Abstract C252: A phase 1, dose-escalation study of MLN0128, an investigational oral mammalian target of rapamycin complex 1/2 (mTORC1/2) catalytic inhibitor, in patients (pts) with advanced non-hematologic malignancies.

Infante, Jeffrey R.; Tabernero, Josep; Jalal, Shadia I.; Burris, Howard A.; Macarulla, Teresa; Perez-Fidalgo, J. Alejandro; Neuwirth, Rachel; Patel, Chirag; Gangolli, Esha; Brake, Rachael; Sturm, Jeffrey; Westin, Eric H.; Gordon, Michael

doi:10.1158/1535-7163.targ-13-c252

Cited by 16 publications

(22 citation statements)

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“…In the present study, dose‐dependent glucose and C‐peptide level elevations occurred in patients receiving CC‐223 ≥30 mg/d. Interestingly, neither hypercholesterolemia nor hypertriglyceridemia was a frequent event in patients treated with CC‐223, a finding similar to that observed with other mTORC1/mTORC2 inhibitors …”

Section: Discussionsupporting

confidence: 77%

“…The MTD was 45 mg/d, although 11.1% of patients at the MTD required dose reductions and 55.6% required interruptions. CC‐223 was associated with a safety profile similar to that of other mTORC1/mTORC2 inhibitors, such as MLN0128/INK128 and AZD8055 . Common CC‐223–related AEs were fatigue, nausea, diarrhea, and hyperglycemia; the most common grade 3 AE was hyperglycemia (18%).…”

Section: Discussionmentioning

confidence: 92%

“…CC-223 was associated with a safety profile similar to that of other mTORC1/mTORC2 inhibitors, such as MLN0128/INK128 and AZD8055. 9,23 Common CC-223-related AEs were fatigue, nausea, diarrhea, and hyperglycemia; the most common grade 3 AE was hyperglycemia (18%). Hyperglycemia, hypercholesterolemia, and other metabolic abnormalities are common in patients treated with other mTOR inhibitors, including the rapalogs everolimus and temsirolimus.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, neither hypercholesterolemia nor hypertriglyceridemia was a frequent event in patients treated with CC-223, a finding similar to that observed with other mTORC1/mTORC2 inhibitors. 9,23 The pharmacokinetics of CC-223 were doseproportional. Pharmacodynamic analyses showed a relationship between CC-223 exposure and pAKT, p4EBP1, and pS6RP reduction in stimulated B cells, T cells, and monocytes, respectively, thus differentiating CC-223 from rapalogs that typically cause pAKT activation and minimal p4EBP1 inhibition.…”

Section: Discussionmentioning

confidence: 99%

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A phase I dose‐escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC‐223 in patients with advanced solid tumors or multiple myeloma

Bendell

Kelley

Shih

et al. 2015

Cancer

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BACKGROUNDThe mammalian target of rapamycin (mTOR) pathway is essential for tumor development, yet mTOR inhibitors have yielded modest results. This phase 1 study investigated the mTORC1/mTORC2 inhibitor CC‐223 in patients with advanced cancer.METHODSPatients with advanced solid tumors or multiple myeloma received an initial dose of 7.5‐60 mg of CC‐223, followed by oral daily dosing in 28‐day cycles until disease progression. The primary objective was to determine the safety, tolerability, nontolerated dosage, maximum tolerated dosage (MTD), and preliminary pharmacokinetic profile. Secondary objectives were to evaluate pharmacodynamic effects and to describe preliminary efficacy.RESULTSTwenty‐eight patients were enrolled and received ≥1 dose of CC‐223. The most common treatment‐related grade 3 adverse events were hyperglycemia, fatigue, and rash. Four patients had dose‐limiting toxicities, including hyperglycemia, rash, fatigue, and mucositis. Therefore, 45 mg/d was determined to be the MTD. The pharmacokinetics of CC‐223 demonstrated a mean terminal half‐life ranging from 4.86 to 5.64 hours and maximum observed plasma concentration ranging from 269 to 480 ng/mL in patients who received CC‐223 ≥45 mg/d. Phosphorylation of mTORC1/mTORC2 pathway biomarkers in blood cells was inhibited by CC‐223 ≥30 mg/d with an exposure‐response relationship. Best responses included 1 partial response (breast cancer; response duration 220 days; 30‐mg/d cohort), stable disease (8 patients across ≥15 mg/d cohorts; response duration range, 36‐168 days), and progressive disease (12 patients). The disease control rate was 32%.CONCLUSIONSCC‐223 was tolerable, with manageable toxicities. Preliminary antitumor activity, including tumor regression, and evidence of mTORC1/mTORC2 pathway inhibition were observed. Cancer 2015;121:3435–43. © 2015 American Cancer Society.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A phase I dose‐escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC‐223 in patients with advanced solid tumors or multiple myeloma

Bendell

Kelley

Shih

et al. 2015

Cancer

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“…MLN0128 has shown activity against a large number of human tumor cell lines with diverse tissue origins and genetic makeups including acute lymphoblastic leukemia, renal cell carcinoma, prostate, breast, endometrial and lung cancers and demonstrated inhibitory activity toward mTOR signaling in human tumor xenograft mouse models with well‐defined pharmacological properties (Janes et al, ; Liu et al, ; Ingels et al, ; Gökman‐Polar et al, ; Edlind & Hsieh, ; Fabrey, Atienza, Briere, Brake, & Vincent, ). To date, two Phase I clinical trials of MLN0128 have been conducted, which showed acceptable safety profiles (Infante et al, ; Burris et al, ). These findings warrant further clinical trials of MLN0128 in patients with various advanced and recurrent cancers (https://www.clinicaltrials.gov/ct2/results?term= MLN0128&Search = Search, accessed 7 August 2016).…”

Section: Introductionmentioning

confidence: 99%

Determination of MLN0128, an investigational antineoplastic agent, in human plasma by LC–MS/MS

Kunati

2016

Biomedical Chromatography

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MLN0128, an mTOR kinase inhibitor, is currently undergoing clinical investigation for treatment of a variety of cancers. To support this work, an LC-MS/MS method has been developed for the determination of MLN0128 in human plasma. A structural analog STK040263 was used as the internal standard. Both MLN0128 and the IS were first extracted from plasma using methyl tert-butyl ether; then separated on a Waters XTerra® MS C column using a mobile phase consisting of methanol-acetonitrile-10.0 mm ammonium formate (34:6:60, v/v/v) at a flow rate of 0.300 mL min . Quantitation of MLN0128 was done by positive electrospray ionization tandem mass spectrometry in multiple-reaction-monitoring mode. This method has a total run time of <4 min with the retention times of 1.95 and 2.94 min for the IS and MLN0128, respectively. The method has been validated per the US Food and Drug Administration guidance for bioanalytical method validation. It has a calibration range of 0.100-50.0 ng mL in human plasma with a correlation coefficient > 0.999. The overall assay accuracy and precision were ≤ ± 4 and ≤8%, respectively. The IS normalized recovery of MLN0128 was 98-100%. The stability studies showed that MLN0128 was stable under all tested conditions. The method developed may be useful for clinical studies of MLN0128.

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TAK‐228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non‐Hodgkin lymphoma, or Waldenström's macroglobulinemia

et al. 2016

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The PI3K/AKT/mTOR signaling pathways are frequently dysregulated in multiple human cancers, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Waldenstr€ om's macroglobulinemia (WM). This was the first clinical study to evaluate the safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary clinical activity of TAK-228, an oral TORC1/2 inhibitor, in patients with MM, NHL, or WM. Thirty-nine patients received TAK-228 once daily (QD) at 2, 4, 6, or 7 mg, or QD for 3 days on and 4 days off each week (QDx3d QW) at 9 or 12 mg, in 28-day cycles. The overall median age was 61.0 years (range 46-85); 31 patients had MM, four NHL, and four WM. Cycle 1 DLTs occurred in five QD patients (stomatitis, urticaria, blood creatinine elevation, fatigue, and nausea and vomiting) and four QDx3d QW patients (erythematous rash, fatigue, asthenia, mucosal inflammation, and thrombocytopenia). The MTDs were determined to be 4 mg QD and 9 mg QDx3d QW. Thirty-six patients (92%) reported at least one drug-related toxicity; the most common grade 3 drug-related toxicities were thrombocytopenia (15%), fatigue (10%), and neutropenia (5%). TAK-228 exhibited a dose-dependent increase in plasma exposure and no appreciable accumulation with repeat dosing; mean plasma elimination half-life was 6-8 hr. Of the 33 response-evaluable patients, one MM patient had a minimal response, one WM patient achieved partial response, one WM patient had a minor response, and 18 patients (14 MM, two NHL, and two WM) had stable disease. These findings encourage further studies including combination strategies.Am. J. Hematol. 91:400-405,

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Abstract C252: A phase 1, dose-escalation study of MLN0128, an investigational oral mammalian target of rapamycin complex 1/2 (mTORC1/2) catalytic inhibitor, in patients (pts) with advanced non-hematologic malignancies.

Cited by 16 publications

References 0 publications

A phase I dose‐escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC‐223 in patients with advanced solid tumors or multiple myeloma

A phase I dose‐escalation study to assess safety, tolerability, pharmacokinetics, and preliminary efficacy of the dual mTORC1/mTORC2 kinase inhibitor CC‐223 in patients with advanced solid tumors or multiple myeloma

Determination of MLN0128, an investigational antineoplastic agent, in human plasma by LC–MS/MS

TAK‐228 (formerly MLN0128), an investigational oral dual TORC1/2 inhibitor: A phase I dose escalation study in patients with relapsed or refractory multiple myeloma, non‐Hodgkin lymphoma, or Waldenström's macroglobulinemia

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