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Annals of Oncology Advance Access published online on November 9, 2009
Annals of Oncology, doi:10.1093/annonc/mdp504
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Phase Ib study of weekly mammalian target of rapamycin inhibitor ridaforolimus (AP23573; MK-8669) with weekly paclitaxel

C. Sessa1,2, D. Tosi2, L. Viganò2, J. Albanell3, D. Hess4, M. Maur1, S. Cresta2, A. Locatelli2, R. Angst4, F. Rojo5, N. Coceani6, V. M. Rivera7, L. Berk7, F. Haluska8 and L. Gianni2,*

1 Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland
2 Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy
3 Department of Medical Oncology, IMAS-Hospital del Mar, Barcelona, Spain
4 Department of Oncology-Hematology, Kantonsspital St. Gallen, Saint Gallen, Switzerland
5 Molecular Therapeutics and Biomarkers in Breast Cancer Program, IMIM-Hospital del Mar, Barcelona, Spain
6 Study Management Unit, Southern Europe New Drugs Organization, Milano, Italy
7 Preclinical and Translational Research Unit
8 Clinical Research Unit, ARIAD Pharmaceuticals Inc., Cambridge, MA, USA

* Correspondence to: Dr L. Gianni, Department of Medical Oncology 1, ‘Montabone’ Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Via Venezian 1, 20122 Milano, Italy. Tel: +39-02-23902789; Fax: +39-02-23902012; E-mail: luca.gianni{at}istitutotumori.mi.it

Background: The additive cytotoxicity in vitro prompted a clinical study evaluating the non-prodrug rapamycin analogue ridaforolimus (AP23573; MK-8669; formerly deforolimus) administered i.v. combined with paclitaxel (PTX; Taxol).

Materials and methods: Patients with taxane-sensitive solid tumors were eligible. The main dose escalation foresaw 50% ridaforolimus increments from 25 mg with a fixed PTX dose of 80 mg/m2, both given weekly 3 weeks in a 4-week cycle. Collateral levels with a lower dose of either drug were planned upon achievement of the maximum tolerated dose in the main escalation. Pharmacodynamic studies in plasma, peripheral blood mononuclear cells (PBMCs) and skin biopsies and pharmacokinetic (PK) interaction studies at cycles 1 and 2 were carried out.

Results: Two recommended doses were determined: 37.5 mg ridaforolimus/60 mg/m2 PTX and 12.5 mg/80 mg/m2. Most frequent toxic effects were mouth sores (79%), anemia (79%), fatigue (59%), neutropenia (55%) and dermatitis (48%). Two partial responses were observed in pharyngeal squamous cell and pancreatic carcinoma. Eight patients achieved stable disease ≥4 months. No drug interaction emerged from PK studies. Decrease of eukaryotic initiation factor 4E-binding protein1 (4E-BP1) phosphorylation was shown in PBMCs. Similar inhibition of phosphorylation of 4E-BP1 and mitogen-activated protein kinase was present in reparative epidermis and vascular tissues, respectively.

Conclusion: Potential antiangiogenic effects and encouraging antitumor activity justify further development of the combination.

angiogenesis, mTOR inhibitor, paclitaxel, phase I, ridaforolimus

Received for publication June 8, 2009. Revision received August 20, 2009. Accepted for publication September 15, 2009.


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