title: Phase I study of BCX1777 (forodesine) in patients with relapsed or refractory peripheral T/natural killer-cell malignancies.
abstract: BCX1777 (forodesine), a novel purine nucleoside phosphorylase inhibitor, induces apoptosis, mainly in T cells. To evaluate the safety, tolerability, and pharmacokinetics of BCX1777, we conducted a phase I study in patients with relapsed or refractory peripheral T/natural killer-cell malignancies. Eligible patients had relapsed or refractory peripheral T/natural killer-cell malignancies without any major organ dysfunction. BCX1777 was administered orally once daily (dose escalation: 100, 200, and 300 mg) until disease progression requiring new therapy or unacceptable adverse events occurred. A total of 13 patients were enrolled and treated in three dose cohorts (100 mg/day, five patients; 200 mg/day, three patients; 300 mg/day, five patients). Although none of the patients developed dose-limiting toxicities, further dose escalation was not performed based on data from overseas. Therefore, the maximum tolerated dose was not determined. Adverse events of grade 3 or greater (≥2 patients) included lymphopenia (62%), anemia (15%), leukopenia (8%), and pyrexia (8%). Plasma pharmacokinetics parameter of BCX1777 (area under the plasma concentration-time curve) at day 1 in each cohort was 1948 ± 884, 4608 ± 1030, and 4596 ± 939 ng•h/mL, respectively. Disease control was achieved in approximately half of patients. One patient with anaplastic large cell lymphoma, which was negative for anaplastic lymphoma kinase, achieved a complete response, and two patients with cutaneous T-cell lymphoma achieved partial responses. BCX1777 was well tolerated at doses up to 300 mg once daily and showed preliminary evidence of activity in relapsed or refractory peripheral T/natural killer-cell malignancies, warranting further investigation.
authors.affiliation: Department of Hematology and Oncology, Nagoya Daini Red Cross Hospital, Nagoya, Japan. mi-ogura@naa.att.ne.jp
authors.forename: Michinori
authors.initials: M
authors.lastname: Ogura
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Tsukasaki
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Nagai
authors.forename: Toshiki
authors.initials: T
authors.lastname: Uchida
authors.forename: Takashi
authors.initials: T
authors.lastname: Oyama
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Suzuki
authors.forename: Jun
authors.initials: J
authors.lastname: Taguchi
authors.forename: Dai
authors.initials: D
authors.lastname: Maruyama
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Hotta
authors.forename: Kensei
authors.initials: K
authors.lastname: Tobinai
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy; D016399:Lymphoma, T-Cell / Q000188:drug therapy*; D016411:Lymphoma, T-Cell, Peripheral / Q000188:drug therapy; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009182:Mycosis Fungoides / Q000188:drug therapy; D055611:Natural Killer T-Cells / Q000473:pathology*; D011684:Purine Nucleosides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012008:Recurrence; D012878:Skin Neoplasms / Q000188:drug therapy; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D011684:Purine Nucleosides; D011744:Pyrimidinones; C113101:forodesine