In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 2500-2500
Abstract:
2500 Background: Cyclin dependent kinases 4 and 6 (CDK4/6) act with D-type cyclins to inactivate the retinoblastoma (Rb) tumor suppressor protein and enable cell cycle progression from G1 to S phase. LY2835219 is a selective inhibitor of CDK4/6 that shows antitumor activity in preclinical models of human cancer and also distributes efficiently to the brain. We performed a phase 1 study to evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor activity of LY2835219. Methods: 3+3 dose escalation was followed by expansions in 5 tumor types (brain metastases permitted): non-small cell lung cancer (NSCLC), glioblastoma, breast cancer, melanoma, and colorectal cancer. LY2835219 was taken orally every 12 or 24 hours (in escalation) and every 12 hours (in expansions) on days 1-28 of a 28-day cycle. Results: 55 patients (pts) received LY2835219. In escalation, 33 pts received LY2835219 on 1 of 2 schedules: 50, 100, 150, 225 mg every 24 hours (Q24H) or 75, 100, 150, 200, 275 mg every 12 hours (Q12H). On the Q24H schedule, the maximum tolerated dose (MTD) was not identified. On the Q12H schedule, the MTD was 200mg Q12H with dose limiting toxicity of G3 fatigue at 200 mg (1/6 evaluable pts) and 275 mg (2/3 evaluable pts). At 200mg Q12H, the mean C max and AUC 0-24hr at steady state were 285 ng/mL and 5502 ng-hr/ml, respectively. In skin, LY2835219 induced pharmacodynamic inhibition of both Rb phosphorylation and topoisomerase IIα expression. In the ongoing expansions, 22 pts have received LY2835219. Across the study, the most common related adverse events were diarrhea (52%, including 5% G3), nausea (30%, 4% G3), fatigue (21%, 7% G3), vomiting (18%, 2% G3), and neutropenia (16%, 7% G3). 15 pts have reached ≥4 cycles for stable disease or better with 3 pts achieving 8, 16, and 26 cycles. One pt with ovarian cancer had a durable CA-125 response with 〉 50% decrease for 16 cycles. One pt with KRAS mutant NSCLC had a 27% decrease by RECIST. One pt with CDKN2A -/- NRAS mutant melanoma had a confirmed partial response. Early clinical activity has been observed in ovarian cancer, NSCLC, breast cancer, and melanoma. Conclusions: LY2835219 shows acceptable safety and early clinical activity as a single agent for patients with advanced cancer. Clinical trial information: NCT01394016.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2013.31.15_suppl.2500
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2013
detail.hit.zdb_id:
2005181-5
detail.hit.zdb_id:
604914-X
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