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

A Phase 2 Study to Evaluate the Efficacy and Safety of Adoptive Transfer of Autologous Tumor Infiltrating Lymphocytes in Patients With Unresectable, Recurrent, or Metastatic Gastrointestinal Stromal Tumors

This phase II trial tests the effect of autologous tumor infiltrating lymphocytes (TILs) in combination with interleukin-2 (aldesleukin) in treating patients with gastrointestinal stromal tumors (GIST) that has spread to nearby tissue or lymph nodes (locally advanced), that has come back after a period of improvement (recurrent) or that has spread from where it first started (primary site) to other places in the body (metastatic). Autologous TILs are made using the patient's own tumor cells collected from a previous surgery. Lymphocytes (a type of white blood cell) are a part of the immune system that helps the body fight infections. Lymphocytes are found in tumor tissue cells because they are working to attack the tumor. The cells from the tumor are grown in a lab to create more immune cells (lymphocytes). This may help the immune system find and destroy any remaining tumor cells. Aldesleukin is a form of interleukin-2, a cytokine made by leukocytes, that is made in the laboratory. Aldesleukin may help white blood cells and T cells regulate the immune response. Chemotherapy, such as cyclophosphamide and fludarabine, are given before receiving TIL to help kill tumor cells in the body and helps make room for the treatment. Colony-stimulating factors, such as filgrastim, may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Giving autologous TILs in combination with aldesleukin may be safe, tolerable, and/or effective in treating patients with locally advanced, recurrent or metastatic GIST.

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.

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