Current Trials with Tumor-infiltrating Lymphocytes in Melanoma Registered by ClinicalTrials.gov per March 2018
| 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, FranceInitiation 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, SwitzerlandInitiation 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, IsraelInitiation 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 | ORRAE | 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, CanadaInitiation 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 + Flu25 mg/m2 for 5 dCohort 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, USInitiation 2016 | Pilot | 12 | Cohort 1 (1st 6 patients): Lymphodepletion + TIL + IL-2Cohort 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, USInitiation 2015 | II | 170 | Cohort 1 Arm 1 Anti-PD1/PD-L1 refractory patients: Lymphodepletion + TIL + IL-2Cohort 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-2Cohort 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-2Cohort 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, USInitiation 2015 | II | 60 | Cohort 1: Lymphodepletion + TIL + IL-2Cohort 2: Lymphodepletion + TIL + IL-2Cohort 3: re-treatment lymphodepletion + TIL + IL-2 | Cohort 1: LN-144 autologous TIL non-cryopreserved productCohort 2: LN-144 autologous TIL cryopreservedCohort 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, USInitiation 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, DenmarkInitiation 2014 | I/II | 12 | Vem 960 b.i.d. 7d before tumor harvest until lymphodepletion (d − 8) + TIL + IL-2 | 4-6 weeks culture timeInfusion 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, DenmarkNKI, Amsterdam, NetherlandsInitiation 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, USInitiation 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, USInitiation 2013 | II | 64 | Cohort 1: Lymphodepletion + TIL + IL-2Cohort 2 Retreatment Arm: 4 doses pembroNon-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, SwedenInitiation 2013 | I | 10 | Cohort 1: Lymphodepletion + TIL + IL-2Cohort 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, CanadaInitiation 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, USInitiation 2006 | II | 189 | Cohort 1: Lymphodepletion + TIL + IL-2Cohort 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 TILCohort 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 toleratedCohort 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, USInitiation 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, UKInitiation 2013 | II | 90 | Arm A: lymphodepletion + TIL + HD IL-2Arm 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 dosesArm 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, DenmarkInitiation 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 timeMaximum 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 LymphocytesFollowing Lymphodepletion With Cyclophosphamide and Fludarabine for Patients With Metastatic Melanoma | University of Washington Cancer Consortium, Seattle, Washington, USInitiation 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, USInitiation 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, USInitiation 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, USInitiation 2011 | II | 102 | Cohort 1: Lymphodepletion + TIL + IL-2Cohort 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 dCohort 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, USInitiation 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 |
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