Artikel
Pemetrexed Combined with Paclitaxel: A Phase I Trial in Advanced Solid Tumors
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Veröffentlicht: | 20. März 2006 |
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Gliederung
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Background: Pemetrexed (Alimta®, AL) and paclitaxel (P) are clinically active in a variety of tumors. The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) of the ALP combination; secondary objectives included determination of dose-limiting toxicities (DLTs), recommended phase II dose, and pharmacokinetic (PK) assessments.
Methods: Escalating dose levels of P (30-120 mg/m2, 3h infusion, d1 and d8) and AL (400-500 mg/m2, 10 min infusion, d8 prior to P) were administered during a 21d cycle. Parenteral vitamin B12, oral folic acid and standard taxane premedication were used to reduce toxicity.
Results: 59 patients (pts) [40 M, 19 F; median age: 59 yrs (range: 31-77)] were enrolled. DLTs, not qualifying for MTD, occurred at the following ALP (mg/m2) doses: 400/30 [1 pt: G3 bilirubin (b), 1 pt: G3 and G4 thrombocytopenia (plts)]; 500/30 (G4 plts); 500/40 (G3 b); 500/75 (G4 ANC); 500/100 (1 pt: G4 leukopenia and G4 ANC). The MTD defined by G4 leukopenia and G4 neutropenia in 4 out of 6 pts and febrile neutropenia in 1 pt, was determined at the ALP (mg/m²) dose of 500/120 To confirm safety at this dose-level, 6 more pts were enrolled at a ALP (mg/m²) dose of 500/100.
Other clinically significant toxicities include: G3/G4 ANC (17/14), G3/G4 anemia (6/1), G3/G4 plts (2), G3 fatigue (2) and G3 stomatitis (1). 4 pts expired while on therapy (1 non-therapy related; 1 gastric ulcer hemorrhage, 1 sepsis, 1 tumor lysis and 1 pneumonia). Stable disease occurred in 18 pts [mesothelioma (3), esophagus (2), lung (1), liver (1), renal (1), stomach (1), thyroid (9)]. Of specific relevance, this regimen shows clear clinical activity in follicular/papillary thyroid cancer with 4/14 pts showing long lasting partial responses [duration (months) 34+, 22+, 18, 15+]. At present there is no clinical evidence of PK interactions. Final PK analysis is pending.
Conclusions: The pemetrexed and paclitaxel combination can be safely combined and shows broad clinical activity. The recommended dose for further studies of the ALP combination is 500/100 mg/m². Promising antitumor activity was observed in thyroid cancer. This warrants further clinical development in this indication.