A phase 1 study of KOS-862 (Epothilone D) co-administered with carboplatin (Paraplatin®) in patients with advanced solid tumors Journal Article
| Authors: | Monk, J. P.; Villalona-Calero, M.; Larkin, J.; Otterson, G.; Spriggs, D.; Hannah, A. L.; Cropp, G. F.; Johnson, R. G.; Hensley, M. L. |
| Article Title: | A phase 1 study of KOS-862 (Epothilone D) co-administered with carboplatin (Paraplatin®) in patients with advanced solid tumors |
| Abstract: | Purpose To determine the maximally tolerated dose (MTD) and pharmacokinetics of carboplatin plus KOS-862 (Epothilone D) a novel cytotoxic macrolide capable of causing mitotic arrest, in patients with advanced solid malignancies. Experimental Design Patients who have progressed on standard regimens were treated at four different levels of KOS-862(mg/m 2)/Carboplatin(AUC): 50/5,75/5, 75/6 and 100/6 in a "3+3" phase I study study design to determine MTD. Patients received KOS-862 on Days 1 and 8, and carboplatin on day 1, of 3-week cycles. Pharmacokinetics of KOS-862 and Carboplatin were studied. Results Twenty-seven patients enrolled in the study. At the top dose level, 2 out of the 9 patients experienced Dose Limiting Toxicity. (grade 3 peripheral motor neuropathy in both patients) Twenty-seven patients had sufficient plasma data points for pharmacokinetic analysis Both the parent drug, KOS-862, and the major inactive metabolite Seco-D KOS-862 (KOS-1965) were quantified in plasma. Kinetics of KOS-862 were the same as seen in monotherapy studies using the same route and time of administration. Two patients had tumor response after study treatment. Ten of 20 evaluable patients had stable disease after 2 cycles of study treatment. The MTD in the present study was KOS-862 100 mg/m 2 + carboplatin AUC=6. Conclusions The pharmacokinetics of KOS-862 were similar in this combination study to those seen in previous monotherapy studies using the same route and time of administration. We have described the MTD of this schedule. The neurotoxicity seen with this regimen should be considered prior to its administration in unselected populations. © Springer Science+Business Media, LLC 2011. |
| Keywords: | adult; clinical article; treatment response; aged; fatigue; neutropenia; paresthesia; advanced cancer; area under the curve; diarrhea; drug efficacy; drug safety; drug withdrawal; liver cell carcinoma; side effect; solid tumor; pancreas cancer; colorectal cancer; carboplatin; multiple cycle treatment; neutrophil count; ovary cancer; peritoneum cancer; anemia; lung non small cell cancer; thrombocytopenia; bladder cancer; drug dose escalation; drug hypersensitivity; dyspnea; pneumonia; prostate cancer; sarcoma; lung small cell cancer; head and neck cancer; urinary tract infection; thrombocyte count; drug clearance; sepsis; stomach cancer; bacteremia; maximum plasma concentration; time to maximum plasma concentration; drug blood level; maximum tolerated dose; phase 1 clinical trial; drug half life; neurologic disease; neuropathic pain; distribution volume; upper respiratory tract infection; epothilone d; hypesthesia; motor neuropathy; phase i; gait disorder; restless legs syndrome; walking difficulty |
| Journal Title: | Investigational New Drugs |
| Volume: | 30 |
| Issue: | 4 |
| ISSN: | 0167-6997 |
| Publisher: | Springer |
| Date Published: | 2012-08-01 |
| Start Page: | 1676 |
| End Page: | 1683 |
| Language: | English |
| DOI: | 10.1007/s10637-011-9731-4 |
| PROVIDER: | scopus |
| PUBMED: | 21826439 |
| PMCID: | PMC5098268 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 2 November 2012" - "CODEN: INNDD" - "Source: Scopus" |
Altmetric
Citation Impact
Related MSK Work