Abstract P3-14-17: Trastuzumab (H) and Rapamycin (R) for Treatment of HER-2 Overexpressing Metastatic Breast Cancer (BC) with Prior Disease Progression on H Based Therapy: Safety and Pharmacodynamic (PD) Results
Authors: Abu-Khalaf MM , Chung G , DiGiovanna MP , Fishbach N , Zelterman D , Tuck D , Harris L. 
Published: April 2011

Abstract
Background: Preclinical data shows upregulation of the PI3K/AKT pathway and synergistic cytotoxicty between H+R in sensitive and resistant HER-2 overexpressing BC cell lines.
Methods: We designed a phase II clinical trial with an early stopping rule for excess toxicity in the first 4 wks of H+R therapy, defined as ≥3 cases of drug related grade 3 or 4 toxicity observed in the first 9 pts enrolled on trial. We report safety and PD results in 11 pts treated with oral R 6 mg daily + standard dosesand schedule of H. LVEF by ECHO or MUGA was assessed at baseline and every 3 months thereafter; treatment was held for LVEF drop below normal limits or ≥20 percentage points. Pre and post therapy tumor samples were collected when feasible. Circulating tumor (CTC) and endothelial (CEC) cells were collected and analyzed using the Veridex Cell Search System at baseline, wks 1, 2 and 4 and with every restaging.
Results: 11 pts with median age 56 y (range 38-70) treated with H+R were evaluable for safety. Median # cycles was 3 (range 1+ to 12). Non-hematologic grade 3 toxicities in first 4 wks occurred in 3 of the first 9 pts: 1 pt had syncope associated with leucopenia/neutropenia and urinary infection; 1pt had mucositis which responded to dose reduction; 1 pt with known diabetes had grade 3 hyperglycemia, however, this was non-fasting. One pt had grade 3 leucopenia/neutropenia which responded to dose reduction. Grade 3 toxicities for 11 pts in all cycles were as follows: leucopenia/neutropenia (2 pts), non-fasting hyperglycemia (2 pts), syncope (1 pt), hypokalemia (1pt), hyponatremia (1 pt), mucositis (1 pt), rash (2 pts), nail changes (1 pt), thrombosis (1 pt). Infection (urine in 1 pt, skin in 1 pt), anemia (1pt), and elevated PTT (1 pt). One grade 4 non-fasting hyperglycemia occurred in a diabetic pt. LVEF dropped below normal limits and recovered subsequently in 2 pts. Nine pts had baseline and at least one subsequent evaluation for radiographic response by RECIST. Best response was unconfirmed partial response (PR) in 1 pt (8 cycles), stable disease (SD) in 5 pts (12, 6+,6, 3, and 2 cycles) and progression (PD) in 3pts. We combined analysis of AKT pathway markers from 12 baseline and 9 post therapy tissue samples collected on this trial and a phase I study of R +chemotherapy. There were high correlations between baseline AKT pathway markers (mTOR, PTEN, Akt, pAkt, S6K1 and pS6K1; (Spearman's rho-0.401-0.907). This correlation was lost in post therapy samples. Higher mean mTOR levels were seen in non-responders (PD) vs. responders (SD/PR) [p value=0.04]. Eight pts had CTC and CEC results, and were evaluable for response. Baseline CTC levels of &gt;5 cells/7.5 ml were seen in 2/2 pts with PD and 0/6 pts with SD/PR. There was no significant difference in CEC levels between responders and non-responders. Conclusion: R 6 mg daily appears to be well tolerated when combined with standard doses of H. PR in 1 pt and SD for ≥6 months was observed in 2 pts with prior progression on H based therapy. Baseline elevated mTOR level correlates with poor response to R based combinations. Post therapy change in marker expression suggests biologic effect of R.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-14-17.