Study Comparing TIL to Standard Ipilimumab in Patients With Metastatic Melanoma

NCT02278887 | Completed Phase 3 DMC

• 1 other identifier: M14TIL
• Study Type: interventional
• Target: 168
• Locations: 2 countries
• Sites: 2

Brief Summary

In this randomized controlled phase III study the investigators will evaluate whether TIL infusion preceded by non-myeloablative chemotherapy and followed by high dose bolus interleukin-2 can result in an improved progression free survival when randomly compared to ipilimumab in 168 stage IV melanoma patients. A health technology assessment (HTA) will be performed to evaluate the impact of the TIL treatment on patients and organizational processes and cost-effectivity.

Conditions

Metastatic Melanoma

Keywords

melanoma; TIL treatment; tumor infiltrating lymphocytes; ipilimumab; interleukin 2; non-myeloablative; randomization

Outcome Measures

Primary Outcomes (1)

• Progression free survival

  Progression free survival according to RECIST 1.1

  3 years

Secondary Outcomes (1)

• Immune related progression free survival

  3 years

Other Outcomes (1)

• Safety

  3 years

Study Arms (2)

Ipilimumab

ACTIVE COMPARATOR

4 cycles of ipilimumab treatment, the standard treatment

Procedure: Translational research; Drug: Ipilimumab infusion

TIL treatment

EXPERIMENTAL

non-myeloablative lymphocyte depleting regimen of chemotherapy followed by infusion of tumor infiltrating lymphocytes and interleukin-2

Procedure: Translational research; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Interleukin-2

Interventions

Translational research PROCEDURE

Before during and at progression/regression biopsies and blood will be taken for translational research

Also known as: tumor tissue, blood

Ipilimumab; TIL treatment

Cyclophosphamide DRUG

The patient receives 2 days cyclophosphamide via IV to deplete T-cells.

Also known as: chemotherapy

TIL treatment

Fludarabine DRUG

The patient receives 5 days fludarabine via IV to deplete T-cells.

Also known as: chemotherapy

TIL treatment

Interleukin-2 DRUG

After infusion of the TIL, the patient receives IL-2 to keep the TIL active.

Also known as: Proleukin

TIL treatment

Ipilimumab infusion DRUG

In arm A patients will be treated with 4 infusion of ipilimumab

Also known as: standard treatment

Ipilimumab

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed unresectable AJCC stage III or stage IV melanoma
• Patients must have metastatic melanoma with a resectable metastatic lesion(s) of sufficient size (≥ 2-3 cm in total) and must be willing to undergo such a resection for experimental purposes.
• Patients should have received maximum one line of systemic therapy (except for ipilimumab) for unresectable or metastatic melanoma.\[
• Patients must be ≥ 18 years and ≤ 75 years of age and must have measurable disease by CT or MRI per RECIST 1.1 criteria (in addition to the resected lesion).
• Patients must have a clinical performance status of ECOG 0 or 1.
• Patients of both genders must be willing to practice a highly effective method of birth control during treatment and for four months after receiving the preparative regimen.
• Patients must be able to understand and sign the Informed Consent document.

You may not qualify if:

• Life expectancy of less than three months.
• Patients with metastatic ocular/ mucosal or other non-cutaneous melanoma.
• Adjuvant treatment with ipilimumab within 6 months prior to randomization.
• 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.
• Patients who have a more than two CNS metastases.
• Patients who have any CNS lesion that is symptomatic, greater than 1 cm in diameter or show significant surrounding edema on MRI scan will not be eligible until they have been treated and demonstrated no clinical or radiologic CNS progression for at least 2 months.
• 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.
• Any autoimmune disease

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• Copenhagen University Hospital at Herlev: collaborator

Study Sites (2)

CCIT Department of Oncology and Haematology Herlev Hospital

Copenhagen, Denmark

Location

Netherlands Cancer Institute

Amsterdam, North Holland, 1066CX, Netherlands

Location

Related Publications (2)

• Tas L, Weitemeyer MB, Rohaan MW, Borch TH, van Akkooi ACJ, Wouters MWJM, Hartemink KJ, Schrage YM, Kuijpers A, Kok NFM, van Zon M, Jedema I, Nijenhuis CM, Nuijen B, Hansen M, Voermans C, Klobuch S, Seijkens TTP, Lalezari F, Met O, Donia M, Svane IM, Haanen JBAG, Holmich LR, van Houdt WJ. Surgical considerations for tumour-infiltrating lymphocyte therapy in melanoma: results from a randomized phase III trial. Br J Surg. 2025 May 31;112(6):znaf090. doi: 10.1093/bjs/znaf090.

  PMID: 40474841 DERIVED

• Rohaan MW, Borch TH, van den Berg JH, Met O, Kessels R, Geukes Foppen MH, Stoltenborg Granhoj J, Nuijen B, Nijenhuis C, Jedema I, van Zon M, Scheij S, Beijnen JH, Hansen M, Voermans C, Noringriis IM, Monberg TJ, Holmstroem RB, Wever LDV, van Dijk M, Grijpink-Ongering LG, Valkenet LHM, Torres Acosta A, Karger M, Borgers JSW, Ten Ham RMT, Retel VP, van Harten WH, Lalezari F, van Tinteren H, van der Veldt AAM, Hospers GAP, Stevense-den Boer MAM, Suijkerbuijk KPM, Aarts MJB, Piersma D, van den Eertwegh AJM, de Groot JB, Vreugdenhil G, Kapiteijn E, Boers-Sonderen MJ, Fiets WE, van den Berkmortel FWPJ, Ellebaek E, Holmich LR, van Akkooi ACJ, van Houdt WJ, Wouters MWJM, van Thienen JV, Blank CU, Meerveld-Eggink A, Klobuch S, Wilgenhof S, Schumacher TN, Donia M, Svane IM, Haanen JBAG. Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma. N Engl J Med. 2022 Dec 8;387(23):2113-2125. doi: 10.1056/NEJMoa2210233.

  PMID: 36477031 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Blood Specimen Collection; Cyclophosphamide; Drug Therapy; fludarabine; Interleukin-2; aldesleukin

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Therapeutics; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• John B.A.G. Haanen, Prof.

  The Netherlands Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 3, 2014
• First Posted: October 30, 2014
• Study Start: September 23, 2014
• Primary Completion: September 1, 2022
• Study Completion: December 31, 2023
• Last Updated: March 10, 2025

Record last verified: 2025-03

Locations

NL (1); DK (1)