title: Phase Ia/Ib study of the pan-class I PI3K inhibitor pictilisib (GDC-0941) administered as a single agent in Japanese patients with solid tumors and in combination in Japanese patients with non-squamous non-small cell lung cancer.
abstract: Pictilisib (GDC-0941) is an oral class I phosphatidylinositol-3-phosphate kinase inhibitor. This phase Ia/Ib study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of pictilisib in monotherapy or in combination with carboplatin-paclitaxel and bevacizumab (CP + BEV) in Japanese patients with advanced solid tumors or non-squamous non-small cell lung cancer. A standard 3 + 3 dose escalation design was applied. In stage 1, 140, 260, or 340 mg/day of pictilisib was administered once daily to 12 patients with advanced solid tumors. In stage 2, 260 or 340 mg/day of pictilisib was administered in combination with CP + BEV to 7 patients with advanced non-squamous non-small cell lung cancer. In stage 1, 1 of 6 patients in the 340 mg/day cohort exhibited dose limiting toxicity (DLT) of grade 3 maculopapular rash. The maximum plasma concentration and area under the curve of pictilisib were dose-dependent. A reduction in phosphorylated AKT in platelet rich plasma was observed. No patient had an objective anti-tumor response. In stage 2, DLT was observed in 1 of 3 patients in the 260 mg/day cohort (grade 3 febrile neutropenia), and 2 of 4 patients in the 340 mg/day cohort (1 each of grade 3 febrile neutropenia and grade 3 febrile neutropenia/erythema multiforme). Partial responses were observed in 3 out of 7 patients. In conclusion, pictilisib was shown to have good safety and tolerability in Japanese patients with advanced solid tumors. A recommended dose of pictilisib in monotherapy was determined to be 340 mg once daily. For combination with CP + BEV, tolerability up to 260 mg/day was confirmed.
authors: Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan. nbryamam@ncc.go.jp.
authors: Noboru
authors: N
authors: Yamamoto
authors: Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
authors: Yutaka
authors: Y
authors: Fujiwara
authors: Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
authors: Kenji
authors: K
authors: Tamura
authors: Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
authors: Shunsuke
authors: S
authors: Kondo
authors: Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
authors: Satoru
authors: S
authors: Iwasa
authors: Department of Experimental Therapeutics, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 1040045, Japan.
authors: Yuko
authors: Y
authors: Tanabe
authors: Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Atsushi
authors: A
authors: Horiike
authors: Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Noriko
authors: N
authors: Yanagitani
authors: Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Satoru
authors: S
authors: Kitazono
authors: Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
authors: Michiyasu
authors: M
authors: Inatani
authors: Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
authors: Jun
authors: J
authors: Tanaka
authors: Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
authors: Makoto
authors: M
authors: Nishio
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D044466:Asian People; D000068258:Bevacizumab / Q000627:therapeutic use; D016190:Carboplatin / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007191:Indazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000627:therapeutic use; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D000970:Antineoplastic Agents; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; D000068258:Bevacizumab; D016190:Carboplatin; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel
keywords: Non-sq NSCLC; PI3K inhibitor; Phase Ia/Ib trial; Pictilisib; Solid tumor