| General information |
| Database: | DB00886 |
| Objective: | To identify the optimal regimen and dosage of the oral mammalian target of rapamycin inhibitor everolimus (RAD001). |
| Authors: | O'Donnell A, et al |
| Title: | Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. |
| Journal: | J Clin Oncol. |
| Year: | 2008 |
| PMID: | 18332470 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | everolimus
|
| Target: | Serine/threonineprotein kinase mTOR
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | Phase I pharmacokinetic and pharmacodynamic study |
| Key Patients Feature: | Patients were more than and equal to 18 years old and had advanced solid tumors refractory to standard therapy, WHO performance status less than and equal to 2, estimated life expectancy more than and equal to 3 months, adequate bone marrow function, liver and kidney function |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | patients administering oral everolimus 5 to 30 mg/wk, with pharmacokinetic (PK) and pharmacodynamic (PD) studies. PD data prompted investigation of 50 and 70 mg weekly and daily dosing at 5 and 10 mg. |
| Primary End Point: | DLT, MDT |
| Secondary End Point: | NA |
| Patients Number: | 92 |
| Trial Results |
| DLT_MTD: | Doselimiting toxicity (DLT), which was assessed using National Cancer Institute Common Toxicity Criteria (CTC) version 2.0, was defined as suspected drug toxicity during the first 4 weeks of therapy, either nonhematologic CTC grade more than and equal to 3 (despite available prophylaxis such as antiemetics) or CTC grade more than and equal to 3 anemia, neutropenia, or thrombocytopenia. Cohorts were expanded to six patients in the event of DLT, MTD was defined as the dose at which more than one of six patients displayed DLT in cycle 1 |
| Objective Response Rate: | Partial responses were observed in four patients, |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 12 patients remained progression free for >or= 6 months |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Fatigue was observed in 31 patients (34%). Grade 3 fatigue was observed in only two patients, in association with stomatitis in one patient and depression in the other; both patients discontinued therapy. Rash in 44 patients (48%) appeared within the first month in 32 patients, was principally acneiform (34%) or erythematous (18%), and occurred most commonly over the upper body and head. It was severe (grade 3) in one patient (10 mg/d), with severity decreasing to grade 1 after interruption and dose reduction to 5 mg/d. GI toxicities reported in 61 patients (66%) included stomatitis, nausea, vomiting, anorexia, constipation, and abdominal pain or distension. Although GI toxicity was usually mild, stomatitis (erythematous, ulcerative) was grade 3 in three patients, one of whom discontinued treatment. Hematologic abnormalities were reported in 17 patients. In general, a mostly moderate decrease in platelet and neutrophil counts occurred rapidly after introduction of treatment but remained constant thereafter. Hemoglobin showed a tendency to decline over time, possibly related to the underlying disease. |
| Conclusions: | Everolimus was satisfactorily tolerated at dosages up to 70 mgwk and 10 mgd with predictable PK. Antitumor activity and PD in tumors require further clinical investigation. Doses of 20 mgwk and 5 mgd are recommended as appropriate starting doses for these studies |