A phase I study of XL184, a RET, VEGFR2, and MET kinase inhibitor, in patients (pts) with advanced malignancies, including pts with medullary thyroid cancer (MTC)
2008; Lippincott Williams & Wilkins; Volume: 26; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2008.26.15_suppl.3522
ISSN1527-7755
AutoresRavi Salgia, Steven I. Sherman, David S. Hong, C. S. Ng, John Frye, Linda Janisch, Mark J. Ratain, Razelle Kurzrock,
Tópico(s)Glutathione Transferases and Polymorphisms
Resumo3522 Background: XL184 is an orally bioavailable inhibitor of RET, MET & VEGFR2. XL184 strongly inhibits cell proliferation in MTC cell lines harboring activated RET, & pharmacodynamic studies showed substantial inhibition of RET & MET phosphorylation in TT (MTC model) xenograft tumors. Methods: Pts received XL184 QD on Days (d) 1–5 of each 14 d cycle (5&9 schedule), or continuous QD dosing. Dosing changed from mg/kg (Cohorts [C] 1–9) to flat dosing in C10. The formulation changed from suspension to capsules in C12. Response, PK & pharmacodynamic parameters are assessed. Results: 55 pts (13 w/MTC) have been treated at 13 dose levels: 0.08 - 11.52 mg/kg, 5&9 (C1–9); 175 mg/d (C10), 265 mg/d (C11), 175 mg/d (C12), & 250 mg/d (C13). 6 DLTs include 1 report each of grade (G) 3 palmar/plantar erythema, & G 3 AST, ALT & lipase elevations at 11.52 mg/kg 5&9, and G 2 & 3 mucositis at 265 mg/d resulting in dose reduction. Prominent non-DLT toxicities include diarrhea & hypopigmentation of the hair. As of 12/3/2007, 27 of 45 pts (60%) had no XL184-related toxicity > G1. PK analysis suggests linear PK; the terminal half-life is 59–136 hrs. Analysis of plasma samples showed a trend toward increased VEGF-A & PlGF & slightly reduced sVEGFR2 levels. 22 pts have had SD ≥ 3 M including 12 pts w/SD ≥ 6 M. 3 pts w/MTC had a confirmed PR (PRc) & 1 pt w/neuroendocrine carcinoma had an unconfirmed PR. All evaluated pts w/MTC had reductions in plasma calcitonin & CEA. Data for pts w/MTC are reported in the following table: Conclusions: XL184 is generally well tolerated & dose escalation continues. The MTD cohort will be expanded to include ≥ 20 pts w/MTC. Anti-tumor activity has been observed in pts w/various cancers, including MTC. Data for Pts w/ MTC Pt # 1 2 3 4 5 6 7 8 9 10 11 12 13 Months on Study 17+ 14+ 10 11+ 6+ 4+ 4+ 3+ 3+ 3+ 1+ <1+ <1+ Tumor Measurements a -22 -39 NM -48 - 12 -16 -30 -14 NM 0 TEE TEE TEE Best Response SD PRc SD PRc SD SD PRc SD SD SD TEE TEE TEE Activating RET Mutation + NA + + + NA NA + + NA NA NA NA Calcitonin a -81 -96 -91 -89 - 52 -78 -83 -88 -50 -52 NA NA NA CEA a -42 -85 -51 -69 - 5 -16 -37 -19 -22 NA NA NA NA a % change from baseline was rounded to the nearest integer. NM, Non-measurable disease; TEE, too early to evaluate; NA, not available Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Exelixis Exelixis Exelixis Exelixis
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