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A phase I study of bortezomib and temozolomide in patients with advanced solid tumors
- Source :
- Cancer Chemotherapy and Pharmacology. 69:505-514
- Publication Year :
- 2011
- Publisher :
- Springer Science and Business Media LLC, 2011.
-
Abstract
- The primary objective was to determine the maximum tolerated doses (MTDs) of the combination of bortezomib and temozolomide in patients with solid tumors. The secondary objective was to evaluate the pharmacokinetics (PK) of bortezomib with and without concurrent hepatic enzyme-inducing anticonvulsants (HEIAs).Bortezomib was administered on days 2, 5, 9, and 12; temozolomide on days 1-5 of a 28-day cycle. Dose escalation proceeded using a standard 3+3 design. Patients with primary or metastatic brain tumors were eligible and were stratified based on whether they were taking HEIAs or not.Of the 25 patients enrolled, 22 were not taking HEIAs. MTDs were only given to patients not receiving HEIAs. Dose-limiting toxicities (DLTs) consisted of grade-3 constipation, hyponatremia, fatigue, elevated hepatic enzymes, and grade-4 neutropenia, thrombocytopenia, constipation, and abdominal pain. Stable disease (8 weeks) was observed in 5 patients. Bortezomib systemic clearance (CL(sys)) on day 9 was 51% of the CL(sys) on day 2 (P 0.01) Similarly, the normalized area under the concentration-time curve (norm AUC) on day 9 was 1.9 times the norm AUC on day 2 (P 0.01). The median bortezomib CL(sys) on days 2 and 9 was significantly higher (P 0.04) in patients taking HEIAs, and the median norm AUC was correspondingly lower (P 0.04).The MTDs for the combination of bortezomib and temozolomide in patients not taking HEIAs are 1.3 and 200 mg/m(2), respectively. The rate of bortezomib elimination in patients taking HEIAs was increased twofold. Additional trials are needed to better define the optimal dosing in such patients.
- Subjects :
- Male
Oncology
Cancer Research
Pharmacology
Toxicology
Bortezomib
immune system diseases
Neoplasms
hemic and lymphatic diseases
Antineoplastic Combined Chemotherapy Protocols
Pharmacology (medical)
Fatigue
Aged, 80 and over
Nausea
Middle Aged
Boronic Acids
Phase i study
Dacarbazine
Treatment Outcome
Liver
Area Under Curve
Enzyme Induction
Pyrazines
Anticonvulsants
Female
medicine.symptom
medicine.drug
Adult
medicine.medical_specialty
Metabolic Clearance Rate
Drug Administration Schedule
Article
Young Adult
Pharmacokinetics
Lymphopenia
Internal medicine
Temozolomide
medicine
Humans
In patient
Aged
Dose-Response Relationship, Drug
business.industry
Temozolomida
business
Subjects
Details
- ISSN :
- 14320843 and 03445704
- Volume :
- 69
- Database :
- OpenAIRE
- Journal :
- Cancer Chemotherapy and Pharmacology
- Accession number :
- edsair.doi.dedup.....ff616181e6442d80f970f8677a93891f