A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas.

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

doi:10.1200/jco.2014.32.15_suppl.2528

Cited by 53 publications

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“…A Phase II study in liposarcoma, a disease with frequent CDK4 amplification, also reported favourable progression-free rates in patients with CDK4 amplification and RB expression 165,166 . The recently reported Phase I study with LEE011 monotherapy in patients with advanced solid tumours demonstrated that LEE011 was well tolerated, with 2 confirmed partial responses and 40% of patients with stable disease 167 . Similarly, abemaciclib exhibited single-agent activity associated with delayed disease progression and particularly robust activity in metastatic ER-positive breast cancer, although data are from a relatively small study with one group of patients 168 .…”

Section: Targeted Inhibition Of Cdk4 and Cdk6mentioning

confidence: 96%

“…Although neutropaenia is a common side effect of cytotoxic agents, the neutropaenia associated with palbociclib and LEE011 is distinct in that it is rapidly reversible, reflecting a cytostatic effect on neutrophil precursors in the bone marrow. Consequently, both palbociclib and LEE011 are dosed intermittently to accommodate a break for haematological recovery 167 . Interestingly, abemaciclib exhibits more prominent gastrointestinal-associated toxicity, whereas neutropaenia is less evident, enabling continuous dosing.…”

Section: Targeted Inhibition Of Cdk4 and Cdk6mentioning

confidence: 99%

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The history and future of targeting cyclin-dependent kinases in cancer therapy

Asghar

Witkiewicz

Turner

et al. 2015

Nat Rev Drug Discov

1,426

1,323

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Cancer represents a pathological manifestation of uncontrolled cell division; therefore, it has long been anticipated that our understanding of the basic principles of cell cycle control would result in effective cancer therapies. In particular, cyclin-dependent kinases (CDKs) that promote transition through the cell cycle were expected to be key therapeutic targets because many tumorigenic events ultimately drive proliferation by impinging on CDK4 or CDK6 complexes in the G1 phase of the cell cycle. Moreover, perturbations in chromosomal stability and aspects of S phase and G2/M control mediated by CDK2 and CDK1 are pivotal tumorigenic events. Translating this knowledge into successful clinical development of CDK inhibitors has historically been challenging, and numerous CDK inhibitors have demonstrated disappointing results in clinical trials. Here, we review the biology of CDKs, the rationale for therapeutically targeting discrete kinase complexes and historical clinical results of CDK inhibitors. We also discuss how CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clinical activity.

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Section: Targeted Inhibition Of Cdk4 and Cdk6mentioning

confidence: 96%

Section: Targeted Inhibition Of Cdk4 and Cdk6mentioning

confidence: 99%

The history and future of targeting cyclin-dependent kinases in cancer therapy

Asghar

Witkiewicz

Turner

et al. 2015

Nat Rev Drug Discov

1,426

1,323

View full text Add to dashboard Cite

show abstract

“…Phase 1 clinical development of ribociclib in patients with tumors with documented RB-positivity utilized a Bayesian logistic regression model incorporating an overdose control principle to guide dose escalation (NCT01237236) (90, 91). Among 85 patients treated, dose limiting toxicities occurred in ten, including neutropenia, thrombocytopenia, pulmonary embolism, hyponatremia, QTcF prolongation and elevated creatinine, resulting in a recommended phase 2 dose of 600 mg daily on the 3/1 schedule.…”

Section: Development Of Additional Cdk4/6 Inhibitors: Ribociclib and mentioning

confidence: 99%

Targeting CDK4 and CDK6: From Discovery to Therapy

2016

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Biochemical and genetic characterization of D-type cyclins, their cyclin D-dependent kinases (CDK4 and CDK6), and the polypeptide CDK4/6 inhibitor p16INK4 over two decades ago revealed how mammalian cells regulate entry into the DNA synthetic (S) phase of the cell division cycle in a retinoblastoma protein (RB)-dependent manner. These investigations provided proof-of-principle that CDK4/6 inhibitors, particularly when combined with co-inhibition of allied mitogen-dependent signal transduction pathways, might prove valuable in cancer therapy. FDA-approval of the CDK4/6 inhibitor palbociclib used with the aromatase inhibitor letrozole for breast cancer treatment highlights long sought success. The newest findings herald clinical trials targeting other cancers.

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“…Based on cross-trial comparison of phase I data of the other CDK4/6 inhibitors currently being evaluated in breast cancer (LEE001 and abemaciclib (LY2835219)), neutropenia was more frequently reported in palbociclib (all grade 66-70% in palbociclib vs. 40% in LEE001 and 16% in abemaciclib), while diarrhea was the most common adverse event reported for abemaciclib (16, 17, 22). …”

Section: Toxicitymentioning

confidence: 99%

Palbociclib for the Treatment of Estrogen Receptor–Positive, HER2-Negative Metastatic Breast Cancer

Morikawa

Henry

2015

Clinical Cancer Research

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Palbociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 that acts by reducing phosphorylation of the tumor suppressor gene Retinoblastoma. When added to the aromatase inhibitor letrozole in a randomized phase II trial for first-line therapy of estrogen receptor-positive, HER2-negative metastatic breast cancer, palbociclib significantly increased progression-free survival compared to letrozole alone (palbociclib + letrozole: 20.2 months (95% CI 13.8-27.5), letrozole:10.2 months (95% CI 5.7-12.6); hazard ratio 0.49 (95% CI 0.32-0.75), p=0.0004). Based on these results the drug was recently granted accelerated approval by the FDA, and confirmatory studies are ongoing. Since this drug has a rational target in an oncologic pathway, concurrent biomarker development is of interest. In breast cancer, the most useful predictive biomarkers identified thus far are estrogen receptor and HER2 receptor status, although additional studies are ongoing. In this article, we review the development of palbociclib and its use in treatment of hormone receptor-positive metastatic breast cancer in the context of other FDA-approved agents in this setting.

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A phase I study of the single-agent CDK4/6 inhibitor LEE011 in pts with advanced solid tumors and lymphomas.

Cited by 53 publications

References 0 publications

The history and future of targeting cyclin-dependent kinases in cancer therapy

The history and future of targeting cyclin-dependent kinases in cancer therapy

Targeting CDK4 and CDK6: From Discovery to Therapy

Palbociclib for the Treatment of Estrogen Receptor–Positive, HER2-Negative Metastatic Breast Cancer

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