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


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/m(2), 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/m(2) PTX and 12.5 mg/80 mg/m(2). 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 > or =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.


CONCLUSIONS
Potential antiangiogenic effects and encouraging antitumor activity justify further development of the combination.
Sessa
C
C
Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland; Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy.
Tosi
D
D
Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy.
Viganò
L
L
Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy.
Albanell
J
J
Department of Medical Oncology, IMAS-Hospital del Mar, Barcelona, Spain.
Hess
D
D
Department of Oncology-Hematology, Kantonsspital St. Gallen, Saint Gallen, Switzerland.
Maur
M
M
Department of Medical Oncology, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
Cresta
S
S
Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy.
Locatelli
A
A
Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy.
Angst
R
R
Department of Oncology-Hematology, Kantonsspital St. Gallen, Saint Gallen, Switzerland.
Rojo
F
F
Molecular Therapeutics and Biomarkers in Breast Cancer Program, IMIM-Hospital del Mar, Barcelona, Spain.
Coceani
N
N
Study Management Unit, Southern Europe New Drugs Organization, Milano, Italy.
Rivera
V M
VM
Preclinical and Translational Research Unit.
Berk
L
L
Preclinical and Translational Research Unit.
Haluska
F
F
Clinical Research Unit, ARIAD Pharmaceuticals Inc., Cambridge, MA, USA.
Gianni
L
L
Department of Medical Oncology I, 'Montabone' Unit for New Drug Development, Fondazione IRCCS Istituto dei Tumori di Milano, Italy. Electronic address: luca.gianni@istitutotumori.mi.it.
D000328:Adult; D000368:Aged; D000465:Algorithms; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome
D047908:Intracellular Signaling Peptides and Proteins; C515074:ridaforolimus; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel; D020123:Sirolimus