Entry Detail
| General information | |
| Database: | DB00682 |
| Objective: | Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells. |
| Authors: | Adenis A, et al |
| Title: | A doseescalatingphase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted solid tumours. |
| Journal: | Br J Cancer. |
| Year: | 2013 |
| PMID: | 24149182 |
| Trial Design | |
| Clinical Trial Id: | NA |
| Agent: | imatinib mesylate |
| Target: | Abl Plateletderived growth factor receptor Mast/stem cell growth factor receptor |
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | imatinib mesylate with fixed dose of metronomic cyclophosphamide |
| Study Type: | a III + III doseescalation study |
| Key Patients Feature: | (A) Following cancers: imatinib and sunitinibrefractory gastrointestinal stromal tumours, chordoma, dermatofibrosarcoma (locally advanced and progressive), metastatic KIT mutationharbouring melanoma, metastatic and progressive cylindroma whatever the primary site, desmoidtumour (lifethreatening locations such as progressive mesenteric location or progressivenasocranial location)(B) Metastatic disease or locally advanced disease not amenable to curative intent surgery(C) Disease incurable with standard therapy(D) Measurable disease according to RECIST (1.0)(E) No more than two previous lines of systemic anticancer treatments ( 4 weeks since the last dose)(F) Four weeks since local therapy (major surgery and last fraction of radiation therapy). Patientsmust have recovered from toxicity(G) Age X18 years(H) PS p(ECOG) 2 within the 7 days before the study(I) Albuminaemia X36 g l 1 and lymphocytes count4700 mm 3(J) Absolute granulocytes X1500 mm 3(K) Platelets X100 000 mm 3(L) Total bilirubin within normal limits(M) Serum creatinine within normal limits(N) Normal left ventricular ejection fraction (by MUGA scan or echocardiogram or NTproBNPdosage)(O) Negative pregnancy test within the 7 days before the study(P) Using effective contraceptive measures(Q) Absence of any psychological, familial, sociological or geographical condition potentiallyhampering compliance with the study protocol and followup schedule; those conditions should bediscussed with the patient before registration in the trial(R) Before patient registration, written informed consent must be given according to ICH/GCP andnational regulations |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). |
| Treatment Info: | they have designed a 3+3 doseescalatingphase 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 sutininibrefractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Doselimiting 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. |
| Primary End Point: | MTD, DLTs, tumor response and toxicity |
| Secondary End Point: | NA |
| Patients Number: | 26 |
| Trial Results | |
| DLT_MTD: | No doselimiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. |
| Objective Response Rate: | There was no objective response. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | in chordoma patients (median PFS 10.2 months; range, 4.2-18 t ). In heavily GIST pretreated patients (median PFS 2.3 months; range, 2.1-6.6) |
| Median OS A vs. C: | 13.4 months (95% CI: 3.0-16.0 t) in the entire study population. |
| Adverse Event(agent arm): | Treatment had been suspended for toxicity reason in seven cases (6 out of 14 patients treated at the phase II recommended dose). Doses were reduced for 4 out of 14 patients treated at the phase II recommended dose. One case of acute myeloid leukaemia in a chordoma patient treated with this association for 4 years, thus, a causal relationship is possible. |
| Conclusions: | This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients. |