Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor.

Rowinsky, Eric K.; Grochow, Louise B.; Hendricks, Carolyn B.; Ettinger, David S.; Forastiere, Arlene A.; Hurowitz, L A; McGuire, William P.; Sartorius, S E; Lubejko, Barbara; Kaufmann, Scott H.

doi:10.1200/jco.1992.10.4.647

Cited by 330 publications

(160 citation statements)

References 15 publications

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“…However, on three occasions, the DL cohorts had to be modified to accrue more patients. Topotecan appears to be a schedule-dependent cytotoxic (Rowinsky et al, 1992). Phase I and II clinical trials have been performed to evaluate the administration of topotecan by continuous i.v.…”

Section: Discussionmentioning

confidence: 99%

A phase I clinical trial of continual alternating etoposide and topotecan in refractory solid tumours

et al. 2005

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The goal of this phase I study was to develop a novel schedule using oral etoposide and infusional topotecan as a continually alternating schedule with potentially optimal reciprocal induction of the nontarget topoisomerase. The initial etoposide dose was 15 mg m À2 b.i.d. days (D)1 -5 weeks 1,3,5,7,9 and 11, escalated 5 mg per dose per dose level (DL). Topotecan in weeks 2,4,6,8,10 and 12 was administered by 96 h infusion at an initial dose of 0.2 mg m À2 day À1 with a dose escalation of 0.1, then at 0.05 mg m À2 day À1 . Eligibility criteria required no organ dysfunction. Two dose reductions or delays were allowed. A total of 36 patients with a median age of 57 (22 -78) years, received a median 8 (2 -19) weeks of chemotherapy. At DL 6, dose-limiting toxicities consisted of grade 3 nausea, vomiting and intolerable fatigue. Three patients developed a line-related thrombosis or infection and one subsequently developed AML. There was no febrile neutropenia. There were six radiologically confirmed responses (18%) and 56% of patients demonstrated a response or stable disease, typically with only modest toxicity. Oral etoposide 35 mg m À2 b.i.d. D1 -5 and 1.8 mg m À2 96 h (total dose) infusional topotecan D8 -11 can be administered on an alternating continual weekly schedule for at least 12 weeks, with promising clinical activity.

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Section: Discussionmentioning

confidence: 99%

A phase I clinical trial of continual alternating etoposide and topotecan in refractory solid tumours

et al. 2005

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“…Treatment courses with CTC grade III-IV myelosuppression were all uneventful except for one patient with septicaemia. In topotecan studies, the dose-limiting toxicity was also noncumulative myelosuppression, predominantly a severe neutropenia of brief duration not necessitating treatment delays (Rowinsky et al, 1992;Verweij et al, 1993). Thrombocytopenia and anaemia occurred mainly in regimens with prolonged intravenous topotecan administration (Hochster et al, 1994;Creemers et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

The bioavailability of oral GI147211 (GG211), a new topoisomerase I inhibitor

Gerrits

Schellens²,

Creemers³

et al. 1997

Br J Cancer

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Summary Topoisomerase I inhibitors are new compounds of interest for cancer chemotherapy. We performed a study with Gl147211, a new semisynthetic camptothecin analogue, to determine the absolute bioavailability of the drug given orally. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard forms of therapy were eligible for the study. Gi147211 was given orally on day 1 and as a 30-min infusion daily on days 2-5. The treatment course was repeated every 3 weeks. In subsequent patient cohorts, the dose of the oral formulation was escalated from 1.5 mg m-2 to 6.0 mg m-2; the dose for i.v. administration was fixed at 1.2 mg m-2. Plasma pharmacokinetics was performed on day 1 and 2 of the first course and on day 1 of the second course using a validated high-performance liquid chromatographic assay. Nineteen patients were entered into the study; one patient was not evaluable because the treatment course was stopped prematurely. Eighteen patients received a total of 47 treatment courses. The absolute bioavailability of G1147211 averaged 1.3 ± 5.2%. Drug appeared quickly in plasma with a median Tma, at 0.5 h. Fasting or fed state had no significant influence on the bioavailability of G1147211. The terminal half-life after administration of oral G1147211 was 6.85 ± 3.13 h, similar to the half-life after intravenous administration. The major toxicities were neutropenia and thrombocytopenia. Nadirs for neutropenia and thrombocytopenia occurred on day 8 and day 15 respectively. Other toxicities predominantly consisted of mild and infrequent nausea and vomiting, and fatigue. The oral administration of the drug is well tolerated. Oral administration of topoisomerase I inhibitor G1147211 results in a low bioavailability with relatively wide interpatient variation. The intravenous route of administration is advised for further development of this promising topoisomerase I inhibitor.

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“…26 Topotecan showed clinical activity against cisplatin-refractory ovarian cancer, with response rates of ϳ20%, which is one of the highest activities of any chemotherapeutic agents against this disease. 17,27,28 The most common adverse event described with topotecan was myelosuppression, with up to 92% of patients experiencing grade 3 or 4 neutropenia and 67% experiencing grade 3 or 4 thrombocytopenia.…”

Section: Topotecanmentioning

confidence: 99%

Thymidine kinase gene therapy with concomitant topotecan chemotherapy for recurrent ovarian cancer

et al. 2000

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Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor.

Cited by 330 publications

References 15 publications

A phase I clinical trial of continual alternating etoposide and topotecan in refractory solid tumours

A phase I clinical trial of continual alternating etoposide and topotecan in refractory solid tumours

The bioavailability of oral GI147211 (GG211), a new topoisomerase I inhibitor

Thymidine kinase gene therapy with concomitant topotecan chemotherapy for recurrent ovarian cancer

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