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 Tmax 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.

Specific Antileukemic Activity of PD0332991, a CDK4/6 Inhibitor, against Philadelphia Chromosome–Positive Lymphoid Leukemia

“…In clinical testing of solid tumor patients, PD0332991 was generally well tolerated at least as monotherapy (28)(29)(30), and a combination trial with bortezomib (44) is currently under way in patients with relapsed mantle cell lymphoma. Thus, PD0332991, probably in combination with chemotherapy (34), will be a new candidate for clinical studies that will hopefully result in advances in the therapy of TKI-resistant CML-LC and Ph þ ALL.…”

Antiproliferative Effects of CDK4/6 Inhibition inCDK4-Amplified Human LiposarcomaIn VitroandIn Vivo

“…Instead, removal of LEE011 led to rapid reestablishment of sensitivity to drug, suggesting a dynamic feedback mechanism that may support some level of cell cycle re-entry in this model, although the durable tumor control seen in the LPS3 and HSAX2655 xenografts indicates that this may not be a universal effect. The phase II study of PD0332991 in liposarcoma used a 14-day on/7-day off dosing schedule, selected on the basis of determination of the maximum tolerated dose in a phase I study (31). Our observations suggest that this intermittent schedule may have been a fortuitous study design that enhanced antitumor activity by avoiding this potential feedback mechanism, although further exploration of dosing schedules with correlative pharmacodynamic studies will be essential to maximize RB hypophosphorylation, cell-cycle arrest, and antitumor activity.…”

Modification of the DNA Damage Response by Therapeutic CDK4/6 Inhibition

“…Responses among RB-proficient in vitro model systems display a potently cytostatic effect, and extended CDK4/6 inhibition can promote a senescencelike phenotype in specific settings (4). Human xenograft model systems of RB-positive breast, colon, prostate, ovarian, and glioblastoma have recapitulated the potently cytostatic effects of PD0332991 in vivo, and early results from Phase I clinical trials demonstrate that the side effects of PD0332991 are relatively well-tolerated (12,13).…”