In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 3078-3078
Abstract:
3078 Background: Dasatinib (D) is a first in class Src kinase inhibitor, and inhibits BCR-Abl, c-Kit, PDGFR-beta, EPHA2 and Src family kinases including Src, Lck, Yes, Fyn at nanomolar concentrations. Initially FDA approved for use in imatinib resistant CML. It is a small molecule targeted therapy hepatically metabolized primarily by CYP3A4. We conducted a phase I study to determine maximum tolerated dose (MTD) and pharmacokinetics (PK) of D in patients (pts) with liver dysfunction (LD). Methods: Pts with advanced solid tumors or lymphoma, Zubrod ≤2, no baseline ascites or pleural effusions, adequate renal and bone marrow function, received PO D daily. Cycles q28 days. Pts stratified into 4 LD groups: normal, mild, moderate, severe, using Child-Pugh classification (CPC). Data also collected for NCI ODWG Organ Dysfunction Working GroupCriteria. D dose was escalated in sequential cohorts of pts within each LD category. Blood analysis for D concentrations were determined during cycle 1 using a validated LC-MC/MS assay. Study objectives included characterizing safety, tolerability, PK, identifying the MTD and obtaining preliminary evidence of efficacy. Results: 54 registered pts, 51 pts received 51 cycles of D at doses starting at 100 mg in mild LD (50-140 mg). Median age 60, male 55%, Zubrod 1 70%. CRC 27%. Groups: normal-17, mild-20, moderate-13, severe-1 pt(s). Related AEs include fatigue 35%, diarrhea 27%, anemia 27%, nausea 25%, vomiting 21%, lymphopenia 13%, rash 13%, pleural effusion 8%. 1 DLT of increased CK in a pt in moderate LD with past history of similar episode with previous sorafenib. Previous linear PK disposition, and no accumulation. No apparent PK differences between normal and mild groups. Cycle 1 Day 1 D 140 mg Normal Group: C max 129 ng/mL. Mild Group 140mg: C max 157 ng/mL. Prolonged disease stabilization (≥4 cycles) in 6 pts, 3 CRC (4,5,8); 1 Pancreas, HCC, Bladder (4,5,6). Conclusions: Recommended dose for Dasatinib given PO QD for pts with mild, moderate, or severe LD using clinical criteria with CPC and no baseline ascites, are 140 mg, 70 mg, insufficient pts, respectively. Dose adjustment not necessary in pts with mild LD.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.3078
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
Permalink