TY - JOUR
T1 - A phase I study of the natural killer T-cell ligand α-galactosylceramide (KRN7000) in patients with solid tumors
AU - Giaccone, Giuseppe
AU - Punt, Cornelis J A
AU - Ando, Yoshitaka
AU - Ruijter, Rita
AU - Nishi, Nobusuke
AU - Peters, Marlies
AU - Von Blomberg, B. Mary E
AU - Scheper, Rik J.
AU - Van der Vliet, Hans J J
AU - Van den Eertwegh, Alfons J M
AU - Roelvink, Marja
AU - Beijnen, Jos
AU - Zwierzina, Heinz
AU - Pinedo, Herbert M.
PY - 2002/12/1
Y1 - 2002/12/1
N2 - 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.
AB - 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.
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M3 - Article
C2 - 12473579
AN - SCOPUS:0036896332
SN - 1078-0432
VL - 8
SP - 3702
EP - 3709
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 12
ER -