Abstract A276: Phase 1 multicenter, open label, dose-escalation study of LEE011, an oral inhibitor of cyclin-dependent kinase 4/6, in patients with advanced solid tumors or lymphomas.

Infante, Jeffrey R.; Shapiro, Geoffrey I.; Witteveen, Petronella O.; Gerecitano, John F.; Ribrag, Vincent; Chugh, Rashmi; Chakraborty, Abhijit; Matano, Alessandro; Zhao, Xumei; Parasuraman, Sudha; Cassier, Philippe

doi:10.1158/1535-7163.targ-13-a276

Cited by 16 publications

(16 citation statements)

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“…Because abemaciclib inhibits renal effl ux transporters [multidrug and toxin extrusion (MATE) 1 and 2-K] that mediate active secretion of creatinine from the proximal tubule, increases in serum creatinine during therapy with abemaciclib may not accurately refl ect renal function, and measures of glomerular fi ltration rate that are independent of active tubular secretion via renal effl ux transporters (such as cystatin C) may yield a more accurate estimate of renal function than serum creatinine for patients receiving the drug. Previous reports have identifi ed neutropenia as an adverse event associated with dual inhibition of CDK4 and CDK6 (34)(35)(36)(37)(38)(39) as a single agent on a continuous schedule in the tumor-specifi c cohorts was associated with an acceptable incidence of investigator-reported grade 3 (9%, 16 of 173 patients) or grade 4 (1%, 2 of 173 patients) neutropenia. Febrile neutropenia was rare, occurring in only 1 patient over the entire study.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors

et al. 2016

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We evaluated the safety, pharmacokinetic profi le, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumorspecifi c cohorts for breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specifi c cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor-positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting ≥ 6 months. SIGNIFICANCE:Abemaciclib represents the fi rst selective inhibitor of CDK4 and CDK6 with a safety profi le allowing continuous dosing to achieve sustained target inhibition. This fi rst-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 740-53.

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Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors

et al. 2016

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“…Results for 78 patients treated on the phase I study of LEE011 have been reported (26). Both intermittent and continuous doses were evaluated with recommended phase II doses of 600 mg daily (continuous) and 900 mg daily for 3 weeks of 4.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: CDK4 Inhibitors for Cancer Therapy

Dickson

2014

Clinical Cancer Research

217

179

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Unrestrained growth is the hallmark of cancer, and disrupted cell-cycle regulation is, therefore, common. CDK4 is the key regulator of the G 1 -S transition. In complex with cyclin D, CDK4 phosphorylates retinoblastoma protein (Rb) and drives cell-cycle progression, a process inhibited by p16. The p16-CDK4-cyclin D-Rb is aberrant in the majority of cancers and is, thus, a logical target for anticancer therapy. Previous attempts to block CDK4 with nonselective cyclin-dependent kinase (CDK) inhibitors led to toxicity and little efficacy. However, the recent development of selective CDK4 inhibitors launched the first successful efforts to target the pathway for cancer therapy. Three oral selective CDK4 inhibitors have entered clinical trials: palbociclib (PD0332991), LEE011, and LY2835219. CDK4 inhibitors have in vitro activity against a broad range of cancers and in patients have shown antitumor activity in breast cancer, lymphoma, sarcoma, and other tumors. Major efforts are under way to develop biomarkers of response, understand potential mechanisms of resistance, and develop rational combinations of CDK4 inhibitors with chemotherapy and other targeted drugs. Clin Cancer Res; 20(13); 3379-83. Ó2014 AACR.

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“…S1; refs. 25,27). To demonstrate its impact on tumor cells in vitro, we examined the effects of LEE011 in liposarcoma cells.…”

Section: Cdk4 Knockdown Inhibits Rb Phosphorylation and Cell Growth Imentioning

confidence: 99%

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

Zhang

Sicińska

Czaplinski

et al. 2014

Molecular Cancer Therapeutics

106

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Well-differentiated/dedifferentiated liposarcomas (WD/DDLPS) are among the most common subtypes of soft tissue sarcomas. Conventional systemic chemotherapy has limited efficacy and novel therapeutic strategies are needed to achieve better outcomes for patients. The cyclin-dependent kinase 4 (CDK4) gene is highly amplified in more than 95% of WD/DDLPS. In this study, we explored the role of CDK4 and the effects of NVP-LEE011 (LEE011), a novel selective inhibitor of CDK4/CDK6, on a panel of human liposarcoma cell lines and primary tumor xenografts. We found that both CDK4 knockdown by siRNA and inhibition by LEE011 diminished retinoblastoma (RB) phosphorylation and dramatically decreased liposarcoma cell growth. Cell-cycle analysis demonstrated arrest at G 0 -G 1 . siRNA-mediated knockdown of RB rescued the inhibitory effects of LEE011, demonstrating that LEE011 decreased proliferation through RB. Oral administration of LEE011 to mice bearing human liposarcoma xenografts resulted in approximately 50% reduction in tumor 18 F-fluorodeoxyglucose uptake with decreased tumor biomarkers, including RB phosphorylation and bromodeoxyuridine incorporation in vivo. Continued treatment inhibited tumor growth or induced regression without detrimental effects on mouse weight. After prolonged continuous dosing, reestablishment of RB phosphorylation and cell-cycle progression was noted. These findings validate the critical role of CDK4 in maintaining liposarcoma proliferation through its ability to inactivate RB function, and suggest its potential function in the regulation of survival and metabolism of liposarcoma, supporting the rationale for clinical development of LEE011 for the treatment of WD/DDLPS. Mol Cancer Ther; 13(9); 2184-93. Ó2014 AACR.

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Abstract A276: Phase 1 multicenter, open label, dose-escalation study of LEE011, an oral inhibitor of cyclin-dependent kinase 4/6, in patients with advanced solid tumors or lymphomas.

Cited by 16 publications

References 0 publications

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors

Molecular Pathways: CDK4 Inhibitors for Cancer Therapy

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

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