Autologous Tumor Infiltrating Lymphocytes With Interleukin-2 for the Treatment of Locally Advanced, Recurrent or Metastatic Gastrointestinal Stromal Tumors

PRIMARY OBJECTIVE:

I. To evaluate the efficacy of a non-myeloablative lymphodepleting preparative regimen followed by infusion of autologous TIL and high-dose aldesleukin in patients with locally advanced, recurrent, or metastatic gastrointestinal stromal tumor (GIST) using the objective response rate (ORR).

SECONDARY OBJECTIVES:

I. To further evaluate the efficacy of this therapy using complete response (CR) rate, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS).

II. To characterize the safety profile of this therapy in patients with locally advanced, recurrent, or metastatic gastrointestinal stromal tumors (GIST).

OUTLINE:

Patients receive cyclophosphamide intravenously (IV) over 2 hours on days -8 and -7, fludarabine IV over 30 minutes on days -6 to -2 and TIL IV over 20-30 minutes on day 0 in the absence of disease progression or unacceptable toxicity. Starting within 24 hours of TIL infusion, patients receive aldesleukin IV over 15 minutes every 8 hours for up to 6 doses on days 0-3 in the absence of disease progression or unacceptable toxicity. Starting on day 1 or day 2, patients may receive filgrastim subcutaneously (SC) until neutrophil count > 1 x 10\^9/L for 3 consecutive days or > 5 x 10\^9/L. Patients with stable disease, partial response or recurrence may receive a second course of treatment. Patients also undergo chest x-ray at screening and urine and blood sample collection, computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET) throughout the study. Additionally, patients may also undergo echocardiography or multigated acquisition scan (MUGA) at screening and may also undergo a second surgery to collect cells on study.

After completion of study treatment, patients are followed up at 4-6 weeks, 12 weeks, every 3 months for 3 visits, then every 6 months up to month 24.

• Aldesleukin (Biological), also known as 125-L-Serine-2-133-interleukin 2, Proleukin, r-serHuIL-2, Recombinant Human IL-2, Recombinant Human Interleukin-2: Given IV
• Biospecimen Collection (Procedure), also known as Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection: Undergo urine and blood sample collection
• Chest Radiography (Procedure), also known as Chest X-ray: Undergo chest x-ray
• Computed Tomography (Procedure), also known as CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography: Undergo CT
• Cyclophosphamide (Drug), also known as (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Asta B 518, B 518, B-518, B518, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR 138719, WR- 138719, WR-138719, WR138719: Given IV
• Echocardiography Test (Procedure), also known as EC, Echocardiography: Undergo echocardiography
• Filgrastim (Biological), also known as Filgrastim Biosimilar Filgrastim-sndz, Filgrastim Biosimilar Tbo-filgrastim, Filgrastim XM02, Filgrastim-aafi, Filgrastim-ayow, Filgrastim-sndz, G-CSF, Granix, Neupogen, Neutroval, Nivestim, Nivestym, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, Releuko, rG-CSF, Tbo-filgrastim, Tevagrastim, XM02, Zarxio: Given SC
• Fludarabine (Drug), also known as Fluradosa: Given IV
• Magnetic Resonance Imaging (Procedure), also known as Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI: Undergo MRI
• Multigated Acquisition Scan (Procedure), also known as Blood Pool Scan, Equilibrium Radionuclide Angiography, Gated Blood Pool Imaging, Gated Heart Pool Scan, MUGA, MUGA Scan, Multi-Gated Acquisition Scan, Radionuclide Ventriculogram Scan, Radionuclide Ventriculography, RNV Scan, RNVG, SYMA Scanning, Synchronized Multigated Acquisition Scanning: Undergo MUGA
• Positron Emission Tomography (Procedure), also known as Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, PT: Undergo PET
• Surgical Procedure (Procedure), also known as Operation, Surgery, Surgery Type, Surgery, NOS, Surgical, Surgical Intervention, Surgical Interventions, Surgical Procedures, Type of Surgery: Undergo a second surgery
• Tumor Infiltrating Lymphocyte Therapy (Biological): Given IV

Primary outcomes

• Objective response rate [Up to 24 months]: Will be estimated by the proportion of patients with a best response of complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors criteria, with corresponding exact 95% confidence limit being reported.

Secondary outcomes

• CR rate [Up to 24 months]: Will be estimated by the proportion of patients with a best response of complete response (CR) by Response Evaluation Criteria in Solid Tumors criteria
• Duration of response [Up to 24 months]: The distribution among patients achieving CR or PR will be characterized by median and quartiles.
• Disease control rate [Up to 24 months]
• Progression-free survival [From the initial date of treatment to the date of documented progression, or the date of death (in the absence of progression), assessed up to 24 months]: Will be estimated by the Kaplan-Meier method. The corresponding median survival times (with 95% confidence limits) will be determined, as will the cumulative percentage of patients remaining progression-free (and the cumulative percentage-alive) at selected time points after initial treatment (e.g., 3, 6,12, 18 months).
• Overall survival [From the initial date of treatment to the recorded date of death, assessed up to 24 months]: Will be estimated by the Kaplan-Meier method. The corresponding median survival times (with 95% confidence limits) will be determined, as will the cumulative percentage of patients remaining progression-free (and the cumulative percentage-alive) at selected time points after initial treatment (e.g., 3, 6,12, 18 months).
• Incidence of adverse events [Up to 30 days after treatment]: Will be described and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The maximum grade of toxicity for each category of interest will be recorded for each patient and the summary results will be tabulated by category and grade.

Sex: All, ages: 18 Years to 75 Years

Inclusion Criteria:

* Measurable locally advanced, recurrent, or metastatic GIST
* Patients with locally advanced disease should be unresectable by conventional surgical approaches
* Patients with distant metastatic spread must be refractory to approved standard systemic therapies (such as imatinib and sunitinib) if they are eligible to receive these treatments
* Patients must be co-enrolled on the companion protocol Cell Harvest and Preparation to Support Adoptive Cell Therapy Clinical Protocols and Pre-Clinical Studies (institutional review board \[IRB\] #2024C0043), and have available TIL cultures for therapy
* Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible
* Greater than or equal to 18 years of age and less than or equal to age 75
* Able to understand and sign the informed consent document
* Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1
* Life expectancy of greater than three months
* Patients of both genders who are of child-bearing potential must be willing to practice birth control from the time of enrollment on this study and for up to four months after receiving the treatment
* Serology:

  * Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)
  * 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 reverse transcriptase-polymerase chain reaction (RT-PCR) and be HCV ribonucleic acid (RNA) negative
* Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus
* Absolute neutrophil count greater than 1000/mm\^3 without the support of filgrastim
* White blood cells (WBC) ≥ 3000/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Hemoglobin > 8.0 g/dl
* Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ≤ to 3.5 times the upper limit of normal
* Serum creatinine ≤ to 1.6 mg/dl and calculated creatinine clearance (Crockcroft-Gault or 24-hour urine creatinine) ≥ 30 mL/min
* Total bilirubin ≤ to 2.0 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

Exclusion Criteria:

* Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant
* Any form of primary immunodeficiency (such as severe combined immunodeficiency disease)
* Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities)
* Active systemic infections (e.g.: requiring anti-infective treatment), coagulation disorders or any other active major medical illnesses
* History of major organ autoimmune disease
* Concurrent systemic steroid therapy including physiologic replacement dosing of systemic steroids (i.e. prednisone ≤ 10 mg/day or equivalent) as well as topical or inhaled corticosteroids are not allowed
* History of severe immediate hypersensitivity reaction to any of the agents used in this study
* History of active coronary or ischemic symptoms
* Documented left ventricular ejection fraction (LVEF) of less than or equal to 45%

  * Note: testing is required in patients with:

    * Age ≥ 65 years old
    * Clinically significant atrial and or ventricular arrhythmias including but not limited to:

      * Atrial fibrillation, ventricular tachycardia, second or third degree heart block or have a history of ischemic heart disease, chest pain
* 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 pack \[pk\]/year of smoking within the past 2 years)
  * Symptoms of respiratory dysfunction
* Patients who are receiving any other investigational agents

• Joal Beane, MD, Principal investigator, Ohio State University Comprehensive Cancer Center