Tumor Infiltrating Lymphocytes and Chemotherapy in Treating Patients with Metastatic Melanoma

Status: Active

Description

This early phase I trial studies the side effects and how well tumor infiltrating lymphocytes with chemotherapy work in treating patients with melanoma that has spread to other places in the body. Specific cells, such as tumor infiltrating lymphocytes developed from the immune cells found within a patients tumor masses may help to target tumor cells. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving tumor infiltrating lymphocyte and chemotherapy may work better in treating patients with melanoma.

Eligibility Criteria

Inclusion Criteria

  • Histologically or cytologically confirmed metastatic melanoma with at least one lesion that is resectable for TIL generation (at least 1.5 cm in diameter). Subjects must have measurable or evaluable disease
  • Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1 at the time of surgical harvest. Assessment by the treating physician that ECOG performance status of no higher than 2 can be maintained at least for the period of cell generation, lymphoablation, cell infusion and IL-2 administration (for at least 6 weeks following cell harvest)
  • Tumor that is not responsive to prior therapy with a PD-1/PD-L1 antagonist alone or in combination with anti-CTLA-4
  • If indicated, willing to practice birth control during treatment and for 4 months after receiving the preparative regimen
  • Able to understand and sign the Informed Consent Document
  • Absolute neutrophil count >= 1000/mm^3 without support of filgrastim
  • Normal white blood cell (WBC) (> 3000/mm^3)
  • Hemoglobin >= 8.0 g/dl (can be transfused to this level)
  • Platelet count greater than 75,000/mm^3
  • Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Subjects 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 HTLV-1 and HTLV-2 antibodies
  • Seronegative for hepatitis B or hepatitis C
  • Seronegative for syphilis
  • Seropositive for Epstein-Barr virus (EBV) (the risk for post-transplant lymphoproliferative disorder is significantly higher for EBV- subjects who receive EBV+ blood products after myelosuppressive therapy)
  • Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) < five times the upper limit of normal
  • Serum creatinine =< 2.0 mg/dl
  • Total bilirubin =< 2 mg/dl, except in subjects with Gilbert’s Syndrome, who must have a total bilirubin =< 3 mg/dl
  • At least 7 days must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and toxicities must have recovered to =< grade 1 (except for toxicities such as alopecia or vitiligo and certain immune checkpoint inhibitor toxicities). Subjects may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to =< grade 1
  • Subjects who have received any anti-CTLA-4, anti-PD-1 or anti-PD-L1 antibody and experienced treatment- related colitis must have complete resolution of diarrhea/colitis as assessed by clinical history. For adrenal insufficiency and hypothyroidism, subjects must be on stable doses of prednisone (=< 10 mg daily) and/or levothyroxine, respectively. All other immune checkpoint toxicity must have resolved to =< grade 1 as assessed by history or exam with the exception of vitiligo, or cardiac, neurologic or pulmonary toxicity, which must have resolved to grade 0

Exclusion Criteria

  • Prior cell transfer therapy that included non-myeloablative or ablative chemotherapy
  • Women of childbearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant
  • Systemic steroid therapy required prednisone > 10 mg daily or its equivalent
  • Any contraindication to neutropenia or thrombocytopenia for up to 2 weeks (no active major infection, no site of active, clinically significant bleeding)
  • Active coagulation disorders
  • Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and acquired immunodeficiency syndrome [AIDS])
  • Opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Subjects who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
  • History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  • Any patient known to have an left ventricular ejection fraction (LVEF) =< 45%. Also: * Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block * Ischemia found on a cardiac stress echocardiogram or a stress-multigated acquisition (MUGA)
  • Documented forced expiratory volume in 1 second (FEV1) less than or equal to 60% predicted tested in subjects with: * A prolonged history of cigarette smoking * Symptoms of respiratory dysfunction
  • Active second malignancy

Locations & Contacts

Connecticut

New Haven
Yale University
Status: Active
Contact: Michael E. Hurwitz
Phone: 203-737-4556
Email: michael.hurwitz@yale.edu

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the feasibility and safety of administering a regimen of tumor infiltrating lymphocyte (TIL)/IL-2, using a cell product manufactured in the Yale Advanced Cell Therapy Laboratories, in subjects with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist used alone or in combination with anti-CTLA-4.

II. To assess for evidence of clinical activity.

III. To conduct a preliminary assessment of the T cell receptor (TCR) clonotypes present in marker positive CD8+ cells (4-1BB, LAG-3, TIM-3, PD-1) versus marker-negative CD8+ T-cells early in the expansion cultures and compare to clonotypes late in the final product and in peripheral blood lymphocytes (PBL) 1 and 2 months post infusion.

OUTLINE:

Patients receive cyclophosphamide intravenously (IV) over 1 hour daily on days -7 and -6, fludarabine phosphate IV over 30 minutes on days -5 to -1, TIL IV over 20-30 minutes on day 0, and aldesleukin IV over 15 minutes every 12 hours for up to 10 doses starting 1-24 hours after TIL infusion.

After completion of study treatment, patients are followed up at 14, 42, 70, and 84 days, and 6, 9, and 12 months.

Trial Phase & Type

Trial Phase

No phase specified

Trial Type

Treatment

Lead Organization

Lead Organization
Yale University

Principal Investigator
Michael E. Hurwitz

Trial IDs

Primary ID 2000020477
Secondary IDs NCI-2018-01955
Clinicaltrials.gov ID NCT03526185