A phase Ib combination study of RO4929097, a gamma-secretase inhibitor, and temsirolimus in patients with advanced solid tumors
- 1.3k Downloads
Background To determine the recommended phase II dose (RP2D) and assess the safety, pharmacokinetics (PKs) and pharmacodynamics of RO4929097in combination with temsirolimus. Methods Escalating doses of RO4929097 and temsirolimus were administered at three dose levels. Patients received once daily oral RO4929097 on a 3 days on/4 days off schedule every week, and weekly intravenous temsirolimus. Blood samples were collected for PK analysis. Archival tissue specimens were collected for Notch pathway biomarker analysis and genotyping of frequent oncogenic mutations. Results Seventeen patients with refractory advanced solid tumors were enrolled in three dose levels (DLs): DL1 (RO4929097 10 mg; Temsirolimus 25 mg), DL2 (RO4929097 20 mg; Temsirolimus 25 mg), and DL3 (RO4929097 20 mg; Temsirolimus 37.5 mg). The most common toxicities related to the study drug combination included: fatigue (82 %; grade 3 6 %), mucositis, (71 %; grade 3 6 %), neutropenia (59 %; grade 3 12 %), anemia (59 %; grade 3 0 %), and hypertriglyceridemia (59 %; grade 3 0 %). Two dose-limiting toxicities, grade 3 rash and grade 3 mucositis, were observed in the same patient in the first dose level prompting dose expansion. Eleven patients (73 %) had stable disease as their best response. Co-administration of RO4929097 was associated with increased clearance and reduced exposure to temsirolimus, suggestive of drug-drug interaction via CYP3A4 induction. No correlation between the expression of Notch pathway biomarkers or genotype and time to progression was noted. Conclusions RO4929097 can be safely combined with temsirolimus in patients with advanced solid tumors. The RP2D was established at 20 mg of RO4929097 combined with 37.5 mg of temsirolimus.
KeywordsRO4929097 Temsirolimus Clinical trial Notch Gamma-secretase inhibitor
The authors declare no conflict of interest for this manuscript.
This study (PJC-005/NCI-8500) is conducted by the Princess Margaret Hospital Phase I Consortium with support from the US National Cancer Institute U01 Cooperative Agreement Award (U01-CA132123).
- 1.Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168Google Scholar
- 5.Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247CrossRefGoogle Scholar
- 6.Jenkins DW, Ross S, Veldman-Jones M, Foltz IN, Clavette BC, Manchulenko K, Eberlein C, Kendrew J, Petteruti P, Cho S, Damschroder M, Peng L, Baker D, Smith NR, Weir HM, Blakey DC, Bedian V, Barry ST (2012) MEDI0639: a novel therapeutic antibody targeting Dll4 modulates endothelial cell function and angiogenesis in vivo. Mol Cancer Ther 11:1650–1660CrossRefGoogle Scholar
- 7.Luistro L, He W, Smith M, Packman K, Vilenchik M, Carvajal D, Roberts J, Cai J, Berkofsky-Fessler W, Hilton H, Linn M, Flohr A, Jakob-Rotne R, Jacobsen H, Glenn K, Heimbrook D, Boylan JF (2009) Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res 69:7672–7680CrossRefGoogle Scholar
- 8.Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, Caparros E, Buteau J, Brown K, Perkins SL, Bhagat G, Agarwal AM, Basso G, Castillo M, Nagase S, Cordon-Cardo C, Parsons R, Zuniga-Pflucker JC, Dominguez M, Ferrando AA (2007) Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 13:1203–1210CrossRefGoogle Scholar
- 9.Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J, Leister C, Korth-Bradley J, Hanauske A, Armand JP (2004) Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 22:2336–2347CrossRefGoogle Scholar
- 13.Shepherd C, Banerjee L, Cheung CW, Mansour MR, Jenkinson S, Gale RE, Khwaja A (2012) PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response. LeukemiaGoogle Scholar
- 14.Tolcher AW, Chugh R, Chambers G, Thorpe V, Dupont J, Hill D, Xu L, Kapoun A, Smith DC (2012) A first-in-human phase I study to evaluate the fully human monoclonal antibody OMP-59R5 (anti-Notch2/3) administered intravenously to patients with advanced solid tumors. J Clin Oncol 30:3025CrossRefGoogle Scholar
- 15.Tolcher AW, Messersmith WA, Mikulski SM, Papadopoulos KP, Kwak EL, Gibbon DG, Patnaik A, Falchook GS, Dasari A, Shapiro GI, Boylan JF, Xu ZX, Wang K, Koehler A, Song J, Middleton SA, Deutsch J, Demario M, Kurzrock R, Wheler JJ (2012) Phase I study of RO4929097, a Gamma secretase inhibitor of notch signaling, in patients with refractory metastatic or locally advanced solid tumors. J Clin Oncol 30:2348–2353CrossRefGoogle Scholar
- 17.Wu J, Wiegand R, LoRusso P, Li J (2011) Validation and implementation of a liquid chromatography/tandem mass spectrometry assay for quantitation of the total and unbound RO4929097, a gamma-secretase inhibitor targeting Notch signaling, in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 879:1537–1543CrossRefGoogle Scholar
- 18.Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, de Leon GP, Chen Y, Finkle D, Venook R, Wu X, Ridgway J, Schahin-Reed D, Dow GJ, Shelton A, Stawicki S, Watts RJ, Zhang J, Choy R, Howard P, Kadyk L, Yan M, Zha J, Callahan CA, Hymowitz SG, Siebel CW (2010) Therapeutic antibody targeting of individual Notch receptors. Nature 464:1052–1057CrossRefGoogle Scholar
Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.