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Published on: July 10, 2019
Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin
Anthony W Tolcher1, Alain Mita, Lionel D Lewis
1Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA. atolcher@start.stoh.com
Purpose:
To determine the maximum-tolerated dose (MTD) and assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155, a small-molecule inhibitor of survivin.
Patients And Methods:
Patients with advanced solid malignancies or lymphoma were treated with escalating doses of YM155 administered by 168-hour continuous intravenous infusion (CIVI). Plasma and urine samples were assayed to determine pharmacokinetic parameters and excretion.
Results:
Forty-one patients received 127 cycles of YM155 at doses ranging from 1.8 to 6.0 mg/m(2)/d by 168-hour CIVI every 3 weeks. Overall, the most common grade 1 to 2 toxicities were stomatitis, pyrexia, and nausea, whereas grade 3 and 4 toxicities were rare. Reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting at 6.0 mg/m(2). The MTD was 4.8 mg/m(2). At the MTD, the mean steady-state concentration, clearance, volume of distribution at steady-state, and terminal elimination half-life were 7.7 ng/mL, 47.7 L/h, 1,763 L, and 26 hours, respectively. One complete and two partial responses lasting 8, 24+ and 48+ months occurred in three patients with non-Hodgkin's lymphoma, two patients with hormone- and docetaxel-refractory prostate cancer had prostate-specific antigen responses, and one patient with non-small-cell lung cancer had a minor response. CONCLUSION YM155 can be administered safely at 4.8 mg/m(2)/d 168 hours CIVI every 3 weeks. The absence of severe toxicities, attainment of plasma concentrations active in preclinical models, and compelling antitumor activity warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.
Insights
The maximum-tolerated dose of YM155, a survivin inhibitor, was determined to be 4.8 mg/m(2)/d. This dose showed promising antitumor activity and a manageable safety profile in patients with advanced cancers.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Survivin is a key protein in cancer cell survival.
- YM155 is a novel small-molecule inhibitor targeting survivin.
- Understanding YM155's MTD and safety is crucial for further development.
Purpose of the Study:
- Determine the maximum-tolerated dose (MTD) of YM155.
- Assess the safety and tolerability of YM155.
- Evaluate pharmacokinetics and preliminary antitumor activity of YM155.
Main Methods:
- Phase I clinical trial with escalating doses of YM155.
- 168-hour continuous intravenous infusion (CIVI) every 3 weeks.
- Pharmacokinetic analysis of plasma and urine samples.
Main Results:
- MTD established at 4.8 mg/m(2)/d.
- Common toxicities included stomatitis, pyrexia, and nausea; severe toxicities were rare.
- Observed responses in non-Hodgkin's lymphoma, prostate cancer, and non-small-cell lung cancer.
Conclusions:
- YM155 is safely administered at 4.8 mg/m(2)/d via 168-hour CIVI.
- Achieved preclinical effective plasma concentrations.
- Warrants further investigation in disease-directed studies, alone or in combination therapy.
