First-in-human phase I study exploring three schedules of OSI-027, a novel small molecule TORC1/TORC2 inhibitor, in patients with advanced solid tumors and lymphoma.
2010; Lippincott Williams & Wilkins; Volume: 28; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2010.28.15_suppl.3006
ISSN1527-7755
AutoresDaniel Shao-Weng Tan, Herlinde Dumez, David Olmos, Shahneen Sandhu, Ann Hoeben, Andrew Stephens, Srinivasu Poondru, Richard Gedrich, S.B. Kaye, Patrick Schöffski,
Tópico(s)PI3K/AKT/mTOR signaling in cancer
Resumo3006 Background: The mTOR pathway regulates cell growth, proliferation and survival; and is a clinically validated target for cancer therapy. Current rapamycin analogs preferentially target TORC1, with therapeutic efficacy limited by compensatory feedback loops resulting in AKT and ERK activation. OSI-027 is an oral inhibitor of TORC1 and TORC2 kinase activity and may have additional clinical activity over TORC1 selective inhibitors. Methods: Patients (pts) with advanced solid tumors or lymphoma received escalating doses of OSI-027 in 3 schedules (S1: days (d) 1-3 q7d, S2: once weekly, and S3: continuous once daily) to determine safety, maximum tolerated dose, pharmacokinetics (PK) and preliminary antitumor activity. Pharmacodynamic (PD) effects on phosphorylation of 4E-BP1 at threonine 37/46, a rapamycin insensitive, mTOR-dependent phosphorylation site, were examined. 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. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI OSI
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