Phase I Trial of Lurbinectedin (PM1183) in Japanese Patients with Advanced Tumors: Results of the Dose Escalation Part.Presented Monday, June 4, 2018
Authors:
Shunji Takahashi, Toshio Shimizu, Toshihiko Doi, Jose Antonio Lopez-Vilariño, Rafael Nuñez, Carmen Maria Kahatt, Carlos Fernandez, Katrin Zaragoza, Hiromi Sasamoto, Arturo Soto-Matos; Cancer Institute Hospital of JFCR, Tokyo, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan; National Cancer Center Hospital, Chiba, Japan; PharmaMar, Madrid,... View More
Abstract Disclosures
Background:PM1183 (lurbinectedin, Zepsyre) is a new anticancer agent that inhibits activated transcription, induces DNA double-strand breaks leading to apoptosis and modulates tumor microenvironment. The recommended dose (RD) in non-Japanese patients (pts) is 3.2 mg/m2 on Day 1 every three weeks (q3wk), with reversible myelosuppression as dose-limiting toxicity (DLT).
Methods:
Japanese pts with solid tumors (excluding CRC or CNS primary tumors), adequate organ function and ECOG PS 0-2 were treated at 3 different dose levels (DLs), 1.5 mg/m2, 2.5 mg/m2 and 3.2 mg/m2, using a 3+3 design.
Results:
Fifteen pts (10 female / 5 male) were treated and evaluated for safety and efficacy. Median age was 52 years (38-65), albumin 4 mg/dL (3.5-4.6) with 2 median previous lines (1-3). Tumors were, among others, biliopancreatic (3), esophageal (2), endometrial (2) and breast (1). 2 out of 4 pts on DL3 (3.2 mg/m2) had a DLT consisting of a grade (G) 4 neutropenia and a G3 neutropenia lasting > 7 days. Eight pts were treated at the RD established on 2.5 mg/m2, with G2 neutropenia leading to dose reduction and dose delay in 1 pt each. Main adverse events at the RD were hematological with 1 pt (12.5%) presenting G3 neutropenia. Other G3/4 toxicities included a non-drug related G4 hypokalemia (12.5%). Non-hematological toxicities were exclusively G1/2, including G2 ALT increase (50%), AST increase (25%), anorexia (25%), nausea (25%), fatigue (12.5%) and dyspnea (12.5%). At RD, 1 pt (12.5%) with metastatic breast cancer achieved a durable partial response and 3 pts (37.5%) had confirmed stable disease. PK at RD (n= 6 pts) showed a similar behavior to non-Japanese pts, with a mean (standard deviation) total body clearance (CL) of 10.5 (4.5) L/h, half-life of 50.7 (18.1) h and volume of distribution at steady-state of 375.5 (172.0) L.
Conclusions:
The RD of PM1183 in Japanese pts is 2.5 mg/m2 q3wk, with mild toxicity. Main DLTs were hematological. Hints of activity were observed in breast cancer. Japanese pts showed a similar CL to non-Japanese pts, but with a 26.5% lower distribution volume. A new cohort is exploring PM1183 3.2 mg/m2 (non-Japanese RD) in Japanese pts receiving G-CSF support.
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