A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765 (SAR245409), a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced malignancies.

Braña, Irene; LoRusso, P.; Baselga, J.; Heath, Elisabeth I.; Patnaik, Akash; Gendreau, Steve; Laird, A. Douglas; Papadopoulos, K.

doi:10.1200/jco.2010.28.15_suppl.3030

Cited by 43 publications

(29 citation statements)

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“…Results have shown reduced activation of key pathway nodes in the order of 50-90% in both tumor and nontumor tissue [54,61]. However, this does not necessarily equate with meaningful clinical benefits.…”

Section: Biomarkersmentioning

confidence: 98%

“…Tumor stabilization or shrinkage has been observed with XL765 in a variety of mouse xenograft models of human cancer, including breast, ovary, lung, prostate and brain cancers. Updated clinical data from the phase I monotherapy study in [54]. The most frequently observed toxicities involved elevated liver enzymes, gastrointestinal complaints and rash.…”

Section: Dual Pi3k-mtor Inhibitorsmentioning

confidence: 99%

“…Regardless, translational research requires biomarker studies to further knowledge and to assist in finding solutions to clinical problems or disappointments, and often raises new questions of interest. Indeed, the reduction in pERK (a marker of MAPK pathway activity) noted in tumors of patients treated with XL765 and XL147 was unexpected, raising the possibility of hitherto unrecognized crosstalk between the PI3K and MAPK pathways [54,61]. At present, an important concern is that many biomarker assays have been neither standardized nor validated.…”

Section: Biomarkersmentioning

confidence: 99%

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Targeting the PI3K/Akt/mTOR Pathway - Beyond Rapalogs

2010

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AbstrAct:It is well established that the PI3K pathway plays a central role in various cellular processes that can contribute to the malignant phenotype. Accordingly, pharmacological inhibition of key nodes in this signaling cascade has been a focus in developmental therapeutics. To date, agents targeting upstream receptor tyrosine kinases are best studied and have achieved greatest clinical success. Further downstream, despite efficacy in certain tumor types, the rapalogs have been somewhat disappointing in the clinic. Novel inhibitors of PI3K, Akt, and mTORC1 and 2 are now passing through early phase clinical trials. It is hoped that these agents will circumvent some of the shortcomings of the rapalogs and lead to meaningful benefits for cancer patients.

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Section: Biomarkersmentioning

confidence: 98%

Section: Dual Pi3k-mtor Inhibitorsmentioning

confidence: 99%

Section: Biomarkersmentioning

confidence: 99%

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Targeting the PI3K/Akt/mTOR Pathway - Beyond Rapalogs

2010

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“…BEZ235 is pharmacodynamically active, exhibiting dose- and schedule-dependent PI3K inhibition (136). A phase I dose escalation study of XL765 (Exelixis) has shown good tolerability, with adverse effects including diarrhea, anorexia, rash, and mild elevations of postprandial insulin levels without effects on glycemia (137). This drug yielded marked disease stabilization in advanced solid tumors.…”

Section: Beyond Rapalogs: Molecular Rationale and New Therapeutic Strmentioning

confidence: 99%

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy

Wander¹,

Hennessy²,

Slingerland³

2011

J. Clin. Invest.

372

363

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“…Agents like BEZ235, GDC-0980, GSK458, SF1126, and XL765 have all shown evidence of tolerability and target inhibition although specific responses in breast tumors have yet to be seen (47)(48)(49)(50)(51). The side effects of the dual inhibitors overlap those seen with PI3K and mTOR-specific agents.…”

Section: Emergence Of Several Pi3k Pathway Inhibitorsmentioning

confidence: 85%

Molecular Pathways: PI3K Pathway Targets in Triple-Negative Breast Cancers

Gordon

Banerji

2013

Clinical Cancer Research

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The triple-negative breast cancer (TNBC) subtype, defined clinically by the lack of estrogen, progesterone, and Her2 receptor expression, accounts for 10% to 15% of annual breast cancer diagnoses. Currently, limited therapeutic options have shown clinical benefit beyond cytotoxic chemotherapy. Defining this clinical cohort and identifying subtype-specific molecular targets remain critical for new therapeutic development. The current era of high-throughput molecular analysis has revealed new insights into these targets and confirmed the phosphoinositide 3-kinase (PI3K) as a key player in pathogenesis. The improved knowledge of the molecular basis of TNBC in parallel with efforts to develop new PI3K pathway-specific inhibitors may finally produce the therapeutic breakthrough that is desperately needed.

show abstract

A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765 (SAR245409), a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced malignancies.

Cited by 43 publications

References 0 publications

Targeting the PI3K/Akt/mTOR Pathway - Beyond Rapalogs

Targeting the PI3K/Akt/mTOR Pathway - Beyond Rapalogs

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy

Molecular Pathways: PI3K Pathway Targets in Triple-Negative Breast Cancers

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