UNASSIGNED: 3042 Background: @entity9363 is an oral cyclin dependent kinase inhibitor of @entity68812 , leading to inhibition of phosphorylation of CDK substrates, cell cycle arrest, inhibition of transcription and induction of apoptotsis. Preclinical studies show activity in cell lines and xenografts. This trial determines the safety and pharmacokinetics (PK) of @entity9363 , given b.d. for 7 days q 21. METHODS: A starting dose of 200mg/day divided in 2 doses was defined by a single dose trial and preclinical toxicology. @entity9363 was given am and pm with the @entity1 fasted 2 hrs before and after. PKs were performed on days 1 and 7 of cycle 1. Dose escalation occurred in the absence of grade >= 3 @entity137 to DLT. RESULTS: 21 @entity1 were enrolled (08/01-09/03) median age 62 (39-73 years), 6 F and 15 M, WHO PS 2=2, 1=17 and 0=2. 42 cycles were administered. We have reached 1600mg/day and DLTs seen are grade 3 @entity1910 and grade 4 hypokalaemia. Other @entity137 include grade 2 elevated @entity1011 ( @entity8818 ) (rapidly reversible upon removal of drug) occurring on day 3, grade 3 transaminitis and grade 2 emesis. Due to these observations we expanded the 1600 mg/day cohort + treated 3 @entity1 with additional investigations; @entity1098 clearance, biochemistry on days 1, 3, 5 and 7, 24 hour urine collections for @entity8818 clearance, urinary electrolytes on days 1 and 7 and urinary @entity904 binding protein ( @entity8 ) and MAG-3 renograms (renal perfusion) pre-treatment, day 3 and 14. One @entity1 experienced a rapid but reversible increase in @entity8818 and this was associated with reduced renal perfusion at day 3, reverting to baseline by day 14. There were no changes urinary @entity904 binding proteins. There is a trend to linear increase in AUC with dose (r(2) = 0.5). Drug to metabolite ratio (pmf-30-128) =1:1.17. CONCLUSIONS: DLTs of hypokalaemia, @entity1910 , and a temporary grade 2 increase in @entity8818 were reached at 1600mg/day. The mechanism for this may be an effect on renal perfusion. [Figure: see text] [Table: see text].

A phase I trial of the oral cyclin dependent kinase inhibitor @entity9363 in XXXX with advanced malignancy.

@entity1 :: ('9606', 'Species') :: ['patients', 'patient'] @entity8818 :: ('D002857', 'Chemical') :: ['Cr'] @entity8 :: ('MESH:D007674', 'Disease') :: ['renal tubular damage'] @entity137 :: ('MESH:D064420', 'Disease') :: ['toxicity', 'toxicities'] @entity1910 :: ('MESH:D005076', 'Disease') :: ['rash'] @entity904 :: ('MESH:D014801', 'Chemical') :: ['retinol'] @entity9363 :: ('MESH:C104586', 'Chemical') :: ['CYC202'] @entity1011 :: ('MESH:D003404', 'Chemical') :: ['creatinine'] @entity1098 :: ('MESH:D004492', 'Chemical') :: ['EDTA'] @entity68812 :: ('1017;1022;1025', 'Gene') :: ['CDKs-2, -7 and -9']
@entity1 :: (9606,Species) :: ['patients']
