Back to resultsA Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes
Primary Purpose
Metastatic Melanoma
Status
Terminated
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
Tumor Infiltrating Lymphocytes
Nivolumab and Ipilimumab
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Melanoma
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.
Sites / Locations
- Yale New Haven Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Cohort 1
Cohort 2
Arm Description
Subjects 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).
Subjects 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.
Outcomes
Primary Outcome Measures
Adverse Events
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.
Serious Adverse Events
To determine the safety of administering a regimen of TIL/IL-2, serious adverse events (SAEs) will be summarized across event type in terms of frequency by event type. SAE's will include events leading to discontinuation, deaths and clinical laboratory test abnormalities
Secondary Outcome Measures
Objective response rate to TIL
Objective response rate (ORR) of the TIL/IL-2 regimen based on investigator review of radiographic images using RECIST 1.1 criteria
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03526185
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
Study Type
Interventional
2. Study Status
Record Verification Date
July 2022
Overall Recruitment Status
Terminated
Why Stopped
lack of funds
Study Start Date
February 6, 2018 (Actual)
Primary Completion Date
December 1, 2020 (Actual)
Study Completion Date
December 1, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Yale University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Melanoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Parallel Assignment
Model Description
2 separate cohorts are included in the study design. These groups will not be directly compared.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
6 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
Subjects 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).
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
Subjects 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.
Intervention Type
Drug
Intervention Name(s)
Tumor Infiltrating Lymphocytes
Other Intervention Name(s)
Autologous TIL, Unselected TIL, Young TIL
Intervention Description
The regimen consists of treatment with cyclophosphamide and fludarabine,followed by infusion of up to 3x1011 lymphocytes (minimum of 1x109) expanded in vitro from subjects own resected tumor followed by the administration of aldesleukin (IL-2).
Intervention Type
Drug
Intervention Name(s)
Nivolumab and Ipilimumab
Intervention Description
• 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.
Primary Outcome Measure Information:
Title
Adverse Events
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.
Time Frame
up to 12 months
Title
Serious Adverse Events
Description
To determine the safety of administering a regimen of TIL/IL-2, serious adverse events (SAEs) will be summarized across event type in terms of frequency by event type. SAE's will include events leading to discontinuation, deaths and clinical laboratory test abnormalities
Time Frame
up to 12 months
Secondary Outcome Measure Information:
Title
Objective response rate to TIL
Description
Objective response rate (ORR) of the TIL/IL-2 regimen based on investigator review of radiographic images using RECIST 1.1 criteria
Time Frame
up to 12 months
Other Pre-specified Outcome Measures:
Title
Assessment of Immune features of TIL: 4-1BB
Description
to conduct a preliminary assessment of TCR clonotypes using deep sequencing of TCRs from the cell product and of immunologic markers present in marker positive CD8+ cells (specifically 4-1BB, LAG-3, TIM-3, PD-1)
Time Frame
up to 12 months
Title
Assessment of Immune features of TIL: LAG-3
Description
to conduct a preliminary assessment of TCR clonotypes using deep sequencing of TCRs from the cell product and of immunologic markers present in marker positive CD8+ cells (specifically 4-1BB, LAG-3, TIM-3, PD-1)
Time Frame
up to 12 months
Title
Assessment of Immune features of TIL: TIM-3
Description
to conduct a preliminary assessment of TCR clonotypes using deep sequencing of TCRs from the cell product and of immunologic markers present in marker positive CD8+ cells (specifically 4-1BB, LAG-3, TIM-3, PD-1)
Time Frame
up to 12 months
Title
Assessment of Immune features of TIL: PD-1
Description
to conduct a preliminary assessment of TCR clonotypes using deep sequencing of TCRs from the cell product and of immunologic markers present in marker positive CD8+ cells (specifically 4-1BB, LAG-3, TIM-3, PD-1)
Time Frame
up to 12 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Facility Information:
Facility Name
Yale New Haven Hospital
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States
12. IPD Sharing Statement
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A Pilot Study Using Short-Term Cultured Anti-Tumor Autologous Lymphocytes
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