Phase I study of everolimus and mitomycin C for patients with metastatic esophagogastric adenocarcinoma.
This study aimed at determining the recommended dose of the mammalian target of rapamycin inhibitor everolimus in combination with mitomycin C (MMC) in patients with previously treated metastatic esophagogastric cancer. In this phase I trial, patients received escalated doses of oral everolimus (5, 7.5, and 10 mg/day) in combination with intravenous MMC 5 mg/m² every 3 weeks. Endpoints were the dose-limiting toxicity (DLT), safety, and response rates. Tumor tissues were tested for HER2-status and mutations in the PTEN, PIK3CA, AKT1, CTNNB1, and E-cadherin type 1 genes. Sixteen patients (12 male, four female) with gastric/gastroesophageal junction cancer were included. All patients were previously treated with a platinum-based chemotherapy. Treatment cohorts were: 5 mg/day, three patients; 7.5 mg/day, three patients; and 10 mg/day, 10 patients. No DLTs occurred during dose escalation. Most frequent grade 3 toxicities were leukopenia (18.8%) and neutropenia (18.8%). All other grade 3 toxicities were below 10%. No grade 4 toxicities occurred. Three (18.8%) patients experienced partial responses and four patients had stable disease (SD). Antitumor activity according to Response Evaluation Criteria In Solid Tumors (RECIST)-criteria was highest in the 10 mg/day cohort. No associations between HER2-status or detected mutations and response were observed. The recommended dose of everolimus combined with MMC is 10 mg/day. Encouraging signs of antitumor activity were seen (http://www.ClinicalTrials.gov;


BACKGROUND
NCT01042782).
Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt am Main, Germany.
Dominique
D
Werner
Akin
A
Atmaca
Claudia
C
Pauligk
Anette
A
Pustowka
Elke
E
Jäger
Salah-Eddin
SE
Al-Batran
D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000068338:Everolimus; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage / Q000009:adverse effects; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis
D016685:Mitomycin; D000068338:Everolimus; D020123:Sirolimus
Esophagogastric; RAD001; everolimus; gastric; mitomycin C