| General information |
| Database: | DB00617 |
| Objective: | a phase I study was conducted to determine the doselimiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of vorinostat with bevacizumab and CPT11 in recurrent glioblastoma. |
| Authors: | Chinnaiyan P, et al |
| Title: | Phase I trial of vorinostat combined with bevacizumab and CPT11 in recurrent glioblastoma. |
| Journal: | Neuro Oncol. |
| Year: | 2012 |
| PMID: | 22028388 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | bevacizumab
|
| Target: | Vascular endothelial growth factor
|
| Cancer Type: | Tumors of the nervous system |
| Cancer Subtype: | glioblastoma |
| Therapy Type: | com |
| Therapeutic Combination Type: | 13 |
| Therapeutic Combination Content: | vorinostat combined with bevacizumab and CPT11 |
| Study Type: | Phase I trial |
| Key Patients Feature: | patients were required to have a histologically confirmeddiagnosis of intracranial glioblastoma or gliosarcomawith pathologic or radiographic confirmation of tumorprogression following standard frontline therapy consisting of external beam radiation therapy and temozolomide. patients were also required to be more than and equal to 18 years of age, have a Karnofsky performance status (KPS) of more than and equal to 60, havesatisfactory hematologic (hemoglobin level, more than and equal to 10 g/dL;absolute neutrophil count, more than and equal to 1500 cells/mL; plateletcount, more than and equal to 100 000 cells/mL) and biochemical results(serum creatinine level, less than and equal to 1.5 mg/dL; aspartate aminotransferase and alanine transaminase levels, , 2.5 timesthe upper limit of normal; bilirubin level, less than and equal to 1.6 mg/dL). |
| Biomarker: | Correlative science involving proteomic profiling of serial patient plasma samples was performed. |
| Biomark Analysis: | Serum proteomic profiling identified IGFBP5 and PDGFAA as markers for improved PFS and recurrence, respectively. |
| Control Group Info: | single arm |
| Treatment Info: | Vorinostat was combined with bevacizumab and CPT11 and was escalated using a standard 3 + 3 design. Vorinostat was escalated up to 2 actively investigated doses of this compound or until the MTD was identified on the basis of DLTs. |
| Primary End Point: | MTD, DLTs and common toxicities. |
| Secondary End Point: | NA |
| Patients Number: | 20 |
| Trial Results |
| DLT_MTD: | The MTD ofvorinostat was established at 400 mg on days 1-7 and15-21 every 28 days when combined with bevacizumaband CPT11. Common toxicities were fatigue and diarrhea.DLTs included fatigue, hypertension/hypotension, and central nervous system ischemia. |
| Objective Response Rate: | The median PFS amongpatients receiving higher dose vorinostat had animproved response, although not statistically significant, when compared with thatamong patients receiving lotheyrdoses (4.25 vs 1.9 months |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 3.6 months |
| Median OS A vs. C: | 7.3 months |
| Adverse Event(agent arm): | Common toxicities were fatigue and diarrhea. DLTs included fatigue, hypertension/hypotension, and central nervous system ischemia. |
| Conclusions: | With the increased toxicities associated with CPT11 coupled with its unclear clinical significance, investigating the efficacy of vorinostat combined with bevacizumab alone may represent a more promising strategy to evaluate in the context of aphase II clinical trial. |