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Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1).
- Source :
-
British journal of cancer [Br J Cancer] 2011 Jun 07; Vol. 104 (12), pp. 1862-8. Date of Electronic Publication: 2011 May 24. - Publication Year :
- 2011
-
Abstract
- Background: This phase I, open-label, first-in-human study determined dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PD 0332991, an oral cyclin-dependent kinase 4/6 inhibitor with potent anti-proliferative activity in vitro/vivo.<br />Methods: A total of 33 patients with retinoblastoma protein-positive advanced solid tumours or non-Hodgkin's lymphoma refractory to standard therapy or for which no therapy was available received PD 0332991 once daily (QD) for 14 days followed by 7 days off treatment (21-day cycles; Schedule 2/1).<br />Results: Six patients had DLTs (18%; four receiving 200 mg QD; two receiving 225 mg QD); the MTD was 200 mg QD. Treatment-related, non-haematological adverse events occurred in 29 patients (88%) during cycle 1 and 27 patients (82%) thereafter. Adverse events were generally mild-moderate. Of 31 evaluable patients, one with testicular cancer achieved a partial response; nine had stable disease (≥10 cycles in three cases). PD 0332991 was slowly absorbed (mean T(max) 4.2 h) and eliminated (mean half-life 26.7 h). Volume of distribution was large (mean 3241 l) with dose-proportional exposure. Using a maximum effective concentration model, neutropenia was proportional to exposure.<br />Conclusion: PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study.
- Subjects :
- Adult
Aged
Drug Administration Schedule
Female
Humans
Lymphoma, Non-Hodgkin drug therapy
Male
Maximum Tolerated Dose
Middle Aged
Piperazines adverse effects
Piperazines pharmacokinetics
Pyridines adverse effects
Pyridines pharmacokinetics
Retinoblastoma Protein analysis
Cyclin-Dependent Kinases antagonists & inhibitors
Neoplasms drug therapy
Piperazines administration & dosage
Pyridines administration & dosage
Subjects
Details
- Language :
- English
- ISSN :
- 1532-1827
- Volume :
- 104
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- British journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 21610706
- Full Text :
- https://doi.org/10.1038/bjc.2011.177