A phase I study of the natural killer T-cell ligand α-galactosylceramide (KRN7000) in patients with solid tumors

Giuseppe Giaccone, Cornelis J A Punt, Yoshitaka Ando, Rita Ruijter, Nobusuke Nishi, Marlies Peters, B. Mary E Von Blomberg, Rik J. Scheper, Hans J J Van der Vliet, Alfons J M Van den Eertwegh, Marja Roelvink, Jos Beijnen, Heinz Zwierzina, Herbert M. Pinedo

Research output: Contribution to journalArticlepeer-review


Purpose: α-galactosylceramide (KRN7000) is a glycosphingolipid that has been shown to inhibit tumor growth and to prolong survival in inoculated mice through activation of natural killer (NK) T cells. We performed a dose escalation study of KRN7000 in advanced cancer patients. Experimental Design: Patients with solid tumors received i.v. KRN7000 (50-4800 μg/m2) on days 1, 8, and 15 of a 4-weekly cycle. Patients were given 1 cycle and, in the absence of dose-limiting toxicity or progression, treatment was continued. Pharmacokinetics (PK) and immunomonitoring were performed in all patients. Results: Twenty-four patients were entered into this study. No dose-limiting toxicity was observed over a wide range of doses (50-4800 μg/m2). PK was linear in the dose range tested. Immunomonitoring demonstrated that NKT cells (CD3+Vα24+Vβ11+) typically disappeared from the blood within 24 h of KRN7000 injection. Additional biological effects included increased serum cytokine levels (tumor necrosis factor α and granulocyte macrophage colony-stimulating factor) in 5 of 24 patients and a transient decrease in peripheral blood NK cell numbers and cytotoxicity in 7 of 24 patients. Importantly, the observed biological effects depended on pretreatment NKT-cell numbers rather than on the dose of KRN7000. Pretreatment NKT-cell numbers were significantly lower in patients compared with healthy controls (P = 0.0001). No clinical responses were recorded and seven patients experienced stable disease for a median duration of 123 days. Conclusion: i.v. KRN7000 is well tolerated in cancer patients over a wide range of doses. Biological effects were observed in several patients with relatively high pretreatment NKT-cell numbers. Other therapeutic strategies aiming at reconstitution of the deficient NKT-cell population in cancer patients may be warranted.

Original languageEnglish (US)
Pages (from-to)3702-3709
Number of pages8
JournalClinical Cancer Research
Issue number12
StatePublished - Dec 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology


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