A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted olid tumours

Abstract

Background:Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells.Methods:We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Dose-limiting toxicities were monitored for the first 6 weeks. Progression-free survival (PFS) and response assessment are based on RECIST 1.0 guidelines. Pharmacokinetics of IM were measured before and after exposure to MC.Results:No dose-limiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. Apart from a case of possibly related acute leukaemia occurring after 4 years of treatment, we did not see unexpected toxicity. No drug–drug pharmacokinetic interaction was observed. There was no objective response. We have observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2–18+) and short-term stable disease in heavily GIST pretreated patients (median PFS=2.3 months; range, 2.1–6.6).Conclusion:This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients.

Molecular Targeted Therapy in the Treatment of Chordoma: A Systematic Review

“…Among 33 studies, nine studies were clinical trials (10–12, 14, 15, 19–22), with eight retrospective case series (16, 17, 23–28), and 16 case reports (13, 29–43). Imatinib was assessed in 18 studies with a total of 221 patients (10, 16, 17, 19, 23–28, 32, 34–36, 38, 39, 41, 42), erlotinib in 10 studies with 16 patients (13, 17, 22, 33, 35, 38, 40–42), cetuximab in five studies (seven patients) (13, 30, 31, 33, 41), sorafenib in four studies (65 patients) (15, 17, 21, 37), pazopanib in four studies with seven patients (16, 28, 41, 43) and sunitinib in three studies with 11 patients (14, 17, 28). Sirolimus, thalidomide, bevacizumab, gefitinib, linsitinib, and everolimus were accessed in two studies each (13, 22, 25, 28–31, 33, 34, 40–42), whereas dasatinib (32 patients) (11), lapatinib (18 patients) (12), rapamycin (one patients) (34), temosirolimus (one patients) (17) and yeast-brachyury (GI-6301) vaccine (11 patients) (20) were only analyzed in one study each (Figures 2 and 3).…”

Metronomic topotecan impedes tumor growth ofMYCN-amplified neuroblastoma cellsin vitroandin vivoby therapy induced senescence

“…Metronomic drug application uses continuous low doses of drugs and has been proven effective in phase I and II clinical trials in adult and pediatric solid tumor patients [ 52 – 54 ]. This treatment modality has been assumed to induce tumor cell dormancy and target the tumor microenvironment by reducing the tumor vasculature and by restoring immune surveillance while having little side effects [ 55 ], however, the contribution of tumor cell senescence has not been investigated.…”

High dose lansoprazole combined with metronomic chemotherapy: a phase I/II study in companion animals with spontaneously occurring tumors

“…This is a very promising result, since a “flaw” of metronomic chemotherapy is the low number of patients experiencing complete responses as well as the difficulty to have a significant delay for the onset of metastatic disease in patients with advanced cancer [10-17]. The broad spectrum of solid tumors that responded to this clinical approach including two patients with metastasized anal sac carcinoma makes this combination extremely promising.…”