Randomized phase III study comparing non-myeloablative lymphocyte depleting regimen of chemotherapy followed by infusion of tumor-infiltrating lymphocytes and interleukin-2 to standard ipilimumab treatment in metastatic melanoma

Marnix H. Geukes Foppena, Marco Doniac, Troels Holz Borchc, Özcan Metc, Joost H. van den Bergd, Christian U. Blanka, Loes Pronkb, Johannes V. van Thienena, Inge Marie Svanec and John B.A.G. Haanena

a Netherlands Cancer Institute, Department of Medical Oncology, Amsterdam, The Netherlands

b Netherlands Cancer Institute, Department of Biometrics, Amsterdam, The Netherlands

c Center for Cancer Immune Therapy, Department of Haematology and Oncology, Herlev Hospital, Herlev, Denmark

d Amsterdam Biotherapeutics Unit, Amsterdam, The Netherlands

 

Corresponding author: M. Geukes Foppen, m.geukes@nki.nl


Background

Historically, patients with metastatic melanoma had an extremely poor prognosis with a median overall survival (OS) of 6 to 9 months. In 2010, the CTLA4 blocking antibody ipilimumab, showed for the first time, an improvement in median OS and was approved for this stage of disease. Yet, only around 20% of the treated patients benefit long-term. In addition, ipilimumab can cause serious, sometimes life-threatening side-effects and puts a high burden on health costs.

Adoptive transfer of tumor-infiltrating lymphocytes (TIL) is another promising new treatment modality for patients with metastatic melanoma. Several independent phase II studies have shown comparable and consistent response rates of around 50%, with very durable responses in patients reaching a complete remission. TIL therapy consists of infusion of high numbers of ex vivo expanded TIL preceded by non-myeloablative (NMA) chemotherapy and followed by high dose interleukin-2 (HD IL-2).

Methods

This is an international, open-label, multi-center, phase III study. Patients with irresectable stage IIIc or IV melanoma, between the ages of 18 and 70 years, with one or more resectable metastases summing up to at least 2-3 cm in diameter and adequate organ function, are randomized 1:1 between TIL therapy and ipilimumab. Patients will be stratified according to BRAF V600 mutation status, line of treatment (1st or 2nd line) and treatment center. Patients randomized to TIL will receive NMA chemotherapy consisting of cyclophosphamide (60 mg/kg/day for 2 days i.v.) and fludarabine (50 mg/m2 for 5 days i.v.), intravenous adoptive transfer of > 5x109 TIL followed by HD IL-2 (600.000 IU/kg/dose every 8 hours, maximally 15 doses). Patients randomized to ipilimumab (3 mg/kg i.v.) will receive this once every three weeks, for up to 4 doses. The primary end-point is progression free survival at six months. Secondary endpoints are OS, complete response rate, ORR and safety profile. Enrollment began in September 2014. 168 randomized patients are required to show a 50% increase in PFS at 6 months. 

 (Clinicaltrials.gov ID NCT02278887)


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