Doubling Down on mTOR Inhibition: Harnessing ZEBRA for Insights

Chan, Jason Yongsheng; Choudhury, Yukti; Tan, Min‐Han

doi:10.1016/j.eururo.2015.09.047

Cited by 3 publications

(1 citation statement)

References 10 publications

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“…It seems unlikely that a challenging safety profile alone might account for such differences in cancer-specific outcome. Some have proposed that dual mTORC1/2 inhibition upregulates FOXO activity, which, in turn, may upregulate receptor tyrosine kinase expression [ 17 , 18 ]. Regardless, in aggregate, our data do not support the strategy of broader mTOR/PI3K pathway inhibition in advanced RCC.…”

Section: Assessment Analysis and Discussionmentioning

confidence: 99%

A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma

et al. 2016

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Lessons LearnedOur results highlight additional toxicities of dual PI3K/mTOR inhibition in the clinical setting that were unforeseen from preclinical models.Because of toxicity and lack of efficacy, BEZ235 should not be further developed in the current formulation for patients with renal cell carcinoma.Background.Allosteric inhibitors of the mammalian target of rapamycin complex 1 (mTORC1) are approved for advanced renal cell carcinoma (RCC). Preclinical models have suggested that dual inhibition of phosphatidylinositol 3-kinase (PI3K) and mTOR kinase may establish superior anticancer effect. We aimed to establish safety for BEZ235, a potent inhibitor of both PI3K and mTOR, in advanced RCC.Methods.Patients with advanced RCC who had previously failed standard therapy received escalating doses of BEZ235 in sachet formulation twice daily until progression or unacceptable toxicity. Primary endpoints were to identify the maximally tolerated dose (MTD) and to determine the recommended dose for the phase II study.Results.The study was terminated early because of high incidence of dose-limiting toxicities (DLTs) across all dose levels tested. Ten patients were treated with BEZ235—six with clear cell and four with non-clear cell subtypes. Five of these patients suffered DLTs: 2 of 2 patients in the original 400 mg b.i.d. cohort, 1 of 6 in the 200 mg b.i.d. cohort, and 2 of 2 in the 300 mg b.i.d. cohort. DLTs included fatigue, rash, nausea and vomiting, diarrhea, mucositis, anorexia, and dysgeusia. Five patients were evaluable for response: Two had stable disease as best response, and three had progressive disease.Conclusion.BEZ235 twice daily resulted in significant toxicity without objective responses; further development of this compound will not be pursued in this disease.

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Section: Assessment Analysis and Discussionmentioning

confidence: 99%

A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma

et al. 2016

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Medical evaluation and pharmacotherapeutical strategies in management of urolithiasis

Haleem

Mamuchashvili

et al. 2021

Therapeutic Advances in Urology

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Treatment of urolithiasis depends on several important factors which include stone location, size, composition, and patient symptoms. Although significant advancements have been made in the surgical management of urolithiasis in the last decade, pharmacotherapy which can prevent the formation of new stones and decrease the recurrence of urolithiasis has not experienced the same level of success. Currently, urolithiasis is regarded as a complicated syndrome that is determined by numerous factors, and any treatment plan for urolithiasis should be individualized while considering any potential damage arising from stone-forming factors. This review introduces the most popular methods currently used to evaluate urolithiasis and the pharmacotherapy of urolithiasis based on patient-specific factors.

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A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms

et al. 2019

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Second-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9–97.3%). Duration of PR was 125–401 days; median SD duration was 297 days (min–max, 50–1519 days). Median progression-free survival was 19.5 months (95% CI 10.4–28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.

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Doubling Down on mTOR Inhibition: Harnessing ZEBRA for Insights

Cited by 3 publications

References 10 publications

A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma

A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma

Medical evaluation and pharmacotherapeutical strategies in management of urolithiasis

A phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptoms

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