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Advanced MelanomaPhase 1BaseTILNCT04165967

Adoptive Tumor-infiltrating Lymphocyte Transfer With Nivolumab for Melanoma

A Phase 1 study testing Combination of TIL Transfer with anti-PD-1 Therapy and low dose IL-2 in people with Advanced Melanoma, run by University Hospital, Basel, Switzerland at 1 site in Switzerland.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This study is to investigate safety and feasibility of a combination therapy of a tumor infiltrating lymphocytes (TIL) transfer with anti-programmed cell death protein (PD)-1 therapy in patients with metastatic melanoma that failed immunotherapy.Tumor-infiltrating lymphocytes will be expanded from resected melanoma… Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Advanced Melanoma
What is being tested?
Combination of TIL Transfer with anti-PD-1 Therapy and low dose IL-2
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
9 participants
Where
1 siteSwitzerland
Study dates
17 Sep 2020to 30 Mar 2023
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histologically confirmed unresectable or metastatic melanoma
  • At least 1 PD-1 targeted immunotherapy and BRAF inhibition in case of BRAF mutated melanoma
  • Resectable tumor mass and measurable disease by CT or MRI per RECIST 1.1 criteria (in addition to the resected lesion)
  • World Health Organization (WHO) clinical performance Status (ECOG) 0-1
  • Adequate organ function
  • Patients of both genders must be willing to practice a highly effective method of birth control during treatment and for five months after receiving the last dose of nivolumab for women and seven months for men
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  • Patients must be able to understand and sign the Informed consent document
  • Hematology: Absolute neutrophil count greater than 1.5 x 109/L without support of filgrastim. Platelet count greater than 100 x 109/L. Hemoglobin greater than 5 mmol/L, or 80 g/L.
  • Chemistry: Serum alanine aminotransferase (ALAT)/ aspartate transaminase (ASAT) less than 3 times the upper limit of normal, unless patients have liver metastases (< 5 times ULN). Serum creatinine clearance 50 ml/min or higher. Total Bilirubin less than or equal to 20 micromol/L, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 50 micromol/L. Lactate dehydrogenase (LDH) ≤ 2x ULN
  • Serology: Seronegative for HIV antibody. Seronegative for hepatitis B antigen, and hepatitis C antibody. Seronegative for syphilis.

Who cannot join

  • Life expectancy of less than three months
  • Patients with metastatic ocular/ mucosal or other non-cutaneous melanoma.
  • Requirement for immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone or equivalent) or other immunosuppressive drugs within the last 3 weeks prior to randomization
  • Uncontrolled central nervous system (CNS) metastases. Controlled CNS metastases must be for at least 4 weeks stable.
  • Documented Forced expiratory volume at one second (FEV1) less than or equal to 50% predicted for patients with:
  • A prolonged history of cigarette smoking (greater than 20 pack/year within the past 2 years)
Show all 12Show fewer
  • Symptoms of respiratory distress
  • All patients' toxicities due to prior non-systemic treatment must have recovered to a grade 1 or less. Patients may have undergone minor surgical procedures or focal palliative radiotherapy (to non-target lesions) within the past 4 weeks, as long as all toxicities have recovered to grade 1 or less.
  • Women who are pregnant or breastfeeding, because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
  • Any active systemic infections, coagulation disorders or other active major medical illnesses.
  • Contraindication for IL-2 or nivolumab (allergies etc.).
  • Any autoimmune disease: patients with a documented history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease are excluded from this study as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, autoimmune thyroiditis (e.g. Hashimoto's disease), autoimmune hepatitis, systemic progressive sclerosis (scleroderma), Systemic Lupus Erythematosus, autoimmune vasculitis (e.g., Wegener's Granulomatosis). Subjects with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barré Syndrome) are excluded from this study. Patients with vitiligo are eligible to enter the study

Trial locations and contacts

1 site in 1 country.

Switzerland1 site

  • Division of Medical Oncology and Cancer Immunology, University Hospital Basel

    Basel, 4031

Other trials in Switzerland

About this study

Official title: A Phase I Study of Adoptive Tumor-infiltrating Lymphocyte Transfer in Combination With Nivolumab in Patients With Advanced Melanoma

This study is to investigate safety and feasibility of a combination therapy of a tumor infiltrating lymphocytes (TIL) transfer with anti-programmed cell death protein (PD)-1 therapy in patients with metastatic melanoma that failed immunotherapy.Tumor-infiltrating lymphocytes will be expanded from resected melanoma samples from the patient and expanded TILs will be transferred to the patient after non-myeloablative chemotherapy with cyclophosphamide and fludarabine. TIL transfer will be combined with low dose Interleukin (IL)-2 and nivolumab anti-PD-1 treatment.

The study uses a personalized Investigational Medicinal Product (IMP), i.e. TIL product and in combination with IL-2 treatment and nivolumab.

Read the detailed description

Adoptive cell therapy has been previously shown to be an effective treatment option for patients with melanoma. Due to an immunosuppressive microenvironment, not all patients respond to this therapy. In this trial, the immune suppressive microenvironment will be targeted by adding a PD-1 blocking antibody in combination with a TIL Transfer. Tumor-infiltrating lymphocytes will be expanded from resected melanoma samples from the patient and expanded TILs will be transferred to the patient after non-myeloablative chemotherapy with cyclophosphamide and fludarabine. TIL transfer will be combined with low dose IL-2 and nivolumab anti-PD-1 treatment. The study uses a personalized IMP, i.e. TIL product and in combination with IL-2 treatment and nivolumab.

Being tested
Combination of TIL Transfer with anti-PD-1 Therapy and low dose IL-2
Keywords
Tumor-infiltrating Lymphocyte (TIL) Transfer, Nivolumab, metastatic melanoma, anti-PD-1 therapy, failed immunotherapy, personalized Investigational Medicinal Product (IMP)
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Combination of TIL Transfer with anti-PD-1 Therapy and low dose IL-2Drug

    Also called TIL Transfer, anti-PD-1 Therapy Nivolumab, low dose IL-2

    The study uses a personalized IMP, i.e. TIL product and in combination with IL-2 treatment and nivolumab.

    Day 0: Autologous TIL: (minimum 5 x 109 and up to a maximum of 2 x 1011 lymphocytes) administered intravenously over 20 to 30 minutes.

    Day 0: Interleukin-2 (Proleukin): 125.000 IU/kg/day s.c. for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing). Actual body weight will be used in calculating the dose of interleukin-2.

    Starting Day 14: Nivolumab application 240 mg i.v. over 30 minutes ever 2 weeks with a maximum to 2 years, or until disease progression or inacceptable toxicity.

Study groups in NCT04165967
Study groupRoleWhat they receive
Tumor-infiltrating lymphocyte product (TIL) transferExperimentalThe TIL product will be produced from excised tumor lesions from the patient. Expanded TILs will be transferred to the patient after non-myeloablative chemotherapy with cyclophosphamide and fludarabine. TIL transfer will be combined with low dose IL-2 and nivolumab anti-PD-1 treatment. The transplant product will be produced in the Good Manufacturing Practice (GMP) facility of the University Hospital in Basel. TIL transfer to Patient at Day 0.
Receives: Drug: Combination of TIL Transfer with anti-PD-1 Therapy and low dose IL-2

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Adverse Events

    Number of Adverse Events to analyze safety of the combination of TIL transfer with IL-2 therapy

    Measured: First 3 months during treatment

  2. Change in body temperature (Degree Celsius)

    Change in Vital signs ( body temperature) to analyze the safety of the combination of TIL transfer with IL-2 therapy

    Measured: at each treatment visit (Day 0, and for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing)

  3. Change in blood pressure (mmHg)

    Change in Vital signs ( blood pressure) to analyze the safety of the combination of TIL transfer with IL-2 therapy

    Measured: at each treatment visit (Day 0, and for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing)

  4. Change in heart beat (beats/minute)

    Change in Vital signs (heart beat) to analyze the safety of the combination of TIL transfer with IL-2 therapy

    Measured: at each treatment visit (Day 0, and for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing)

  5. Change in respiratory frequency (inspiration/minute)

    Change in Vital signs (respiratory frequency) to analyze the safety of the combination of TIL transfer with IL-2 therapy

    Measured: at each treatment visit (Day 0, and for maximum 12 days as inpatients with a 2 days break after the first 4-5 doses (maximum 10 days dosing)

  6. Change in full blood Counts (number of cells)

    Change in Laboratory Parameter (full blood counts) to analyze haematological toxicity

    Measured: at each treatment visit (every 2 weeks) from Day 0= Baseline to week 42

Secondary outcomes (8)

  1. Overall Response Rate (ORR) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT scan

    Changes of Tumor volume according to RECIST 1.1

    Measured: First 3 months after TIL administration

  2. Progression Free Survival (PFS)

    Progression free survival, defined as the time between registration to progression or death whichever occurs first.

    Measured: between pre-treatment and 3-months post-treatment

  3. Overall Survival (OS) defined as the time between registration to death due to any cause

    Overall survival will be measured from the beginning of the treatment to the death of the patient or to survival status analysis acquired during the last follow up.

    Measured: 2 years after TIL transfer

  4. Tumor response according to revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

    Tumor response according to revised Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria

    Measured: between pre-treatment and 3-months post-treatment

  5. Objective response rate (ORR)

    In order to assess the objective response rate CT scans and FDG-PET/CT scans will be performed. Response will be measured by best reduction of tumor volume according to RECIST 1.1

    Measured: 2 years after TIL transfer

  6. Number of Adverse Events according to CTCAE 4.0

    Overall Safety during whole treatment period analyzed by collection of Adverse Events according to CTCAE 4.0

    Measured: 2 years after TIL transfer

  7. Metabolic Response

    Response measured by 18FDG-uptake

    Measured: during the first 3 months after TIL transfer

  8. Number of Serious Adverse Events according to CTCAE 4.0

    Overall Safety during whole treatment period analyzed by collection of Serious Adverse Events according to CTCAE 4.0

    Measured: 2 years after TIL transfer

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Nov 2019
  2. Study start17 Sep 2020
  3. Primary completion30 Mar 2023
  4. Study completion30 Mar 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
Tumor-infiltrating infiltrate will be expanded from resected melanoma samples from the patient and expanded TILs will be transferred to the patient after non-myeloablative chemotherapy with cyclophosphamide and fludarabine. TIL transfer will be combined with low dose IL-2 and nivolumab anti-PD-1 treatment.
Masking
None (open label)
Enrolment
9 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04165967
Sponsor's protocol ID
2019-01908; me18Laeubli
Other IDs
2019
Acronym
BaseTIL
Status last verified
Aug 2023
First submitted
5 Nov 2019
Last updated
10 Apr 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Schadendorf D, van Akkooi ACJ, Berking C, Griewank KG, Gutzmer R, Hauschild A, Stang A, Roesch A, Ugurel S. Melanoma. Lancet. 2018 Sep 15;392(10151):971-984. doi: 10.1016/S0140-6736(18)31559-9.

    PubMed 30238891

  • Grob JJ, Garbe C, Ascierto P, Larkin J, Dummer R, Schadendorf D. Adjuvant melanoma therapy with new drugs: should physicians continue to focus on metastatic disease or use it earlier in primary melanoma? Lancet Oncol. 2018 Dec;19(12):e720-e725. doi: 10.1016/S1470-2045(18)30596-5.

    PubMed 30507438

  • Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbe C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. doi: 10.1056/NEJMoa1709684. Epub 2017 Sep 11.

    PubMed 28889792

  • Rosenberg SA. Karnofsky Memorial Lecture. The immunotherapy and gene therapy of cancer. J Clin Oncol. 1992 Feb;10(2):180-99. doi: 10.1200/JCO.1992.10.2.180. No abstract available.

    PubMed 1732421

  • Rosenberg SA. Progress in human tumour immunology and immunotherapy. Nature. 2001 May 17;411(6835):380-4. doi: 10.1038/35077246.

    PubMed 11357146

  • Rosenberg SA, Yannelli JR, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst. 1994 Aug 3;86(15):1159-66. doi: 10.1093/jnci/86.15.1159.

    PubMed 8028037

  • Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science. 1986 Sep 19;233(4770):1318-21. doi: 10.1126/science.3489291.

    PubMed 3489291

  • Mills CD, North RJ. Expression of passively transferred immunity against an established tumor depends on generation of cytolytic T cells in recipient. Inhibition by suppressor T cells. J Exp Med. 1983 May 1;157(5):1448-60. doi: 10.1084/jem.157.5.1448.

    PubMed 6189937

  • Fernandez-Cruz E, Woda BA, Feldman JD. Elimination of syngeneic sarcomas in rats by a subset of T lymphocytes. J Exp Med. 1980 Oct 1;152(4):823-41. doi: 10.1084/jem.152.4.823.

    PubMed 6968337

  • Greenberg PD, Kern DE, Cheever MA. Therapy of disseminated murine leukemia with cyclophosphamide and immune Lyt-1+,2- T cells. Tumor eradication does not require participation of cytotoxic T cells. J Exp Med. 1985 May 1;161(5):1122-34. doi: 10.1084/jem.161.5.1122.

    PubMed 3921652

  • Eberlein TJ, Rosenstein M, Rosenberg SA. Regression of a disseminated syngeneic solid tumor by systemic transfer of lymphoid cells expanded in interleukin 2. J Exp Med. 1982 Aug 1;156(2):385-97. doi: 10.1084/jem.156.2.385.

    PubMed 6980254

  • Overwijk WW, Theoret MR, Finkelstein SE, Surman DR, de Jong LA, Vyth-Dreese FA, Dellemijn TA, Antony PA, Spiess PJ, Palmer DC, Heimann DM, Klebanoff CA, Yu Z, Hwang LN, Feigenbaum L, Kruisbeek AM, Rosenberg SA, Restifo NP. Tumor regression and autoimmunity after reversal of a functionally tolerant state of self-reactive CD8+ T cells. J Exp Med. 2003 Aug 18;198(4):569-80. doi: 10.1084/jem.20030590.

    PubMed 12925674

  • Antony PA, Piccirillo CA, Akpinarli A, Finkelstein SE, Speiss PJ, Surman DR, Palmer DC, Chan CC, Klebanoff CA, Overwijk WW, Rosenberg SA, Restifo NP. CD8+ T cell immunity against a tumor/self-antigen is augmented by CD4+ T helper cells and hindered by naturally occurring T regulatory cells. J Immunol. 2005 Mar 1;174(5):2591-601. doi: 10.4049/jimmunol.174.5.2591.

    PubMed 15728465

  • Rooney CM, Smith CA, Ng CY, Loftin S, Li C, Krance RA, Brenner MK, Heslop HE. Use of gene-modified virus-specific T lymphocytes to control Epstein-Barr-virus-related lymphoproliferation. Lancet. 1995 Jan 7;345(8941):9-13. doi: 10.1016/s0140-6736(95)91150-2.

    PubMed 7799740

  • Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, Riddell SR. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. 1995 Oct 19;333(16):1038-44. doi: 10.1056/NEJM199510193331603.

    PubMed 7675046

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Combination of TIL Transfer with anti-PD-1 Therapy and low dose IL-2 in people with Advanced Melanoma, run by University Hospital, Basel, Switzerland at 1 site in Switzerland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Apr 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Adverse Events (time frame: First 3 months during treatment). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04165967, which also lists 33 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Apr 2024.

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