Clinical and laboratory studies of the novel cyclin-dependent kinase inhibitor dinaciclib (SCH 727965) in acute leukemias.
OBJECTIVE
Dinaciclib inhibits cyclin-dependent kinases 1, 2, 5, and 9 with a better therapeutic index than flavopiridol in preclinical studies. This study assessed the activity of dinaciclib in acute leukemia both in the clinic and in vitro.


METHODS
Adults with relapsed/refractory acute myeloid leukemia (n = 14) and acute lymphoid leukemia (n = 6) were treated with dinaciclib 50 mg/m(2) given as a 2-h infusion every 21 days.


RESULTS
Most patients had dramatic but transient reduction in circulating blasts; however, no remissions were achieved on this schedule. The most common toxicities were gastrointestinal, fatigue, transaminitis, and clinical and laboratory manifestations of tumor lysis syndrome, including one patient who died of acute renal failure. Dinaciclib pharmacokinetics showed rapid (2 h) achievement of maximum concentration and a short elimination/distribution phase. Pharmacodynamic studies demonstrated in vivo inhibition of Mcl-1 expression and induction of PARP cleavage in patients' peripheral blood mononuclear cells 4 h after dinaciclib infusion, but the effects were lost by 24 h and did not correlate with clinical outcome. Correlative in vitro studies showed that prolonged exposures to dinaciclib, at clinically attainable concentrations, result in improved leukemia cell kill.


CONCLUSIONS
While dinaciclib given as a 2-h bolus did not exhibit durable clinical activity, pharmacokinetic and pharmacodynamic data support the exploration of prolonged infusion schedules in future trials in patients with acute leukemias.
Division of Hematology/Oncology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA, igojo1@jhmi.edu.
Ivana
I
Gojo
Mariola
M
Sadowska
Alison
A
Walker
Eric J
EJ
Feldman
Swaminathan Padmanabhan
SP
Iyer
Maria R
MR
Baer
Edward A
EA
Sausville
Rena G
RG
Lapidus
Da
D
Zhang
Yali
Y
Zhu
Ying-Ming
YM
Jou
Jennifer
J
Poon
Karen
K
Small
Rajat
R
Bannerji
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003497:Cyclic N-Oxides; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007212:Indolizines; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D011726:Pyridinium Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003497:Cyclic N-Oxides; D007212:Indolizines; D011726:Pyridinium Compounds; C553669:dinaciclib; D011065:Poly(ADP-ribose) Polymerases; D018844:Cyclin-Dependent Kinases