Lymphodepletion Plus Adoptive Cell Therapy With High Dose IL-2 in Adolescent and Young Adult Patients With Soft Tissue Sarcoma

Study Overview
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Brief Summary
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This is a single-arm trial that will evaluate the safety and feasibility of the Tumor-infiltrating lymphocyte (TIL) treatment and the persistence of TIL survival in vivo following treatment

Official Title
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A Phase I Trial of Lymphodepletion Plus Adoptive Cell Therapy With High-Dose IL-2 in Adolescent and Young Adult Patients With Soft Tissue Sarcoma

Conditions
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Sarcoma

Intervention / Treatment
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* Drug: TIL
* Drug: Interleukin-2
* Drug: Fludarabine
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must fulfill all of the following criteria to be eligible for the study at the time of tumor resection and initiation of TIL expansion. Stated willingness to comply with all study procedures and availability for the duration of the study Participants must have metastatic, high-grade soft tissue sarcoma, all subtypes will be eligible Residual measurable disease after resection of target lesion(s) for TIL growth 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. Participants must have progressed on at least one prior standard of care treatment regimen for metastatic disease. A negative pregnancy test (urine or serum) must be documented at screening for women of childbearing potential. A MUGA scan (ejection fraction > 50% is required) ≤ 6 months prior to lymphodepletion. Pulmonary function tests should be completed ≤ 6 months prior to lymphodepletion and forced expiratory volume (FEV1) > 65% or FVC > 65% of predicted are required Adequate renal, hepatic, and hematologic function, including creatinine of ≤ 1.7 gm/dL, 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, AST and ALT of less than 3 X institutional upper limit of normal, hemoglobin of 8 gm/dL or more, white blood cells of 3000 per mm^3 and total granulocytes of 1000 per mm^3 or more, and platelets of 100 000 per mm^3 or more. Participants must have a positive screening EBV antibody titre on screening test. Participants that have had previously grown sterile, validated TILs under good manufacturing practice 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. Unless surgically sterile by bilateral tubal ligation or vasectomy of partner(s), the participant agrees to continue to use a method of contraception throughout the study such as: barrier (i.e. condom, diaphragm), hormonal, IUD, or sponge plus spermicide. Prothrombin time (PT) and partial thromboplastin time (PTT) within 1.5 times the institutional upper limit of normal Participants with echocardiogram (EKG) within 14 days of initiation of chemotherapy demonstrating no new rhythm, axis, or ST segment If new ST changes are present, patients may be included if cardiac stress test indicates no evidence of inducible cardiac ischemia. Urinalysis within 14 days demonstrating no evidence of a urinary tract infection. Participants 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: Participants with active systemic infections requiring intravenous antibiotics, coagulation disorders, or other major medical illnesses of the cardiovascular, respiratory, or immune system are excluded. Participants that have completed a chemotherapy regimen given with the intent of lymphodepletion or cellular immunotherapy which included non-myeloablative lymphodepletion strategy. Participants testing positive for 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. Participants with hepatitis C antibody must have a negative (undetectable) viral load by polymerase chain reaction (PCR). Participants who are pregnant or nursing are excluded. Participants needing chronic immunosuppressive systemic steroids are excluded Participants with autoimmune diseases that require immunosuppressive medications are excluded 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 Participants with central nervous system metastases will be excluded. Inability to comprehend and give informed consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Infusion of Tumor-infiltrating lymphocyte<br>Participants will undergo tumor resection from which the tumor infiltrating lymphocyte (TIL) product will be generated. All participants will receive nonmyeloablative lymphodepleting chemotherapy with cyclophosphamide and fludarabine to enhance T-cell persistence and effectiveness in vivo. Cyclophosphamide will be administered at 60 mg/kg/day IV in 250 mL normal saline (NS). Fludarabine will then be infused at 25 mg/m^2 intravenous piggyback (IVPB). All participants will receive not less than 10^9, and up to 1x10^12 T cells in ≥250 mL NS as an inpatient by intravenously (IV). Eight (8) to sixteen (16) hours after completing the T cell infusion, all participants will receive high-dose interleukin-2 (IL-2) on an inpatient basis at the standard dose of 600 000 IU/kg as an intravenous bolus over an approximate 15-minute period every 8 to 16 hours for up to 15 doses on days 1 to 5, as tolerated. | Drug: TIL<br>* Participants will receive an infusion of Tumor-infiltrating lymphocytes (TIL) after tumor resection and TIL product is generated.<br>* Other names: Tumor-infiltrating lymphocytes;Drug: Interleukin-2<br>* Participants will receive Interleukin-2 (IL-2) 600 000 IU/kg intravenously (IV) bolus (about 15 minutes) every 8 to 16 hours for up to 15 doses, beginning approximately 8 to 16 hours after T-cell infusion.<br>* Other names: IL-2;Drug: Fludarabine<br>* Participants will receive an intravenously (IV) infusion of Fludarabine 25 mg/m2 for approximately 30 minutes for 5 days, prior to T-Cell infusion<br>* Other names: Fludara;Drug: Cyclophosphamide<br>* Participants will receive Cyclophosphamide 60 mg/kg/day intravenously (IV) in 250 mL normal saline (NS) over approximately 2 hours, 7 days prior to T-Cell infusion<br>* Other names: Neosar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who experienced Serious Adverse Events and Adverse Events | Participants able to safely tolerate preparatory lymphodepletion, infusion of tumor-infiltrating lymphocytes (TIL) and subsequent IL-2, as measured by adverse events and serious adverse events. | Baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with objective antitumor response | Number of participants with objective response (Complete Response (CR) + Progressive Response (PR)) rate at 12 weeks following TIL infusion, as measured by RECIST v1.1 | At 12 weeks | 
| Number of participants with circulating tumor-infiltrating lymphocytes (TIL) product at 6 weeks | Number of participants with persistence of TIL infusion product at 6 weeks following treatment, as measured by T-cell receptor repertoire comparison between the infusion product and circulating Peripheral blood mononuclear cell (PBMC). | At 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Soft Tissue Sarcoma, Adoptive Cell Therapy