K Yamazaki1, T Doi2, M Ikeda2, T Okusaka3, A Schueler4, M Watanabe5, A Ohtsu2. 1. Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan. k.yamazaki@scchr.jp. 2. National Cancer Center Hospital East, Kashiwa, Japan. 3. National Cancer Centre Hospital, Tokyo, Japan. 4. Merck Healthcare KGaA, Darmstadt, Germany. 5. Merck Serono Co Ltd, Tokyo, Japan.
Abstract
PURPOSE: This study aimed to confirm the recommended phase II dose (RP2D) of pimasertib in Japanese patients. METHODS: This two-part, phase I dose-escalation and expansion study was conducted in Japanese patients (≥ 18 years old) with advanced solid tumors (ST) including hepatocellular carcinoma (HCC). In Part 1, patients with ST (Arm A) and HCC (Arm B) received escalating doses (3 + 3 design) of oral pimasertib [starting at 45 mg twice daily (BID)] in 21-day cycles, until disease progression or unacceptable toxicity. Dose levels could be escalated/de-escalated depending on tolerance. The primary outcome was the number of patients who experienced ≥ 1 dose-limiting toxicity (DLT). Safety and efficacy were also studied. Part 2 aimed to confirm observations in Part 1. RESULTS: In total, 26 patients (ST, n = 19; HCC, n = 7) were treated with pimasertib in Part 1: 30 mg (ST, n = 4; HCC, n = 5), 45 mg (ST, n = 9; HCC, n = 2), and 60 mg (ST, n = 6). Four patients reported DLTs [ST: hypokalemia (60 mg), and both stomatitis and muscle weakness (60 mg); HCC: retinal detachment (30 mg) and diarrhea (45 mg)]. All patients had ≥ 1 treatment-related adverse event. Partial response (n = 3) and stable disease (n = 1) were seen in patients with ST (pimasertib 45 mg). CONCLUSION: A maximum tolerated dose of pimasertib 45 mg BID was established in Japanese patients with ST, but not established in patients with HCC. The global RP2D of 60 mg BID was not confirmed in Japanese patients. Pimasertib monotherapy in unselected patients with ST may not warrant further investigation; Part 2 was not conducted.
PURPOSE: This study aimed to confirm the recommended phase II dose (RP2D) of pimasertib in Japanese patients. METHODS: This two-part, phase I dose-escalation and expansion study was conducted in Japanese patients (≥ 18 years old) with advanced solid tumors (ST) including hepatocellular carcinoma (HCC). In Part 1, patients with ST (Arm A) and HCC (Arm B) received escalating doses (3 + 3 design) of oral pimasertib [starting at 45 mg twice daily (BID)] in 21-day cycles, until disease progression or unacceptable toxicity. Dose levels could be escalated/de-escalated depending on tolerance. The primary outcome was the number of patients who experienced ≥ 1 dose-limiting toxicity (DLT). Safety and efficacy were also studied. Part 2 aimed to confirm observations in Part 1. RESULTS: In total, 26 patients (ST, n = 19; HCC, n = 7) were treated with pimasertib in Part 1: 30 mg (ST, n = 4; HCC, n = 5), 45 mg (ST, n = 9; HCC, n = 2), and 60 mg (ST, n = 6). Four patients reported DLTs [ST: hypokalemia (60 mg), and both stomatitis and muscle weakness (60 mg); HCC: retinal detachment (30 mg) and diarrhea (45 mg)]. All patients had ≥ 1 treatment-related adverse event. Partial response (n = 3) and stable disease (n = 1) were seen in patients with ST (pimasertib 45 mg). CONCLUSION: A maximum tolerated dose of pimasertib 45 mg BID was established in Japanese patients with ST, but not established in patients with HCC. The global RP2D of 60 mg BID was not confirmed in Japanese patients. Pimasertib monotherapy in unselected patients with ST may not warrant further investigation; Part 2 was not conducted.