MedKoo product information:

OSI-027

mTOR kinase inhibitor OSI-027 is an orally bioavailable mammalian target of rapamycin (mTOR) kinase inhibitor with potential antineoplastic activity. mTOR kinase inhibitor OSI-027 binds to and inhibits both the raptor-mTOR (TOR complex 1 or TORC1) and the rictor-mTOR (TOR complex 2 or TORC2) complexes of mTOR, which may result in tumor cell apoptosis and a decrease in tumor cell proliferation. mTOR is a serine/threonine kinase that is upregulated in some tumors and plays an important role downstream in the PI3K/Akt/mTOR signaling pathway. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Current developer:    OSI Pharmaceuticals, Inc.

Phase I trial results:  To date, 34 pts have been enrolled (13M/21F, median age 59 yrs) and 31 treated (S1 11 pts, S2 12 pts, S3 8 pts). S1 and S2 pts were dosed at 10, 15 and 20 mg, S3 pts at 5, 10 and 20 mg. Median number of weeks on study was 6 (range <1-34). Three DLTs have been reported: grade (G) 2 decreased LVEF (10mg S1), and 2 pts with G3 fatigue (15 mg S2 and 20 mg S3). Other drug-related toxicities included G3 nausea and vomiting (1), G3 pneumonia (1); G1/2 fatigue (4), nausea (2), diarrhea (1), anorexia (1), elevated creatinine (1), and reversible increase in QTc (1). Preliminary PK indicate exposure (AUC, Cmax) of OSI-027 increased with dose. The median Tmax and terminal T3/4 were 2-6 hrs and 6-17 hrs, respectively. Preliminary PD data indicate that substantial decreases in 4E-BP1 (T37/46) phosphorylation were observed in PBMCs from 13 of 23 pts following OSI-027 treatment. Eight pts have had SD lasting ≥ 12 wks (26% of pts treated, range 12-33 wks); tumor types were colorectal (3 pts), melanoma, neuroendocrine, endometrial, renal, and cervical cancer (1 pt each). Conclusions: OSI-027 is a potent TORC1/2 kinase inhibitor. Preliminary evidence of pharmacological activity has been observed. It is well tolerated at the doses and schedules tested to date. MTD has not been reached and dose escalation is ongoing. (source: Journal of Clinical Oncology, 2010 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 28, No 15_suppl (May 20 Supplement), 2010: 3006. or http://meeting.ascopubs.org/cgi/content/abstract/28/15_suppl/3006).

1: Vakana E, Sassano A, Platanias LC. Induction of autophagy by dual mTORC1-mTORC2 inhibition in BCR-ABL-expressing leukemic cells. Autophagy. 2010 Oct 19;6(7). [Epub ahead of print] PubMed PMID: 20699667.

2: Carayol N, Vakana E, Sassano A, Kaur S, Goussetis DJ, Glaser H, Druker BJ, Donato NJ, Altman JK, Barr S, Platanias LC. Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12469-74. Epub 2010 Jun 28. PubMed PMID: 20616057; PubMed Central PMCID: PMC2906574.