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MINI 15 - Chemotherapy Developments for Lung Cancer (ID 128)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
MINI15.01 - A Phase I/II Study Evaluating the Combination of Resminostat and Docetaxel for Platinum-Pretreated NSCLC (ID 700)
16:45 - 18:15 | Author(s): T. Tamura
Resminostat, an oral hydroxamate-type inhibitor of class I and II histone deacetylases, has shown a broad spectrum of anti-tumor activity against human cancer cell lines, and synergetic or additive effects in combination with docetaxel in non-small cell lung cancer (NSCLC) cell lines. We initiated a phase I/II study to evaluate the safety and efficacy of combining resminostat and docetaxel in patients (pts) with NSCLC pretreated with platinum-based therapy. The purpose of the phase I portion was to evaluate dose-limiting toxicities (DLTs) in the first cycle, estimate the maximum tolerated dose (MTD) of resminostat when administered in combination with docetaxel, and determine the recommended dose (RD) for the phase II portion. Here, we report the results of the phase I portion.
NSCLC pts with failure of a platinum-based therapy were eligible for the study. Patients were treated with docetaxel on day 1 and resminostat on days 1 to 5 every 21 days. Phase I was an open-label, 3+3 cohort, dose-escalation study. While the docetaxel dose was fixed at 75 mg/m, the resminostat dose was escalated from 400mg (Dose Level 1: DL1) to 600 mg (DL2). DLT was defined as follows: grade 4 thrombocytopenia, grade 4 neutropenia lasting >7 days, febrile neutropenia lasting >3 days, and any other clinically significant grade 3/4 non-hematological toxicity.
A total of 9 pts (DL1: 3 pts, DL2: 6 pts) were enrolled in the phase I portion: male/female, 6/3; median age, 60 yr (50-71 yr); histologically proven adenocarcinoma/squamous cell carcinoma, 7/2; performance status, 0/1 in 7/2 pts. No DLTs were observed at DL1 or DL2. The most frequent grade 3/4 adverse events in any cycle were neutropenia (8 pts, 88.9%), leukocytopenia (8 pts, 88.9%), and febrile neutropenia (4 pts, 44.4%). These events were transient and resolved prior to the next cycle. No pharmacokinetic (PK) interaction between resminostat and docetaxel was observed. A partial response was observed in 1 pts (DL1) and stable disease in 3 pts (DL2).
DL1 N=3 DL2 N=6 PK parameters (Geometric Mean) Resminostat Docetaxel Resminostat Docetaxel C~max ~(ng/mL) 3,010 2,840 5,610 3,140 T~max ~(h) 1.78 1.00 1.47 1.03 AUC~inf~(h∙ng/mL) 11,800 3,030 25,500 3,280 t~1/2~ (h) 2.98 8.21 3.02 8.73
The combination of resminostat and docetaxel was tolerable up to DL2 (docetaxel 75 mg/m, resminostat 600 mg); the MTD was not reached. Dose Level 2 was determined as the RD for the phase II portion of this study, which is currently ongoing.
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