[406] Multicenter phase I clinical trial of daily and weekly RAD001 (everolimus) in combination with vinorelbine and trastuzumab in patients with HER-2-overexpressing metastatic breast cancer with prior resistance to trastuzumab.

Fasolo A, Gianni L, Rorive A, Bergh J, Dieras V, Cardoso F, Vittori L, Pylvaenaeinen I, Sahmoud T, Jerusalem G Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; C.H.U. Sart-Tilman, Liege, Belgium; Karolinska Institute and University Hospital, Stockholm, Sweden; Institut Curie, Paris, France; Jules Bordet Institute, Brussels, Belgium; Novartis Pharmaceuticals, Basel, Switzerland

Background: Resistance to trastuzumab (H) is associated with loss of PTEN and AKT/mTOR activation. Preclinically, RAD001, an oral inhibitor of mTOR, enhances the efficacy of H suggesting that RAD001 could reverse resistance to H.
Methods: Vinorelbine (V) was administered at a dose of 25 mg/m², IV over 10-15 min on days 1 and 8 q3w. H 4 mg/kg loading dose administered IV over 90 min on Day 1 (if pt was not already receiving H), followed by weekly H 2 mg/kg IV over 30 min. In the daily RAD001 arm, 3 cohorts were planned (2.5, 5 and 10mg) and in the weekly RAD001 arm, 4 cohorts were planned (20, 30, 50 and 70mg). Treatment continued until progression or unacceptable toxicity.
Results: As of June 10 2008, 28 heavily pretreated pts were enrolled: 15 to 5mg/d, 6 to 20mg/w and 7 to 30mg/w cohorts. All pts received prior taxanes. Median number of prior CT regimens was 3 (range: 1-5). The main safety events were grade 2 and 3 stomatitis which led to dose reduction of RAD001 in 3 pts and dose interruption in 3. Grade 4 and 3 Neutropenia were seen in 24 pts (leading to dose reduction of V in 11 pts). Twenty two pts have been evaluated for efficacy (table 1). 1 pt had a CR (45+ weeks), 2 pts had PR (35+, 38 weeks), 15 pts SD (Median 26+, range 8+ to 58 weeks) and 4 pts PD. Clinical benefit rate (CR+PR+SD > 24 wks) is 55%+.
Conclusions: Initial findings show that RAD001 is generally well tolerated in combination with V and H and shows promising anticancer activity and clinical benefit in heavily pretreated patients with HER2+ advanced breast cancer. Updated results will be presented.

Table 1

Best Response	5mg/d (n=11)	20mg/w (n=6)	30mg/w (n=5)
CR	1	0	0
PR	1	1	0
SD	7	3	5
Progression	2	2	0

Friday, December 12, 2008 7:00 AM

Poster Discussion Session: Novel Targeted Therapies (7:00 AM-9:00 AM)