Study Comparing TIL to Standard Ipilimumab in Patients With Metastatic Melanoma

NCT ID: NCT02278887

Last Updated: 2025-03-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 168 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-09-23
• Study Completion Date: 2023-12-31

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.

Detailed Description

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. This will be done via questionnaires at baseline, just after treatment and during follow-up. Also healthcare providers will be interviewed after 6 months after starting the trial.

Conditions

Metastatic Melanoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ipilimumab

4 cycles of ipilimumab treatment, the standard treatment

Group Type: ACTIVE_COMPARATOR

Translational research

Intervention Type: PROCEDURE

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

Ipilimumab infusion

Intervention Type: DRUG

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

TIL treatment

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

Group Type: EXPERIMENTAL

Translational research

Intervention Type: PROCEDURE

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

Cyclophosphamide

Intervention Type: DRUG

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

Fludarabine

Intervention Type: DRUG

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

Interleukin-2

Intervention Type: DRUG

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

Interventions

Translational research

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

Intervention Type: PROCEDURE

Cyclophosphamide

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

Intervention Type: DRUG

Fludarabine

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

Intervention Type: DRUG

Interleukin-2

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

Intervention Type: DRUG

Ipilimumab infusion

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

Intervention Type: DRUG

Other Intervention Names

tumor tissue; blood; chemotherapy; chemotherapy; Proleukin; standard treatment

Eligibility Criteria

Inclusion Criteria

• 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.

Exclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Copenhagen University Hospital at Herlev

OTHER

Sponsor Role: collaborator

The Netherlands Cancer Institute

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

John B.A.G. Haanen, Prof.

Role: PRINCIPAL_INVESTIGATOR

The Netherlands Cancer Institute

Locations

CCIT Department of Oncology and Haematology Herlev Hospital

Copenhagen, , Denmark

Netherlands Cancer Institute

Amsterdam, North Holland, Netherlands

Countries

Denmark; Netherlands

References

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.

Reference Type: DERIVED

PMID: 40474841 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36477031 (View on PubMed)

Other Identifiers

M14TIL

Identifier Type: -

Identifier Source: org_study_id