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|Ref Type||Journal Article|
|Authors||Shapiro GI, Rodon J, Bedell C, Kwak EL, Baselga J, Braña I, Pandya SS, Scheffold C, Laird AD, Nguyen LT, Xu Y, Egile C, Edelman G|
|Title||Phase I safety, pharmacokinetic, and pharmacodynamic study of SAR245408 (XL147), an oral pan-class I PI3K inhibitor, in patients with advanced solid tumors.|
|Journal||Clinical cancer research : an official journal of the American Association for Cancer Research|
|Date||2014 Jan 01|
|Abstract Text||SAR245408 is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I study determined the maximum tolerated dose (MTD) of two dosing schedules [first 21 days of a 28-day period (21/7) and continuous once-daily dosing (CDD)], pharmacokinetic and pharmacodynamic profiles, and preliminary efficacy.Patients with refractory advanced solid malignancies were treated with SAR245408 using a 3 + 3 design. Pharmacokinetic parameters were determined after single and repeated doses. Pharmacodynamic effects were evaluated in plasma, hair sheath cells, and skin and tumor biopsies.Sixty-nine patients were enrolled. The MTD of both schedules was 600 mg; dose-limiting toxicities were maculopapular rash and hypersensitivity reaction. The most frequent drug-related adverse events included dermatologic toxicities, diarrhea, nausea, and decreased appetite. Plasma pharmacokinetics showed a median time to maximum concentration of 8 to 22 hours, mean terminal elimination half-life of 70 to 88 hours, and 5- to 13-fold accumulation after daily dosing (first cycle). Steady-state concentration was reached between days 15 and 21, and exposure was dose-proportional with doses up to 400 mg. SAR245408 inhibited the PI3K pathway (∼40%-80% reduction in phosphorylation of AKT, PRAS40, 4EBP1, and S6 in tumor and surrogate tissues) and, unexpectedly, also inhibited the MEK/ERK pathway. A partial response was seen in one patient with advanced non-small cell lung cancer. Eight patients were progression-free at 6 months. Pharmacodynamic and clinical activity were observed irrespective of tumor PI3K pathway molecular alterations.SAR245408 was tolerable at doses associated with PI3K pathway inhibition. The recommended phase II dose of the capsule formulation is 600 mg administered orally with CDD.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||Advanced Solid Tumor||not applicable||XL147||Phase I||Actionable||In a Phase I trial, 43.9% (25/56) of patients with advanced solid tumors had stable disease as a best response to treatment with Pilaralisib (XL147), and one patient with NSCLC showed a partial response, and in a separate therapy arm, Pilaralisib (XL147) in tablet formulation demonstrated safety and some antitumor activity in advanced solid tumor patients, including 11.1% (2/18) of patients with a partial response (PMID: 29593099, PMID: 24166903; NCT00486135).||29593099 24166903|
|Unknown unknown||lung non-small cell carcinoma||not applicable||XL147||Phase I||Actionable||In a Phase I study, 25/56 (43.9%) of patients with advanced solid tumors had stable disease as a best response to treatment with XL147, and one patient with NSCLC showed a partial response to XL147 (PMID: 24166903).||24166903|
|PIK3CA mutant||Advanced Solid Tumor||sensitive||XL147||Phase I||Actionable||In a Phase I clinical trial, XL147 (SAR24508) was shown to be safe and potentially efficacious, with clinical activity seen irrespective of tumor PI3K pathway molecular alterations (PMID: 24166903).||24166903|