Myelotoxicity of oral topotecan in relation to treatment duration and dosage: a phase I study

e14524 Background: E7080 is an oral multi-targeted kinase inhibitor of VEGFRs, PDGFRs, FGFRs and c-kit. In the phase I study for advanced solid tumors, E7080 was repeated every 3 weeks (twice daily by 2 wks-on/ 1 wk-off). The toxicities were manageable and the preliminary antitumor activity including one partial response was observed at doses up to MTD [ASCO 2008; abstract 3527]. This study was conducted to evaluate whether the change of plasma biomarkers in the E7080 phase I study could predict the antitumor activity or the disease control duration. Methods: The treatment duration was determined as a period from the first dosing to treatment failure. Plasma angiogenic proteins and circulating endothelial cells (CEC)/ progenitor cells (CEP) were measured in blood samples collected on Days 1 (pre-dose), 8 and 15 of Cycles 1 and 2. CEC and CEP population with (+) or (-) c-kit expression were analyzed by FACS. Correlation was determined by Spearman's rank correlation coefficient (r) and test for non-correlation (p). Results: 19 (76%) out of 25 evaluable patients had PR/SD including 6 (24%) patients with the treatment duration of ≥180 days. VEGF increase and sVEGFR1 and -R2 decreases in plasma were seen with the increased dose of E7080. But these changes had no correlations with disease control. E7080 decreased c-kit(+) CEC and CEP, but not c-kit(-) population. Importantly, patients showing the decrease of c-kit(+) CEC in Cycle 1 had received E7080 treatment for significantly longer duration (r=-0.468, p=0.018). The decrease of c- kit(+) CEC diminished during treatment-off for final 7 days in Cycle 1 and repeatedly decreased in Cycle 2 treatment. The decrease of c- kit(+) ratio in CEP correlated with the increase of plasma SCF (r=-0.457, p=0.021) and SDF1 (r=-0.466, p=0.018), but not with VEGF or thrombopoietin. Conclusions: The change of c-kit(+) CEC correlated with the disease control duration in the phase I study of E7080. SCF and SDF1 may play a role in c-kit(+) CEP accumulation. C-kit(+)-selective changes of CEC could be a candidate biomarker to predict the disease control duration in anti-angiogenic therapy of E7080. [Table: see text]

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A phase I study of carboplatin plus oral topotecan in advanced malignancies

Journal of Clinical Oncology ◽

10.1200/jco.2004.22.14_suppl.2137 ◽

2004 ◽

Vol 22 (14_suppl) ◽

pp. 2137-2137

Author(s):

E. Kim ◽

H. Hochster ◽

Y. Novik ◽

A. Chachoua ◽

J. Speyer ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Advanced Malignancies ◽

Oral Topotecan

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A phase I study of weekly doxorubicin and oral topotecan for patients with relapsed or refractory small cell lung cancer (SCLC): A Fred and Pamela Buffet Cancer Center Clinical Trials Network study

Cancer Treatment and Research Communications ◽

10.1016/j.ctarc.2019.100162 ◽

2020 ◽

Vol 22 ◽

pp. 100162

Author(s):

Vinicius Ernani ◽

Rahat Jahan ◽

Lynette M. Smith ◽

Alissa S. Marr ◽

Sarah E. Kimbrough ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Phase I ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Phase I Study ◽

Small Cell ◽

Cancer Center ◽

Small Cell Lung ◽

Oral Topotecan

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A Phase I Study of Oral Topotecan and Pegylated Liposomal Doxorubicin (Doxil) in Platinum-Resistant Ovarian and Peritoneal Cancer

American Journal of Clinical Oncology ◽

10.1097/coc.0b013e31816a6221 ◽

2008 ◽

Vol 31 (5) ◽

pp. 476-480 ◽

Cited By ~ 11

Author(s):

Peter G. Rose ◽

Mary Smrekar ◽

Pam Haba ◽

Nancy Fusco ◽

Michael Rodriguez

Keyword(s):

Phase I ◽

Phase I Study ◽

Liposomal Doxorubicin ◽

Pegylated Liposomal Doxorubicin ◽

Peritoneal Cancer ◽

Platinum Resistant ◽

Oral Topotecan

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Phase I study of safety, tolerability, and pharmacokinetics of pazopanib in combination with oral topotecan in patients with advanced solid tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2536 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2536-2536 ◽

Cited By ~ 4

Author(s):

Bojana Milojkovic Kerklaan ◽

Martijn P. J. K. Lolkema ◽

Lot A. Devriese ◽

Emile E. Voest ◽

A. Nol-Boekel ◽

...

Keyword(s):

Phase I ◽

Solid Tumors ◽

Phase I Study ◽

Topoisomerase I ◽

Treated Patient ◽

Maximum Tolerated Dose ◽

Advanced Solid Tumors ◽

Hand Foot Syndrome ◽

Grade 3 ◽

Oral Topotecan

2536 Background: To determine the maximum-tolerated dose (MTD), safety, tolerability and pharmacokinetics of the oral anti-angiogenic drug pazopanib in combination with oral topotecan, an inhibitor of topoisomerase-I. Methods: Two-stage, two-arm, dose escalation and pharmacokinetic phase I study of pazopanib and oral topotecan in patients with advanced solid tumors, (NCT00732420, www.clinicaltrials.gov). This interim report describes the bioavailability and safety results for daily pazopanib combined with oral topotecan (days 1, 8, 15) in a 28-day cycle. Results: Twenty-eight of 32 patients completed at least one cycle and were evaluable for analysis. Three dose-limiting toxicities (DLTs) occurred: grade 3 hand-foot-syndrome, diarrhea and neutropenia. Pazopanib 800 mg/topotecan 10 mg exceeded the MTD with two DLTs in six patients. The most frequent treatment-related toxicities were grade 3 anemia (3/28), leukocytopenia, neutropenia and fatigue (2/28 each). One death due to hepatic failure occurred at pazopanib 800mg/toptecan 2mg in a heavily pre-treated patient with sarcoma that may have been related to paracetamol ingestion but attribution to the pazopanib can not be excluded. Topotecan AUC0-∞ increased 1.58-fold (90%CI: 1.09–1.29) and Cmax increased 1.78-fold (90%CI: 1.08-2.92) when given with pazopanib compared to single administration (n=7). Pazopanib AUC0-24 and Cmax ratios were not increased when co-administered with topotecan: 0.98 (90%CI: 0.95-1.02) and 0.96 (90%CI: 0.92-1.01). Twenty-three patients were evaluable for response (RECIST): PR (2/23; 9%, both ovarian cancer); SD (13/23; 57%) and PD (8/23; 35%). Pazopanib 800 mg/topotecan 8 mg is currently being explored in an expansion cohort. A second treatment arm of pazopanib 800 mg with topotecan daily x5 is ongoing and will be reported separately. Conclusions: Daily pazopanib and weekly oral topotecan is tolerable with handfoot syndrome, neutropenia and fatigue as dose limited side effects. Pazopanib increased topotecan exposure 1.58-fold (AUC0-∞) and 1.78-fold (Cmax). Clinical trial information: NCT00732420.

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