Tumor Infiltrating Lymphocytes and Chemotherapy with or without Immunotherapy in Treating Patients with Metastatic Melanoma
This early phase I trial studies the side effects and how well tumor infiltrating lymphocytes and chemotherapy with or without immunotherapy work in treating patients with melanoma that has spread to other places in the body (metastatic). Specific cells, such as tumor infiltrating lymphocytes developed from the immune cells found within a patient's 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. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Giving tumor infiltrating lymphocyte and chemotherapy with or without immunotherapy may work better in treating patients with melanoma.
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 =< 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)
- COHORT II ONLY: ECOG performance status of =< 2 at the time of initiation of ipilimumab/nivolumab therapy
- Tumor that is not responsive to prior therapy with a PD-1/PD-L1 antagonist alone or in combination with anti-CTLA-4 unless subjects were deemed unable to receive anti-PD-1, anti-PD-L1 or anti-CTLA-4 therapies because of coexisting comorbidities (e.g. severe autoimmune disease)
- If indicated, willing to practice birth control during treatment and for 12 months after finishing the treatment 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 a 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
- COHORT II: In subjects who have received any anti-CTLA-4, anti-PD-1 or anti-PD-L1 antibody and experienced treatment-related side effects, the following criteria will be used for treatment with ipilimumab and/or nivolumab: * Colitis =< grade 3 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 =< grade 3 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 1
- COHORT II: Patients who have received prior PD-1/PD-L1 antagonist therapy and developed severe autoimmune disease precluding further immune checkpoint therapy
- COHORT II: Patients who have active or known autoimmune disease that precludes immune checkpoint inhibitor therapy or that requires systemic steroids > 10 mg prednisone or its equivalent daily or requires other immunosuppressant agents
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03526185.
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. (Cohort I)
II. To assess for evidence of clinical activity. (Cohort I)
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. (Cohort I)
IV. To determine the feasibility and safety of administering a regimen of TIL/IL-2, using a cell product manufactured in the Yale Advanced Cell Therapy Laboratories, followed by anti-PD-1 and anti-CTLA-4 therapy with nivolumab and ipilimumab in subjects with metastatic melanoma who are not responding or have progressed after receiving prior therapy with a PD-1/PD-L1 antagonist alone or in combination with anti-CTLA-4. (Cohort II)
V. Evaluate the efficacy of TIL/IL-2 therapy in combination with subsequent anti-PD-1 nivolumab and anti-CTLA-4 Ipilimumab by assessing the objective response rate by immune-related Response Evaluation Criteria in Solid Tumors (RECIST) (irRECIST). (Cohort II)
VI. To conduct a preliminary assessment of the TCR clonotypes present in marker positive CD8+ cells (e.g. 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. (Cohort II)
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT I: 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 in the absence of disease progression or unacceptable toxicity.
COHORT II: Patients receive cyclophosphamide 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. Within 14 days of hospital discharge, patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes every 3 weeks for 4 doses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 14, 42, 70, and 84 days, and 6, 9, and 12 months.
Trial PhasePhase O
Trial Typetreatment
Lead OrganizationYale University
Principal InvestigatorMichael E. Hurwitz
- Primary ID2000020477
- Secondary IDsNCI-2018-01955
- ClinicalTrials.gov IDNCT03526185