PURPOSE: Marimastat is an orally bioavailable inhibitor of matrix metalloproteinases. A phase I study was initiated to determine whether conventional doses of carboplatin and paclitaxel are tolerated when combined with marimastat and to assess the influence of marimastat on paclitaxel pharmacokinetics. EXPERIMENTAL DESIGN: Three dose levels were evaluated. Marimastat (10 or 20 mg oral administration b.i.d.) was administered continuously with paclitaxel (175 or 200 mg/m(2) as a 3-hour i.v. infusion) and carboplatin (at a dose providing an area under the free drug plasma concentration-time curve of 7 mg min/mL) administered each 3 weeks. Toxicity and response were evaluated throughout the intended four cycles of combined therapy. The plasma pharmacokinetics of paclitaxel was determined in each patient both without concurrent marimastat and after receiving marimastat for 1 week. RESULTS: Twenty-two chemotherapy-naive patients with stage IIIb (27%) or stage IV (73%) non-small cell lung cancer were enrolled. Their median age was 56 years (range, 39-73 years), 50% were female, and their performance status (Eastern Cooperative Oncology Group) ranged from 0 to 2. Treatment was well tolerated, as 18 (82%) of the patients completed all four cycles of chemotherapy without dose-limiting toxicity. Grade 2 musculoskeletal toxicities were reported in 3 of 12 patients receiving marimastat (20 mg b.i.d.). Nine patients required dose reductions, predominantly related to low-grade myelosuppression. Partial responses occurred in 12 of 21 (57%) evaluable patients with disease stabilization in another 5 (19%). Marimastat had no effect on paclitaxel pharmacokinetics. CONCLUSIONS: The administration of marimastat (10 mg b.i.d.) with paclitaxel (200 mg/m(2)) and carboplatin at an area under the free drug plasma concentration-time curve of 7 mg min/mL was well tolerated with no apparent pharmacokinetic interaction. Study of this drug combination in the adjuvant setting should be considered if tissue inhibition of matrix metalloproteinase activity can first be shown.
PURPOSE:Marimastat is an orally bioavailable inhibitor of matrix metalloproteinases. A phase I study was initiated to determine whether conventional doses of carboplatin and paclitaxel are tolerated when combined with marimastat and to assess the influence of marimastat on paclitaxel pharmacokinetics. EXPERIMENTAL DESIGN: Three dose levels were evaluated. Marimastat (10 or 20 mg oral administration b.i.d.) was administered continuously with paclitaxel (175 or 200 mg/m(2) as a 3-hour i.v. infusion) and carboplatin (at a dose providing an area under the free drug plasma concentration-time curve of 7 mg min/mL) administered each 3 weeks. Toxicity and response were evaluated throughout the intended four cycles of combined therapy. The plasma pharmacokinetics of paclitaxel was determined in each patient both without concurrent marimastat and after receiving marimastat for 1 week. RESULTS: Twenty-two chemotherapy-naive patients with stage IIIb (27%) or stage IV (73%) non-small cell lung cancer were enrolled. Their median age was 56 years (range, 39-73 years), 50% were female, and their performance status (Eastern Cooperative Oncology Group) ranged from 0 to 2. Treatment was well tolerated, as 18 (82%) of the patients completed all four cycles of chemotherapy without dose-limiting toxicity. Grade 2 musculoskeletal toxicities were reported in 3 of 12 patients receiving marimastat (20 mg b.i.d.). Nine patients required dose reductions, predominantly related to low-grade myelosuppression. Partial responses occurred in 12 of 21 (57%) evaluable patients with disease stabilization in another 5 (19%). Marimastat had no effect on paclitaxel pharmacokinetics. CONCLUSIONS: The administration of marimastat (10 mg b.i.d.) with paclitaxel (200 mg/m(2)) and carboplatin at an area under the free drug plasma concentration-time curve of 7 mg min/mL was well tolerated with no apparent pharmacokinetic interaction. Study of this drug combination in the adjuvant setting should be considered if tissue inhibition of matrix metalloproteinase activity can first be shown.
Authors: U Lassen; L R Molife; M Sorensen; S-A Engelholm; L Vidal; R Sinha; R T Penson; P Buhl-Jensen; E Crowley; J Tjornelund; P Knoblauch; J S de Bono Journal: Br J Cancer Date: 2010-06-15 Impact factor: 7.640
Authors: Adam C Mueller; Miles Piper; Andrew Goodspeed; Shiv Bhuvane; Jason S Williams; Shilpa Bhatia; Andy V Phan; Benjamin Van Court; Kathryn L Zolman; Brisa Peña; Ayman J Oweida; Sara Zakem; Cheryl Meguid; Michael W Knitz; Laurel Darragh; Thomas E Bickett; Jacob Gadwa; Luisa Mestroni; Matthew R G Taylor; Kimberly R Jordan; Peter Dempsey; M Scott Lucia; Martin D McCarter; Marco Del Chiaro; Wells A Messersmith; Richard D Schulick; Karyn A Goodman; Michael J Gough; Casey S Greene; James C Costello; Antonio Galveo Neto; David Lagares; Kirk C Hansen; Adrie Van Bokhoven; Sana D Karam Journal: Cancer Res Date: 2021-02-01 Impact factor: 12.701
Authors: X Zhuang; J M J Herbert; P Lodhia; J Bradford; A M Turner; P M Newby; D Thickett; U Naidu; D Blakey; S Barry; D A E Cross; R Bicknell Journal: Br J Cancer Date: 2014-12-23 Impact factor: 7.640