Ridaforolimus (AP23573; MK-8669) in Combination with Trastuzumab for Patients with HER2-Positive Trastuzumab-Refractory Metastatic Breast Cancer: A Multicenter Phase 2 Clinical Trial.
Authors: Yardley D. , Seiler M. , Ray-Coquard I. , Melichar B. , Hart L. , Dieras V. , Barve M. , Melnyk A. , Dorer D. , Turner C. , Dodion P. 
Published: December 2010

Abstract
Background: Trastuzumab (T) resistance may be due to aberrant signaling through the PI3K/Akt pathway. Pre-clinical and retrospective clinical data suggest that mTOR inhibition can overcome this mechanism of trastuzumab resistance. Ridaforolimus (R), an mTOR inhibitor, in combination with HER2 inhibition offers the potential for vertical pathway synergy.Methods: A single-arm, two-stage phase 2 trial was performed to evaluate R combined with T. Eligibility criteria included: female patients with HER2+ (IHC 3+ or FISH+) metastatic breast cancer (MBC), age ≥18 years, ECOG performance status ≤ 1, RECIST criteria measurable disease, LVEF ≥ 50%, who developed T resistance (defined as disease progression on T treatment with no more than 2 prior T regimens). R was administered orally at 40 mg once daily for 5 consecutive days per week. T was administered intravenously with a loading dose of 4 mg/kg followed by 2 mg/kg/wk. The treatment cycle for both agents was 4 weeks. In Stage 1 of the trial, 14 patients were assessed for safety after at least 1 cycle of therapy and objective response (OR) assessed every 2 cycles according to modified RECIST guidelines. At the time of the Stage 1 interim analysis, if one or more patients exhibited an OR, study enrollment continued to a total accrual of 33 patients. Patients continued study treatment until disease progression or other discontinuation criteria were met.Results: As of June 2009, 22 patients, median age 55 years (range 33-81), were enrolled. Thirteen and 9 pts had 1 and 2 prior T regimens, respectively. Nine patients discontinued prior to the first scheduled study assessment: 6 patients for progressive disease, 1 for AE (G2 stomatitis), 1 for a protocol violation (treatment with radiation), and 1 due to death from an intestinal perforation (diagnosed at autopsy; assessed by investigator as possibly related to R). One other patient discontinued after 7 months of treatment due to elevated transaminases related to R. Twelve patients remain on treatment. There were 2 PR (1 confirmed and 1 unconfirmed) among the first 14 patients. The prospectively defined Stage 1 safety review demonstrated mostly Grade 1/2 AEs that were within the expected safety profile of either study drug. Six related Grade 3 AEs (3 stomatitis/mucositis, 1 hyperglycemia, 1 neutropenia, and 1 dysphagia) were reported. There were no study related Grade 4 AEs. Ten SAEs have been reported in 5 patients; 2 were assessed by investigators as possibly related to R (death from intestinal perforation and venous thrombosis).Conclusions: R in combination with T is feasible and well tolerated with early evidence of encouraging anti-tumor activity in T resistant HER2+ MBC. Enrollment is ongoing and updated data will be presented.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3091.