Phase I study of everolimus (E) plus low-dose weekly cisplatin (C) for patients with advanced solid tumors.

Abstract

e13013 Background: Preclinical studies demonstrate synergistic antitumor activity with the combination of E + C. Methods: Part A used a standard 3 + 3 dose escalation scheme. There were 4 planned dose levels (DLs) of E: 2.5, 5, 7.5, and 10 mg/day. Regimen was E per oral for days 1-21 and C 20 mg/m2 intravenously (fixed dose) on days 1, 8, and 15 of a 28-day cycle. For pharmacokinetics (PK), blood samples were collected on Day 1 and Day 8 of Cycle 1 in Part A. After the phase II-recommended dose was established (Part A), 6 additional subjects with easily accessible tumors for office biopsy were enrolled for pharmacodynamic correlates (Part B). Response was assessed by RECIST q 2 cycles for all subjects. Results: 30 patients enrolled (29 treated): 18 M, 12F; median age 62 (31-79); median number of prior cytotoxic chemotherapy regimens 1 (0-3; 80% with prior RT). DLTs were: DL1, 1 (sudden death of unclear cause in patient with melanoma metastatic to liver); DL2, 1 (bowel obstruction); DL3, 0; DL4, 0. Most common adverse events (≥ grade 3) among 29 patients evaluable for toxicity: lymphopenia (33%), hypophosphatemia (13%), hemoglobin (10%), and hyperglycemia (11%). PK analysis of E demonstrated dose proportional increases in Cmax (mean 91.9 ng/ml at DL4) and AUC0-INF(mean 680.4 hr*ng/ml at DL4). Two objective responses were seen (CR, metastatic pulmonary carcinoid; PR, metastatic sinus carcinoma). Prolonged SD ≥ 6 cycles occurred in 2 pulmonary carcinoid subjects, and in oropharyngeal SCC, basal cell carcinoma, and esthesioneuroblastoma (n=1 each). In Part B, pretreatment and on-treatment biopsies (Day 20) obtained in the oropharynx SCC subject showed no significant changes in expression of p-AKT, p21, or p53 as assessed by immunohistochemistry. Conclusions: The phase II recommended dose is E 10 mg/day (days 1 - 21) + C 20 mg/m2 (days 1, 8, and 15) on a 28-day cycle. PK data demonstrate dose-proportional increases in exposure, as previously described for E monotherapy. Antitumor activity was observed in several tumor types, including metastatic sinus carcinoma that had been previously treated with C. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis