A phase I study of daily everolimus plus low-dose weekly cisplatin for patients with advanced solid tumors Journal Article
| Authors: | Fury, M. G.; Sherman, E.; Haque, S.; Korte, S.; Lisa, D.; Shen, R.; Wu, N.; Pfister, D. |
| Article Title: | A phase I study of daily everolimus plus low-dose weekly cisplatin for patients with advanced solid tumors |
| Abstract: | Purpose: Preclinical studies demonstrate synergistic anti-tumor activity with the combination of everolimus and cisplatin. We conducted a phase I study to establish the recommended phase II of oral everolimus to be given with low-dose weekly intravenous cisplatin. Methods: Part A used a standard 3 + 3 dose escalation scheme. There were 4 planned dose levels of everolimus: 2.5, 5, 7.5, and 10 mg/day. Subjects received oral everolimus during days 1-21 and cisplatin 20 mg/m 2 intravenously (fixed dose) on days 1, 8, and 15 of a 28-day cycle. Pharmacokinetic (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 were enrolled in an expansion cohort (Part B). Response was assessed by RECIST q 2 cycles for all subjects. Results: Thirty patients were enrolled (18 male, 12 female) and 29 were treated. Median age was 61 years (31-79) and the median number of prior cytotoxic chemotherapy regimens was 2 (0-3). Eighty-three percent of subjects had received prior RT. DLTs occurred at dose level 1 (sudden death of unclear cause in a patient with melanoma metastatic to liver) and dose level 2 (bowel obstruction). No DLTs occurred at dose levels 3 and 4. The most common adverse events (≥grade 3) among 28 patients evaluable for toxicity were lymphopenia (36%), hyperglycemia (11%), fatigue (11%), and venous thrombosis (11%). PK analysis of everolimus demonstrated dose-proportional increases in C max (mean 91.9 ng/ml) and AUC 0-INF (mean 680.5 h*ng/ml) at dose level 4. Three partial responses were seen (metastatic pulmonary carcinoid, n = 2; metastatic sinus carcinoma, n = 1). Prolonged stable disease ≥6 cycles occurred in subjects with pulmonary carcinoid, oropharyngeal squamous cell carcinoma, basal cell carcinoma, papillary thyroid carcinoma, and esthesioneuroblastoma (n = 1 each). Conclusion: The phase II recommended dose is everolimus 10 mg/day (days 1-21) + cisplatin 20 mg/m 2 (days 1, 8, and 15) of a 28-day cycle. PK data demonstrate dose-proportional increases in exposure, as previously described for everolimus monotherapy. Anti-tumor activity was observed in several tumor types. © 2011 Springer-Verlag. |
| Keywords: | cisplatin; solid tumor; everolimus; phase i |
| Journal Title: | Cancer Chemotherapy and Pharmacology |
| Volume: | 69 |
| Issue: | 3 |
| ISSN: | 0344-5704 |
| Publisher: | Springer |
| Date Published: | 2012-03-01 |
| Start Page: | 591 |
| End Page: | 598 |
| Language: | English |
| DOI: | 10.1007/s00280-011-1734-5 |
| PROVIDER: | scopus |
| PUBMED: | 21913034 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 1 May 2012" - "CODEN: CCPHD" - "Source: Scopus" |
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