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Phase I and pharmacologic study of high doses of the topoisomerase I inhibitor topotecan with granulocyte colony-stimulating factor in patients with solid tumors.
J Clin Oncol. 1996 Apr; 14(4):1224-35.JC

Abstract

PURPOSE

To evaluate the feasibility of escalating doses of the topoisomerase I (topo I) inhibitor topotecan (TPT) with granulocyte colony-stimulating factor (G-CSF) in minimally pretreated adults with solid tumors and to study whether G-CSF scheduling variably affects the ability to escalate TPT doses.

MATERIALS AND METHODS

Thirty-six patients received 121 courses of TPT as a 30-minute infusion daily for 5 days every 3 weeks at doses that ranged from 2.0 to 4.2 mg/m2/d. G-CSF 5 microg/kg/d subcutaneously (SC) was initiated concurrently with TPT (starting on day 1). Because the concurrent administration of TPT and G-CSF resulted in severe myelosuppression at the lowest TPT dose level, an alternate posttreatment G-CSF schedule in which G-CSF dosing began after TPT (starting on day 6) was subsequently evaluated. Plasma sampling was performed to characterize the pharmacologic behavior of high-dose TPT and to determine whether G-CSF altered the pharmacokinetic profile of TPT.

RESULTS

Severe myelosuppression precluded the administration of TPT at the first dose, 2.0 mg/m2/d, with G-CSF on the concurrent schedule. However, dose escalation of TPT with G-CSF on a posttreatment schedule proceeded to 4.2 mg/m2/d. The dose-limiting toxicities (DLTs) were thrombocytopenia and neutropenia. One partial response was noted in a patient with colorectal carcinoma refractory to fluoropyrimidines. Pharmacokinetics were linear within the dosing range of 2.0 to 3.5 mg/m2/d, but TPT clearance was lower at the 4.2-mg/m2/d dose level. At 3.5 mg/m2/d, which is the maximum-tolerated dose (MTD) and recommended dose for subsequent-phase studies of TPT with G-CSF, the area under the concentration-versus-time curves (AUCs) for total TPT and lactone averaged 2.2- and 2.3-fold higher, respectively, than the AUCs achieved at the lowest TPT dose, 2.0 mg/m2/d. The pharmacologic behavior of high-dose TPT was not significantly altered by the scheduling of G-CSF.

CONCLUSION

G-CSF administered after 5 daily 30-minute infusions of TPT permits a 2.3-fold dose escalation of TPT above the MTD in solid-tumor patients, whereas concurrent therapy with G-CSF and TPT results in severe myelosuppression.

Authors+Show Affiliations

Division of Pharmacology, The Johns Hopkins Oncology Center, Baltimore, MD, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8648378

Citation

Rowinsky, E K., et al. "Phase I and Pharmacologic Study of High Doses of the Topoisomerase I Inhibitor Topotecan With Granulocyte Colony-stimulating Factor in Patients With Solid Tumors." Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, vol. 14, no. 4, 1996, pp. 1224-35.
Rowinsky EK, Grochow LB, Sartorius SE, et al. Phase I and pharmacologic study of high doses of the topoisomerase I inhibitor topotecan with granulocyte colony-stimulating factor in patients with solid tumors. J Clin Oncol. 1996;14(4):1224-35.
Rowinsky, E. K., Grochow, L. B., Sartorius, S. E., Bowling, M. K., Kaufmann, S. H., Peereboom, D., & Donehower, R. C. (1996). Phase I and pharmacologic study of high doses of the topoisomerase I inhibitor topotecan with granulocyte colony-stimulating factor in patients with solid tumors. Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology, 14(4), 1224-35.
Rowinsky EK, et al. Phase I and Pharmacologic Study of High Doses of the Topoisomerase I Inhibitor Topotecan With Granulocyte Colony-stimulating Factor in Patients With Solid Tumors. J Clin Oncol. 1996;14(4):1224-35. PubMed PMID: 8648378.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phase I and pharmacologic study of high doses of the topoisomerase I inhibitor topotecan with granulocyte colony-stimulating factor in patients with solid tumors. AU - Rowinsky,E K, AU - Grochow,L B, AU - Sartorius,S E, AU - Bowling,M K, AU - Kaufmann,S H, AU - Peereboom,D, AU - Donehower,R C, PY - 1996/4/1/pubmed PY - 1996/4/1/medline PY - 1996/4/1/entrez SP - 1224 EP - 35 JF - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JO - J Clin Oncol VL - 14 IS - 4 N2 - PURPOSE: To evaluate the feasibility of escalating doses of the topoisomerase I (topo I) inhibitor topotecan (TPT) with granulocyte colony-stimulating factor (G-CSF) in minimally pretreated adults with solid tumors and to study whether G-CSF scheduling variably affects the ability to escalate TPT doses. MATERIALS AND METHODS: Thirty-six patients received 121 courses of TPT as a 30-minute infusion daily for 5 days every 3 weeks at doses that ranged from 2.0 to 4.2 mg/m2/d. G-CSF 5 microg/kg/d subcutaneously (SC) was initiated concurrently with TPT (starting on day 1). Because the concurrent administration of TPT and G-CSF resulted in severe myelosuppression at the lowest TPT dose level, an alternate posttreatment G-CSF schedule in which G-CSF dosing began after TPT (starting on day 6) was subsequently evaluated. Plasma sampling was performed to characterize the pharmacologic behavior of high-dose TPT and to determine whether G-CSF altered the pharmacokinetic profile of TPT. RESULTS: Severe myelosuppression precluded the administration of TPT at the first dose, 2.0 mg/m2/d, with G-CSF on the concurrent schedule. However, dose escalation of TPT with G-CSF on a posttreatment schedule proceeded to 4.2 mg/m2/d. The dose-limiting toxicities (DLTs) were thrombocytopenia and neutropenia. One partial response was noted in a patient with colorectal carcinoma refractory to fluoropyrimidines. Pharmacokinetics were linear within the dosing range of 2.0 to 3.5 mg/m2/d, but TPT clearance was lower at the 4.2-mg/m2/d dose level. At 3.5 mg/m2/d, which is the maximum-tolerated dose (MTD) and recommended dose for subsequent-phase studies of TPT with G-CSF, the area under the concentration-versus-time curves (AUCs) for total TPT and lactone averaged 2.2- and 2.3-fold higher, respectively, than the AUCs achieved at the lowest TPT dose, 2.0 mg/m2/d. The pharmacologic behavior of high-dose TPT was not significantly altered by the scheduling of G-CSF. CONCLUSION: G-CSF administered after 5 daily 30-minute infusions of TPT permits a 2.3-fold dose escalation of TPT above the MTD in solid-tumor patients, whereas concurrent therapy with G-CSF and TPT results in severe myelosuppression. SN - 0732-183X UR - https://www.unboundmedicine.com/medline/citation/8648378/Phase_I_and_pharmacologic_study_of_high_doses_of_the_topoisomerase_I_inhibitor_topotecan_with_granulocyte_colony_stimulating_factor_in_patients_with_solid_tumors_ L2 - https://ascopubs.org/doi/10.1200/JCO.1996.14.4.1224?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -