http://dx.doi.org/10.1158/1078-0432.CCR-10-0748
scopus: 77957602393
Phase I safety, pharmacokinetics, and inhibition of src activity study of saracatinib in patients with solid tumors
October 2010
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Purpose: This dose-escalation study evaluated the safety, tolerability, and pharmacokinetics (PK) of the oral Src inhibitor saracatinib (AZD0530) in patients with advanced solid malignancies. Tumor biopsy samples were taken to investigate the effect of saracatinib on Src activity in tumors. Experimental Design: Part A of the study followed a multiple-ascending dose design to establish the maximum tolerated dose (MTD) of saracatinib. Part B was a randomized, parallel-group, cohort-expansion phase to further assess tolerated doses. Safety, tolerability, and Src activity (immunohistochemistry and lysate-based methodologies) were assessed after 21 days of once-daily oral dosing. PK was assessed after single and multiple dosing. Results: In part A, 30 patients received once-daily saracatinib at doses of 60 to 250 mg; the MTD was established as 175 mg. In part B, 51 patients were randomized to receive 50 mg (n = 16), 125 mg (n = 16), or 175 mg (n = 19) of saracatinib. The most common grade ≥3 events considered to be treatment related were anemia, diarrhea, and asthenia. Tumor Src activity was reduced following saracatinib treatment. The area under the concentration-time curve and Cmax of saracatinib increased with increasing dose. Saracatinib accumulated 4- to 5-fold on once-daily dosing to reach steady-state exposure after 10 to 17 days of dosing. The half-life was ∼40 hours. Conclusions: Saracatinib was well tolerated in patients with advanced solid malignancies. A reduction in tumor Src activity was observed. PK data show that saracatinib is suitable for once-daily oral dosing. Based on this study, the recommended dose for the phase II studies was chosen to be 175 mg/d.
- adult
- article
- female
- human
- male
- aged
- major clinical study
- priority journal
- controlled study
- clinical trial
- controlled clinical trial
- randomized controlled trial
- area under the curve
- unclassified drug
- multicenter study
- colorectal tumor
- diarrhea
- neutropenia
- drug dose increase
- drug tolerability
- pneumonia
- cancer radiotherapy
- antineoplastic activity
- cancer immunotherapy
- anorexia
- myalgia
- thrombocytopenia
- coughing
- nausea
- clinical assessment
- single drug dose
- immunohistochemistry
- drug safety
- kidney failure
- therapy effect
- febrile neutropenia
- protein tyrosine kinase
- steady state
- respiratory failure
- open study
- anemia
- septic shock
- cancer hormone therapy
- recommended drug dose
- activity
- asthenia
- breast tumor
- cancer fatigue
- chemotherapy induced emesis
- competitive inhibition
- drug accumulation
- drug clearance
- drug dose
- drug fatality
- drug metabolite
- drug screening
- drug half life
- enzyme
- escalation
- kidney tumor
- leukopenia
- m 594347
- maximum plasma concentration
- maximum tolerated dose
- n (5 chloro 1,3 benzodioxol 4 yl) 7 [2 (4 methyl 1 iperazinyl)ethoxy] 5 (tetrahydro 2h pyran 4 yloxy) 4 quinazolinamine
- ovary tumor
- pancreas tumor
- phase 1 clinical trial
- saracatinib
- solid tumor
- tumor biopsy
