Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2015 Oct 1;121(19):3481-90.
doi: 10.1002/cncr.29422. Epub 2015 Jul 15.

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

Affiliations
Free PMC article
Clinical Trial

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

Johanna C Bendell et al. Cancer. .
Free PMC article

Abstract

Background: The 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.

Methods: Patients 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.

Results: Twenty-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%.

Conclusions: CC-223 was tolerable, with manageable toxicities. Preliminary antitumor activity, including tumor regression, and evidence of mTORC1/mTORC2 pathway inhibition were observed.

Keywords: AKT; mTOR; mTORC1/mTORC2; rapalogs.

Figures

Figure 1
Figure 1
(A) Response relative to time on CC‐223 treatment and (B) best percentage change from baseline in total length of target lesions were evaluated in 28 and 19 patients, respectively. Abbreviations: CRC, colorectal carcinoma; GBC, glioblastoma multiforme; HCC, hepatocellular carcinoma; MM, multiple myeloma; NET, (gastrointestinal) neuroendocrine tumor (of nonpancreatic origin); NSCLC, non–small cell lung cancer; RCC, renal cell carcinoma.
Figure 2
Figure 2
Mean (+standard deviation [SD]) plasma concentration‐time profiles of CC‐223 are presented on semi‐log scale on (A) day −1 after single dose and (B) day 15 after multiple doses.
Figure 3
Figure 3
Dose‐related plasma biomarker inhibition. Following a single dose of CC‐223 on day −1, cycle 1, inhibition (post‐dose assessments relative to the baseline value) of (A) pS6RP, (B) p4EBP1, and (C) pAKT in stimulated peripheral blood B cells, T cells, and monocytes, respectively, was observed in all patients following doses ranging from 30 to 60 mg. The phosphorylation of AKT (for mTORC2 activity) and p4EBP1 and pS6RP (mTORC1 activity) in relevant cell types were evaluated using flow cytometry with specific antibodies and expressed as equivalent reference fluorophore, ERF. (D) Model of CC‐223 mechanism of action. CC‐223 inhibits phosphorylation of 4EBP1, S6RP, and AKT through suppression of both mTORC1 and mTORC2. Abbreviations: 4EBP1, 4E–binding protein 1; AKT, protein kinase B; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; p4EBP1, phosphorylated 4E‐binding protein 1; p70S6K, p70 S6 kinase 1; pAKT, phosphorylated protein kinase B; PDK1, 3‐phosphoinositide‐dependent protein kinase 1; PI3K, phosphoinositide 3‐kinase; pS6RP, phosphorylated S6 ribosomal protein; S6RP, S6 ribosomal protein.
Figure 4
Figure 4
Pharmacokinetics/pharmacodynamics correlations: (A) pS6RP in stimulated B cells. (B) pS6RP in stimulated monocytes. (C) p4EBP1 in stimulated T cells. (D) pAKT in stimulated B cells. (E) pAKT in stimulated monocytes. Abbreviations: EC50, half maximal effective concentration; p4EBP1, phosphorylated 4E‐binding protein 1; pAKT, phosphorylated protein kinase B; PRED, predicted; pS6RP, phosphorylated S6 ribosomal protein.

Comment in

Similar articles

See all similar articles

Cited by 32 articles

See all "Cited by" articles

References

    1. Massacesi C, di Tomaso E, Fretault N, Hirawat S. Challenges in the clinical development of PI3K inhibitors. Ann N Y Acad Sci. 2013;1280:19‐23. - PMC - PubMed
    1. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029‐1033. - PMC - PubMed
    1. Demetri GD, Chawla SP, Ray‐Coquard I, et al. Results of an international randomized phase III trial of the mammalian target of rapamycin inhibitor ridaforolimus versus placebo to control metastatic sarcomas in patients after benefit from prior chemotherapy. J Clin Oncol. 2013;31:2485‐2492. - PubMed
    1. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal‐cell carcinoma. N Engl J Med. 2007;356:2271‐2281. - PubMed
    1. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double‐blind, randomised, placebo‐controlled phase III trial. Lancet. 2008;372:449‐456. - PubMed

Publication types

Substances

Feedback