Clinical Trials /

A Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes

NCT03526185

Description:

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, 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. Additionally, a second cohort of patients 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 will receive anti-PD-1 and anti-CTLA-4 therapy with Nivolumab and Ipilimumab.

Related Conditions:
  • Metastatic Melanoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes
  • Official Title: A Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes Following a Lymphocyte Depleting Regimen in Metastatic Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 2000020477
  • NCT ID: NCT03526185

Conditions

  • Metastatic Melanoma

Interventions

DrugSynonymsArms
Tumor Infiltrating LymphocytesAutologous TIL, Unselected TIL, Young TILCohort 1
Nivolumab and IpilimumabCohort 2

Purpose

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, 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. Additionally, a second cohort of patients 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 will receive anti-PD-1 and anti-CTLA-4 therapy with Nivolumab and Ipilimumab.

Detailed Description

      The objectives of this study have been expanded since its original registration to inlcude an
      additional cohort of patients (now designated Cohort 1 and Cohort 2). Cohort 1 is the
      original group of patients described in the initial registration of the study.

      Cohort 1 Objectives:

        -  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, 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.

        -  To assess for evidence of clinical activity.

        -  To conduct a preliminary assessment of the 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 2 Objectives:

        -  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.

        -  To 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 RECIST (irRECIST).

        -  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.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort 1ExperimentalSubjects will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m2/day) on days -5 through -1. Prophylactic antibiotics will be administered as medically indicated until recovery of ANC to > 500 and recovery of ALC to > 400 On day 0 subjects will receive the infusion of autologous TIL and one hour later (but can be delayed up to 24 hours) will begin low-dose aldesleukin (IL-2) (72,000 IU/kg IV every 12 hours for up to 10 doses).
  • Tumor Infiltrating Lymphocytes
Cohort 2ExperimentalSubjects will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m2/day) on days -5 through -1. Prophylactic antibiotics will be administered as medically indicated until recovery of ANC to > 500 and recovery of ALC to > 400 On day 0 subjects will receive the infusion of autologous TIL and one hour later (but can be delayed up to 24 hours) will begin low-dose aldesleukin (IL-2) (72,000 IU/kg IV every 12 hours for up to 10 doses). Within 1 week post discharge subjects will be treated with Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg every 3 weeks for 4 doses. Following this, patients will receive Nivolumab 480 mg every 4 weeks. Adjuvant Nivolumab will continue until evidence of disease progression or inability to tolerate treatment.
  • Tumor Infiltrating Lymphocytes
  • Nivolumab and Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

        For Cohorts 1 and 2:

          -  Metastatic melanoma;

          -  A metastatic lesion at least 1.5 cm in diameter that can be removed surgically

          -  Measurable or evaluable disease not including the resected lesion

          -  ECOG PS of 0 or 1 prior to cell 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 refractory to or progressing following prior PD-1/PD-L1 therapy alone or in
             combination with an anti-CTLA-4 agent

          -  Ability to understand risks and benefits of the treatment and to give informed consent

        Exclusion Criteria:

        For Cohorts 1 and 2:

          -  Received prior cell transfer therapy that included non-myeloablative or ablative
             chemotherapy

          -  Any significant major organ dysfunction (see protocol)

          -  Residual toxicity > gr1 from immune checkpoint inhibitor other than persistent
             endocrinopathy on hormone replacement; all symptoms of prior colitis and enteritis
             must have resolved completely as assessed by history

          -  Any contraindication to neutropenia or thrombocytopenia for up to 2 weeks (no active
             major infection, no site of active, clinically significant bleeding)

          -  Concurrent major medical illnesses

          -  Any form of immunodeficiency

          -  Requirement for steroids > 10 mg prednisone daily or equivalent

          -  Severe hypersensitivity to any of the agents used in this study

          -  Contraindications for IL-2 administration

        At the time of lymphoablation subjects must meet baseline eligibility criteria with the
        following additions and exceptions:

        • Confirmation by lab that cell product can be ready for harvest and infusion within 7 days

        For Cohort 2 only:

        At the time of the start of anti-PD-1/anti-CTLA-4 therapy, subjects must meet baseline
        eligibility criteria with the following additions and exceptions:

          -  Patient cannot have a steroid requirement > 10 mg prednisone daily or equivalent

          -  Patients who have received prior PD-1/PD-L1 antagonist therapy and developed severe
             autoimmune disease precluding further immune checkpoint therapy

          -  Any organ dysfunction that makes the subject ineligible for anti-PD1 and anti-CTLA-4
             treatment as deemed by the treating investigator

          -  ECOG PS of 0-2

          -  Hgb of at least 8.0 gm/dl (may be transfused to this level)

          -  Creatinine not greater than 2.5 mg/dl

          -  AST or ALT not > 5x ULN and total bilirubin not > 2.5 mg/dl

          -  No clinically significant change in major organ function compared to initial
             eligibility evaluation

          -  Prior to initiating the lymphoablation regimen, there can be no untreated brain lesion
             > 1.0 cm, and/or with significant evidence of hemorrhage. Subjects may begin
             lymphoablation no less than 1 full day after completing WBRT or stereotactic
             radiotherapy for brain lesions.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Adverse Events
Time Frame:up to 12 months
Safety Issue:
Description:To determine the safety of administering a regimen of TIL/IL-2, incidence of drug-related adverse events (AEs) will be summarized across adverse event type in terms of frequency by event type.

Secondary Outcome Measures

Measure:Objective response rate to TIL
Time Frame:up to 12 months
Safety Issue:
Description:Objective response rate (ORR) of the TIL/IL-2 regimen based on investigator review of radiographic images using RECIST 1.1 criteria

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Yale University

Last Updated

May 22, 2019