title: Phase 1 study of ixazomib alone or combined with lenalidomide-dexamethasone in Japanese patients with relapsed/refractory multiple myeloma.
abstract: We report the first clinical investigation conducted in Japan to confirm the safety, tolerability, and pharmacokinetics of ixazomib alone and combined with lenalidomide-dexamethasone (Rd) in Japanese patients with relapsed/refractory multiple myeloma. Adult patients with measurable disease and ≥2 prior lines of therapy received oral ixazomib 4.0 mg on days 1, 8, 15 alone or combined with lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, 22 in 28-day cycles. Fourteen patients who had received a median of seven prior therapies were enrolled (seven per cohort). One of six evaluable patients in each cohort experienced dose-limiting toxicities [diarrhea, nausea, hypokalemia, hypertension, thrombocytopenia, hyponatremia (ixazomib cohort); thrombocytopenia, and neutropenia (ixazomib + Rd cohort)]. The most common drug-related adverse events were neutropenia, thrombocytopenia, leukopenia, and lymphopenia. Drug-related grade ≥3 adverse events occurring in ≥3 patients per cohort were (ixazomib/ixazomib + Rd cohort, n): neutropenia (4/2), thrombocytopenia (3/2), and lymphopenia (5/2). Ixazomib was rapidly absorbed with a median Tmaxof approximately 1-2-h post-dose, and had a geometric mean terminal half-life of 5-6 days. Of 13 response-evaluable patients, one achieved a partial response (duration ∼38 weeks; ixazomib cohort) and seven had stable disease.
authors.affiliation: Department of Hematology, Japanese Red Cross Medical Center, 4-1-22 Hiroo Shibuya-ku, Tokyo, 150-8935, Japan. ken-suzuki@mtb.biglobe.ne.jp.
authors.forename: Kenshi
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Medicine and Clinical Science, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Handa
authors.affiliation: Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Chou
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishizawa
authors.affiliation: Clinical Pharmacology Department, Takeda Development Center Japan, Takeda Pharmaceutical Company Limited, Osaka, Japan.
authors.forename: Takatoshi
authors.initials: T
authors.lastname: Takubo
authors.affiliation: Oncology Clinical Research Department, Oncology Therapeutic Area Unit for Japan and Asia, Takeda Pharmaceutical Company Limited, Osaka, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kase
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D044466:Asian People; D001896:Boron Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003907:Dexamethasone / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D000077269:Lenalidomide; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy; D061988:Proteasome Inhibitors / Q000008:administration & dosage; D012008:Recurrence; D016879:Salvage Therapy / Q000009:adverse effects / Q000379:methods*; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D001896:Boron Compounds; D061988:Proteasome Inhibitors; D013792:Thalidomide; C548400:ixazomib; D003907:Dexamethasone; D000077269:Lenalidomide; D005998:Glycine
keywords: Ixazomib; Japan; Multiple myeloma; Pharmacokinetics; Safety