Phase I study of PD 0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (Schedule 2/1)

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.

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).

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.

Conclusion: PD 0332991 was generally well tolerated, with DLTs related mainly to myelosuppression. The MTD, 200 mg QD, is recommended for phase II study.

Conflict of interest statement

MAD declare no conflict of interest. GKS has received compensation (less than $10 000) from Pfizer for attending an advisory board and has had travel expenses paid by Pfizer for attending an advisory board; his institution (Memorial Sloan-Kettering Cancer Center) has received funding from Pfizer for the current study, as well as for other research. PML has received compensation (less than $10 000) from Pfizer for attending an advisory board and has had travel expenses paid by Pfizer for attending an advisory board; her institution (Karmanos Cancer Institute) has received funding from Pfizer for the current study, as well as for other research. SR, MNS, KW, RC are employees of Pfizer and own stock/stock options in Pfizer. PO’D has received a consulting fee (less than $10 000) from Pfizer, for other research, and his institution (Abramson Cancer Center, University of Pennsylvania) has received funding from Pfizer for the current study and for other research. Work presented in this manuscript is original and has not been published elsewhere. Some of the data have been presented previously as listed in Appendix.

Figures

Figure 1

Pharmacodynamic modelling: percentage change in neutrophil count vs individual AUC during cycle 1. ANC, absolute neutrophil count; AUC, area under the plasma concentration–time curve.