7 days prior to treatment
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Clinical performance status of ECOG 0 to 1 at the time of chemotherapy infusion. ECOG performance status of 0 to 1 will be inferred if the patient’s level of energy is >= 50% of baseline
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Absolute neutrophil count greater than or equal to 750/mm^3
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Platelet count greater than or equal to 100 000/mm^3
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Hemoglobin greater than or equal to 8.0 g/dL
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Serum ALT and AST less than 3 times the institutional upper limit of normal
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Serum creatinine less than or equal to 1.7 mg/dL
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Total bilirubin less than or equal to 2.0 mg/dL, except in patients with Gilbert’s syndrome who must have a total bilirubin less than 3.0 mg/dL
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Prothrombin time (PT) and partial thromboplastin time (PTT) within 1.5 times the institutional upper limit of normal
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Patients with echocardiogram (EKG) within 14 days of initiation of chemotherapy demonstrating no new rhythm, axis, or ST segment changes will be included. If new ST changes are present, patients may be included if cardiac stress test indicates no evidence of inducible cardiac ischemia
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Urinalysis within 14 days demonstrating no evidence of a urinary tract infection
STEP 2: CHEMOTHERAPY/CELL INFUSION INCLUSION CRITERIA: Patients with evidence of ongoing disease regression that is attributed to a therapy that is not part of the trial and that was administered after TIL harvest and expansion but prior to adoptive transfer of TILs should continue on prior therapy and may be treated with TIL only if their disease is stable or there is evidence of progressive disease. In this event as described above, the TIL will be frozen and stored for future use, in the event of progression, prior to the rapid expansion step

Exclusion Criteria

STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Patients with active systemic infections requiring intravenous antibiotics, coagulation disorders, or other major medical illnesses of the cardiovascular, respiratory, or immune system are excluded
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Patients that have completed a chemotherapy regimen given with the intent of lymphodepletion or cellular immunotherapy which included a non-myeloablative lymphodepletion strategy
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Patients testing positive for human immunodeficiency virus (HIV) titer, hepatitis B surface antigen, human T-cell leukemia-lymphoma virus (HTLV) I or II antibody, or both rapid plasma regain (RPR) and fluorescent treponemal antibody (FTA) are excluded. Patients with hepatitis C antibody must have a negative (undetectable) viral load by polymerase chain reaction (PCR)
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Patients who are pregnant or nursing are excluded
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Patients needing chronic immunosuppressive systemic steroids are excluded
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Patients with autoimmune diseases that require immunosuppressive medications are excluded
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Presence of a significant psychiatric disease, which in the opinion of the principal investigator or his designee, would prevent adequate informed consent or render immunotherapy unsafe or contraindicated
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Patients with central nervous system metastases will be excluded
STEP 1: RESECTION OF TUMOR & INITIATION OF TIL EXPANSION: Inability to comprehend and give informed consent

PRIMARY OBJECTIVE:

I. To determine the safety and feasibility of treatment with adoptively transferred tumor-specific T cells following nonmyeloablative lymphodepleting chemotherapy followed by high-dose IL-2 for patients with advanced sarcoma.

SECONDARY OBJECTIVES:

I. To observe the objective antitumor responses per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria.

II. To evaluate the degree of sustained persistence of infused T cells.

TERTIARY/EXPLORATORY OBJECTIVE:

I. Evaluate the properties of the tumor-infiltrating lymphocyte (TIL) culture and expansion including degree of expansion and immunologic phenotype of the infusion product.

OUTLINE:

Patients receive cyclophosphamide intravenously (IV) over 2 hours on days -7 and -6, fludarabine IV daily over 15-30 minutes on days -5 to -1, TIL IV over 15-60 minutes on day 0, and high-dose aldesleukin IV over 15 minutes every 8-16 hours for up to 15 doses on days 1-5 in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at days 42 and 84, then every 3 months for 12 months, then every 3 months thereafter.

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Lymphodepletion with Adoptive Cell Therapy and High-Dose IL-2 for the Treatment of Metastatic Soft Tissue Sarcoma in Young Adult Patients

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