Phase I and Pharmacokinetic Study of Oral Irinotecan Given Once Daily for 5 Days Every 3 Weeks in Combination With Capecitabine in Patients With Solid Tumors

Figlin

Clinical Cancer Research

2012

The taxanes are recognized as a major class of chemotherapeutic agents; however, mechanisms of innate and acquired resistance can limit their usefulness. Cabazitaxel, a novel taxane with microtubule-stabilizing potency similar to docetaxel, exhibits activity against tumor cell lines resistant to paclitaxel and docetaxel. Cabazitaxel showed linear pharmacokinetics and a terminal elimination half-life comparable with that of docetaxel, findings which support dosing as a single infusion in three-week treatment cycles. Dose-ranging studies recommended doses of 20 or 25 mg/m 2 every three weeks. Antitumor activity was shown in patients with advanced cancer and chemotherapy failure (including taxane failure). Other early studies investigated the efficacy of cabazitaxel in pretreated metastatic breast cancer, either as a single agent or in combination with capecitabine. Objective antitumor response rates of up to 24% and sustained tumor stabilizations were also observed. The TROPIC phase III study, conducted in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel, established cabazitaxel as the first chemotherapeutic agent to offer a survival advantage in this patient population. Across these studies, the dose-limiting hematologic toxicity was neutropenia (including febrile neutropenia), usually controllable with colony-stimulating factor/ granulocyte-colony stimulating factor support.

Section: Studies In Patients With Metastatic Breast Cancersupporting

confidence: 80%

Cabazitaxel: More Than a New Taxane for Metastatic Castrate-Resistant Prostate Cancer?

Figlin

Clinical Cancer Research

2012

Drug Metabolism and Disposition

“…Finally, one aspect that may have an effect on variability of axitinib in RCC patients is disease state. Axitinib has not been tested with latter lines of treatment in RCC; however, exposure variability of axitinib in patients is similar to what has been observed with other oral chemotherapeutic therapies (Hartvig et al, 1988;Regazzi et al, 1998;Wohl et al, 2002;Soepenberg et al, 2005;Preiss et al, 2006).…”

Section: Discussionmentioning

confidence: 95%

In Vitro Kinetic Characterization of Axitinib Metabolism

Zientek

Goosen

Tseng

et al. 2015

, respectively. Using a CYP3A4-specific inhibitor (Cyp3cide) in liver microsomes expressing CYP3A5, 66% of the axitinib intrinsic clearance was attributable to CYP3A4 and 15% to CYP3A5. Axitinib N-glucuronidation was primarily catalyzed by UDPglucuronosyltransferase (UGT) UGT1A1, which was verified by chemical inhibitors and UGT1A1 null expressers, with lesser contributions from UGTs 1A3, 1A9, and 1A4. The K m and V max values describing the formation of the N-glucuronide in HLM or rUGT1A1 were 2.7 mM or 0.75 mM and 8.9 or 8.3 pmol·min 21 ·mg 21 , respectively. In summary, CYP3A4 is the major enzyme involved in axitinib clearance with lesser contributions from CYP3A5, CYP2C19, CYP1A2, and UGT1A1.

“…infusion and is converted to its active metabolite SN-38 by carboxylesterase [24]. Oral irinotecan has unpredictable bioavailability, but some form of oral agent would have practical advantages, especially if used with an oral fluoropyrimidine [24][25][26][27][28]. No interaction between oral irinotecan and capecitabine was observed in a pharmacokinetic study [28].…”

Section: Dna Topoisomerase Inhibitionmentioning

confidence: 99%

“…Oral irinotecan has unpredictable bioavailability, but some form of oral agent would have practical advantages, especially if used with an oral fluoropyrimidine [24][25][26][27][28]. No interaction between oral irinotecan and capecitabine was observed in a pharmacokinetic study [28]. The variable oral bioavailability can partly be explained by the high affinity of topoisomerase 1 inhibitor for the efflux pumps breast cancer resistance protein (BCRP) (ABCG2) and P-glycoprotein, which are found in the gastrointestinal tract.…”

Section: Dna Topoisomerase Inhibitionmentioning

confidence: 99%

Novel Therapeutic Developments Other Than EGFR and VEGF Inhibition in Colorectal Cancer

Wilson

2006

The Oncologist

Learning Objectives After completing this course, the reader will be able to: Discuss the current status of new cytotoxics that may provide new treatment paradigms for patients with colorectal cancer. Explain these new agents’ mechanisms of action. Discuss the current clinical development of these agents and how they might be integrated into the current armamentarium. Access and take the CME test online and receive 1 AMA PRA Category 1 Credit™ at http://CME.TheOncologist.com