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Table 1 Current Trials with Tumor-infiltrating Lymphocytes in Melanoma Registered by ClinicalTrials.gov per March 2018

From: Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option

Trial Institute Phase Estimated enrollment Intervention TIL product Lymphodepletion regimen IL-2 regimen Disease Stage Primairy Outcome Measures Identification number
a. Recruiting Trials
Combined Therapy of Nivolumab and Adoptive T Cell Therapy in Metastatic Melanoma Patients: Pilot Study Phase I/II Nantes University Hospital, Nantes, France
Initiation 2018
I/II 11 TIL + IL-2 + Nivo (3 mg/kg every 2 w until w52) Cohort 1: 5 × 108 TIL (3 patients)
Cohort 2: 1-20 × 109 TIL at 14 w and 18 w
Not described 600,000 IU/kg/d for 5d Stage IIIb, IIIc or IV melanoma AE NCT03374839
Phase I Study to Assess Feasibility and Safety of Adoptive Transfer of Autologous Tumor-infiltrating Lymphocytes in Combination With Interleukin-2 Followed by Nivolumab Rescue for Advanced Metastatic Melanoma CHUV, Lausanne, Switzerland
Initiation 2018
I 10 Lymphodepletion + TIL + IL-2 +/− Nivo (3 mg/kg, every 2w max 24 months) rescue Unspecified Cy i.v. for 2d and Flu i.v. 5d (not otherwise specified) HD IL-2 t.i.d. max 8 doses Stage IV melanoma Feasibility AE NCT03475134
A Phase 2, Single-Center, Open Label Study of Autologous, Adoptive Cell Therapy Following a Reduced Intensity, Non-myeloablative, Lymphodepleting Induction Regimen in Metastatic Melanoma Patients Sheba Medical Center, Israel
Initiation 2017
II 30 Lymphodepletion + TIL + IL-2 Unspecified Flu (25 mg/m2 for 3 d) + TBI (2 Gy as single treatment) 720,000 IU/kg t.i.d.. until tolerable toxicity, max 10 doses Measurable metastatic melanoma ORR
AE
NCT03166397
Phase Ib Trial of Pembrolizumab Administered in Combination With or Following Adoptive Cell Therapy- A Multiple Cohort Study; The ACTIVATE (Adoptive Cell Therapy InVigorated to Augment Tumor Eradication) Trial Princes Margaret Cancer Centre, Canada
Initiation 2017
Ib 24 Cohort 1: Lymphodepletion + TIL + IL-2 + pembro (200 mg q 3 w)
Cohort 2: Lymphodepletion + TIL + IL-2 + pembro (200 mg q 3 w)
1 × 1010–1.6 × 1011 TILs Cohort 1: Cy i.v. 60 mg/kg/d for 2d + Flu
25 mg/m2 for 5 d
Cohort 2: Cy i.v. 30 mg/kg per day for 2 days
Cohort 1 + 2: 125,000 IU/kg s.c./d Unresectable stage III/ IV melanoma or Platinum resistant ovarian cancer AE NCT03158935
A Pilot Clinical Trial Combining PD-1 Blockade, CD137 Agonism and Adoptive Cell Therapy for Metastatic Melanoma Lee Moffitt Cancer Center, Florida, US
Initiation 2016
Pilot 12 Cohort 1 (1st 6 patients): Lymphodepletion + TIL + IL-2
Cohort 2 (2nd 6 patients): Pre-treatment nivo + lymphodepletion + TIL + IL-2
Unspecified, outgrowth in 4–8 w with CD137 activating antibody Cy 2 d beginning 3–6 w after tumor collection for TIL growth + Flu for 5 d Unspecified Unresectable cutaneous or mucosal stage III/IV melanoma AE Feasibility NCT02652455
A Prospective Randomized and Phase 2 Trial for Metastatic Melanoma Using Adoptive Cell Therapy With Tumor Infiltrating Lymphocytes Plus IL-2 Either Alone or Following the Administration of Pembrolizumab NIH Clinical Center, Bethesda, Maryland, US
Initiation 2015
II 170 Cohort 1 Arm 1 Anti-PD1/PD-L1 refractory patients: Lymphodepletion + TIL + IL-2
Cohort 1 Arm 2 Anti-PD1/PD-L1 refractory patients: Lymphodepletion + Pembro 2 mg/kg i.v. on d − 2, (and d 21 (+/−  2 d), 42 (+/−  2 d), and 63 (+/−  2 d) following cell infusion) + TIL + IL-2
Cohort 2 Arm 3 Anti-PD1/PD-L1 naive patients: Lymphodepletion + Pembro 2 mg/kg i.v. on d-2 (and days 21 (+/−  2 d), 42 (+/−  2 d), and 63 (+/−  2 d)) following cell infusion + TIL + IL-2
Cohort 1 Arm 1 (Retreatment) Anti-PD1/PD-L1 refractory patients with no response to study treatment or PD after PR/CR: Pembro 2 mg/kg i.v. on d − 2, and d 21 (+/−  2 d), 42 (+/−  2 d), and 63 (+/−  2 d)
Young TIL, not otherwise specified Cohort 1 + 2: Cy 60 mg/kg i.v. for 2d + Flu 25 mg/m2for 5d Cohort 1 + 2: 720,000 IU/kg i.v. t.i.d., max 12 doses Measurable metastatic melanoma ORR NCT02621021
A Phase 2, Multicenter Study to Assess the Efficacy and Safety of Autologous Tumor Infiltrating Lymphocytes (LN-144) for Treatment of Patients With Metastatic Melanoma Iovance Investigative Site, Los Angeles, California, US
Initiation 2015
II 60 Cohort 1: Lymphodepletion + TIL + IL-2
Cohort 2: Lymphodepletion + TIL + IL-2
Cohort 3: re-treatment lymphodepletion + TIL + IL-2
Cohort 1: LN-144 autologous TIL non-cryopreserved product
Cohort 2: LN-144 autologous TIL cryopreserved
Cohort 3:
LN-144 autologous TIL re-treatment for 2nd LN-144 infusion
Lymphodepleting chemotherapy, not otherwise specified Unspecified Unresectable metastatic melanoma ORR NCT02360579
A Pilot Study of Lymphodepletion Plus Adoptive Cell Transfer With T-Cells Transduced With CXCR2 and NGFR Followed by High Dose Interleukin-2 in Patients With Metastatic Melanoma MD Anderson Cancer Center, Houston, Texas, US
Initiation 2015
Pilot 15 Lymphodepletion + transduced TIL + IL-2 Up to 1.5 × 1011 TIL (CXCR2 and NGFR transduced TIL) Cyc 60 mg/kg for 2d + Flu 25 mg/m2for 5d 720,000 IU/kgi.v. every 8–16 h, max 15 doses Metastatic melanoma or stage III in-transit, subcutaneous, or regional nodal disease AE NCT01740557
T-cell Therapy in Combination With Vemurafenib for Patients With BRAF Mutated Metastatic Melanoma CCIT, Copenhagen, Herlev, Denmark
Initiation 2014
I/II 12 Vem 960 b.i.d. 7d before tumor harvest until lymphodepletion (d − 8) + TIL + IL-2 4-6 weeks culture time
Infusion 1 × 109-2 × 1011 TIls
Cy 60 mg/kg for 2d + Flu 25 mg/m2 for 5 d Decrescendo regimen (18 MIU/m2 for 6 h, 18 MIU/m2 for 12 h, 18 MIU/m2 for 24 h followed by 4,5 MIU/m2 for another 3 × 24 h) Unresectable stage III/IV melanoma AE NCT02354690
Randomized Phase III Study Comparing a Non-myeloablative Lymphocyte Depleting Regimen of Chemotherapy Followed by Infusion of Tumor Infiltrating Lymphocytes and Interleukin-2 to Standard Ipilimumab Treatment in Metastatic Melanoma CCIT, Copenhagen, Herlev, Denmark
NKI, Amsterdam, Netherlands
Initiation 2014
III 168 Cohort 1: Ipi 4 cycles (i.v. 3 mg/kg q 3 weeks)
Cohort 2: Lymphodepletion + TIL + IL-2
Unspecified Cy 60 mg/kg iv for 2d + Flu 25 mg/m2 for 5d 600,000 IU/kg t.i.d., max 15 doses Unresectable stage III/IV melanoma PFS NCT02278887
A Pilot Study of Lymphodepletion Plus Adoptive Cell Transfer With TGF-beta Resistant (DNRII) and NGFR Transduced T-Cells Followed by High Dose Interleukin-2 in Participants With Metastatic Melanoma MD Anderson Cancer Center, Houston, Texas, US
Initiation 2014
Pilot 15 Lymphodepletion + transduced TIL + IL-2 Transduced DNRII TIL, equal number of transduced NGFR TIL, up to a total of 1.5 × 1011 TIL Cy 60 mg/kg i.v. for 2d + Flu 25 mg/m2 i.v. for 5d 720,000 IU/kg i.v. every 8–16 h max 15 doses on d 1–5 + 22–26 Metastatic melanoma or stage III in-transit, subcutaneous, or regional nodal disease (turnstile I) Feasibility NCT01955460
A Phase II Study for Metastatic Melanoma Using High Dose Chemotherapy Preparative Regimen Followed by Cell Transfer Therapy Using Tumor Infiltrating Lymphocytes Plus IL-2 With the Administration of Pembrolizumab in the Retreatment Arm NIH, Bethesda, Maryland, US
Initiation 2013
II 64 Cohort 1: Lymphodepletion + TIL + IL-2
Cohort 2 Retreatment Arm: 4 doses pembro
Non-responders of patients with PR/CR and progress with prior pembro/nivo treatment may receive a second treatment.
D 0 (2–4 d after last dose of flu), Pembro 2 mg/kg i.v. +/−  4 h prior to cell infusion. D 21 (+/−  2 d) following cell infusion, Pembro 2 mg/kg i.v. D 42 (+/−  2 d) following cell infusion, Pembro 2 mg/kg IV. D 63 (+/−  2 d) following cell infusion, Pembro 2 mg/kg i.v.
Young TIL Cy 60 mg/kg/day for 2 d + Flu 25 mg/m2 i.v. for 5 d 720,000 IU/kg i.v. t.i.d., max 12 doses Measurable metastatic melanoma ORR NCT01993719
A Phase I Study to Evaluate Safety, Feasibility and Immunologic Response of Adoptive T Cell Transfer With or Without Dendritic Cell Vaccination in Patients With Metastatic Melanoma Karolinska University Hospital Stockholm, Sweden
Initiation 2013
I 10 Cohort 1: Lymphodepletion + TIL + IL-2
Cohort 2: Lymphodepletion
+ TIL + IL-2 + i.d. DC vaccinations with up to 1.5 × 107 DC pulsed with autologous tumor lysate and NY-ESO-1 peptide after completion of IL-2
Up to 5 × 1010 TILs i.v. infusion Cy 60 mg/kg i.v. (d − 7&-6) + Flu 25 mg/m2 i.v. (d − 5 to − 1) 100,000 IU/kg t.i.d., maximum 14 doses Inoperable stage III or stage IV melanoma Safety NCT01946373
Phase II Study Evaluating The Infusion Of Autologous Tumor-Infiltrating Lymphocytes (TILs) And Low-Dose Interleukin-2 (IL-2) Therapy Following A Preparative Regimen Of Non-Myeloablative Lymphodepletion Using Cyclophosphamide And Fludarabine In Patients With Metastatic Melanoma Princess Margaret Cancer Centre Toronto, Ontario, Canada
Initiation 2013
II 12 Lymphodepletion + TIL + IL-2 1 × 1010–1.6 × 1011 TILs Cy 60 mg/kg i.v. for 2 d + Flu 25 mg/m2 i.v. for 5 d 125,000 IU/kg/d for 2 w (2 d rest between each w) Measurable, unresectable stage III/IV melanoma ORR NCT01883323
Lymphodepletion Plus Adoptive Cell Transfer With or Without Dendritic Cell Immunization in Patients With Metastatic Melanoma MD Anderson Cancer Center Houston, Texas, US
Initiation 2006
II 189 Cohort 1: Lymphodepletion + TIL + IL-2
Cohort 2: Lymphodepletion + TIL infusion + IL-2 + 1 × 107–2.5 × 108 MART-1 peptide-pulsed DC i.v.
Cohort 3 Prior treatment with BRAF-inhibitor: Lymphodepletion followed by TIL + IL-2 + 1 × 107–2.5 × 108MART-1 peptide-pulsed DC i.v.
Cohort 4 Leptomeningeal Disease: TIL d 1 + d 15
Cohort 1–3: Up to 1.5 × 1011 TIL
Cohort 4: 5.0 × 109 TIL on d 1 + 10 × 109TIL on d 15
Cy 60 mg/kg for 2 d + Flu 25 mg/m2 for 5d Cohort 1–3:
720,000 IU/kg every 8–16 h, max doses on d 1–5 + 22–26 (+/−  7 d), as tolerated
Cohort 4: 1.2 MIU of IL- 2 on d 2, 4, 9, 11, 16 and 18 as tolerated. Subsequently 2×/w IL-2 to weekly IL-2. After 4–6 w IL-2 maintenance
Metastatic melanoma, uveal melanoma or stage III in-transit or regional nodal disease ORR NCT00338377
b. Trials not yet recruiting
A Phase 2 Study to Evaluate the Efficacy and Safety of Adoptive Transfer of Autologous Tumor Infiltrating Lymphocytes in Patients With Metastatic Uveal Melanoma UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, US
Initiation 2018
II 59 Lymphodepletion + TIL + HD IL-2 1 × 109 - 2 × 1011 TIL per current standard protocol Cy and Flu (not otherwise specified) 600,000 IU/kg t.i.d. max 6 doses Measurable metastatic uveal melanoma ORR NCT03467516
A Randomised Phase II Study in Metastatic Melanoma to Evaluate the Efficacy of Adoptive Cellular Therapy With Tumor Infiltrating Lymphocytes (TIL) and Assessment of High Versus Low Dose Interleukin-2 The Christie NHS Foundation Trust, Manchester, UK
Initiation 2013
II 90 Arm A: lymphodepletion + TIL + HD IL-2
Arm B: lymphodepletion + TIL + LD IL-2
Unscpecified Cy 60 mg/kg 2 d + Flu 25 mg/m25 d Arm A: HD IL-2, max 12 doses
Arm B: LD IL-2, max 12 doses
Metastatic melanoma ORR NCT01995344
c. Non-recruiting Trials
T Cell Therapy in Combination With Peginterferon for Patients With Metastatic Melanoma CCIT, Copenhagen, Herlev, Denmark
Initiation 2014
I/II 12 Lymphodepletion + TIL + IL-2 + s.c. injections of peginterferon- α 3× (d − 2, d 7 and d 14) 4-6 weeks culture time
Maximum number of TILs
Cy 60 mg/kg i.v for 2d + Flu 25 mg/m2 i.v for 5d Continuous infusion decrescendo regimen (18 MIU/m2 IL-2 over 6 h, 18 MIU/m2 IL-2 over 12 h, 18 MIU/m2 IL-2 over 24 h followed by 4.5 MIU/m2 IL-2 over 24 h for 3d Unresectable stage III/IV melanoma AE NCT02379195
Cellular Adoptive Immunotherapy Using Autologous Tumor-infiltrating Lymphocytes
Following Lymphodepletion With Cyclophosphamide and Fludarabine for Patients With Metastatic Melanoma
University of Washington Cancer Consortium, Seattle, Washington, US
Initiation 2013
II 13 Lymphodepletion + TIL + IL-2 Unspecified Cy for 2d + Flu for 5d (not otherwise specified) Unspecified Stage III/IV melanoma ORR NCT01807182
Co-stimulation With Ipilimumab to Enhance Lymphodepletion Plus Adoptive Cell Transfer and High Dose IL-2 in Patients With Metastatic Melanoma Moffitt Cancer Center and Research Institute, Tampa, Florida, US
Initiation 2012
Pilot 13 Pre-treatment with ipi (cycle 1) prior to surgery to retrieve TILs. Cycle 2 of ipi 1 w after surgery (3 w after 1st cycle) followed by Lymphodepletion + TIL + IL-2 6 weeks outgrowth Cy for 2d + Flu for 5d (not otherwise specified) HD IL-2, otherwise unspecified. T.i.d., max 15 doses Unresectable stage III/IV melanoma Safety Feasibility NCT01701674
Phase II Clinical Trial of Vemurafenib With Lymphodepletion Plus Adoptive Cell Transfer and High Dose IL-2 in Patients With Metastatic Melanoma Moffitt Cancer Center and Research Institute, Tampa, Florida, US
Initiation 2012
II 17 Vem (3w prior to TIL + post TIL for 2 yr) followed by Lymphodepletion + TIL infusion + IL-2 Unspecified Cy for 2d + Flu for 5d (not otherwise specified) HD IL-2 (not otherwise specified) Unresectable metastatic stage IV melanoma or stage III intransit or regional nodal disease ORR Dropout rate NCT01659151
Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Tumor Infiltratring Lymphocytes Plus IL-2 Following Non-Myeloablative Lymphocyte Depleting Chemo Regimen Alone or in Conjunction With 12Gy Total Body Irradiation (TBI) NIH, Bethesda, Maryland, US
Initiation 2011
II 102 Cohort 1: Lymphodepletion + TIL + IL-2
Cohort 2: Lymphodepletion followed by TBI + TIL + IL-2
Cohort 1 + 2: 1 × 109-2 × 1011young TILs Cohort 1 + 2: Cy 60 mg/kg for 2 d + Flu 25 mg/m2 for 5 d
Cohort 2: 2Gy of TBI 2×/day for 3d (total dose 12Gy) 3d prior to TIL infusion
Cohort 1 + 2: 720,000 IU/kg i.v. t.i.d., max 15 doses Measurable metastatic melanoma ORR NCT01319565
Lymphodepletion Plus Adoptive Cell Transfer With High Dose IL-2 in Patients With Metastatic Melanoma Moffitt Cancer Center, Tampa, Florida, US
Initiation 2009
I/II 19 Lymphodepletion + TIL + IL-2 Unspecified Cyc 60 mg/kg for 2d + Flu 25 mg/m2 for 5d 720,000 IU/kg i.v. t.i.d max 15 doses Unresectable stage III/IV melanoma Feasibility NCT01005745
  1. Abbreviations: AE adverse event, b.i.d. bis in die, CCIT Center for Cancer Immune Therapy, CD Cluster of differentiation, CHUV Centre hospitalier universitaire Vaudois, CR complete response, CXCR C-X-C chemokine receptor, Cy cyclophosphamide, d day, DC dendritic cell, Flu fludarabine, Gy Gray, HD high-dose, hr hour, i.d intradermal, i.v. intravenous, IL-2 interleukin-2, Ipi ipilimumab, IU international unit, kg kilogram, LD low dose, LN-144 TIL production technology developed by Iovance Biotherapeutics, MART-1 Melanoma antigen recognized by T cells 1, max maximum, mg milligram, NA not available, NGFR nerve growth factor receptor, NHS National Health Service, NIH National Institutes of Health, Nivo nivolumab, NKI National Cancer Institute, ORR objective response rate, PD progressive disease, PD-1 Programmed cell death protein-1, PDL-1 Programmed death ligand-1, Pembro pembrolizumab, PFS progression free survival, PR partial response, q every, RR response rate, s.c. subcutaneous, t.i.d. ter in die, TBI total body irradiation, TIL tumor-infiltrating lymphocytes, UK United Kingdom, UPMC Universite Pierre and Marie Curie, US United States, Vem vemurafenib, w week, x times, yr year