Phase I trial of low-dose continuous topotecan infusion in patients with cancer: an active and well-tolerated regimen.

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.

Section: Discussionmentioning

confidence: 99%

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

Gerrits

Schellens²,

Creemers³

et al. 1997

“…In a phase I study with continuous intravenous topotecan administration for 21 days every 28 days in 44 patients with solid tumours, the MTD was 0.53 mg m-2 day-', with myelosuppression as DLT (Hochster et al, 1994). The steady-state lactone TPT concentration was low, approximately 4 ng ml-'.…”

Section: Prolonged Exposurementioning

confidence: 99%

“…No consistent relationship was found between drug level and haematological toxicity. Partial tumor responses were noted in two patients with ovarian cancer, one patient with breast cancer, one patient with renal cell cancer and one patient with non-small-cell lung cancer (NSCLC) (Hochster et al, 1994). Blood transfusions and platelet transfusions were necessary in 45% and 11% of patients respectively.…”

Section: Prolonged Exposurementioning

confidence: 99%

Topoisomerase I inhibitors: the relevance of prolonged exposure for present clinical development

Gerrits

Jonge²,

Schellens³

et al. 1997

113

Summary Topoisomerase inhibitors constitute a new class of anti-cancer agents. Recently, topotecan and irinotecan were registered for clinical use in ovarian cancer and colorectal cancer respectively. Cytotoxicity of topoisomerase inhibitors is S-phase specific, and in vitro and in vivo studies have suggested that, for efficacy, prolonged exposure might be more important than short-term exposure to high concentration. Clinical development of those topoisomerase inhibitors that have reached this stage is also focused on schedules aiming to achieve prolonged exposure. In this review, we summarize all published preclinical studies on this topic for topoisomerase inhibitors in clinical development, namely 20-S-camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin, topotecan, irinotecan and G1147211. In addition, preliminary data on clinical studies concerning this topic are also reviewed. The data suggest that prolonged exposure may indeed be relevant for anti-tumour activity. However, the optimal schedule is yet to be determined. Finally, clinical data are yet too immature to draw definitive conclusions.

“…In the phase I study of heavily pretreated patients, the maximum tolerated dose was 0.53 mg m-2 day-' (Hochster et al, 1994). The starting dose of topotecan in the patients with advanced breast cancer was lower than that of the lung cancer patients because of previous exposure to marrow toxic treatments combined with the expected haematological toxicity of topotecan therapy.…”

Section: Treatmentmentioning

confidence: 99%

“…A phase I trial of low-dose continuous infusional topotecan in heavily pretreated patients reported objective responses with ovarian cancer, breast cancer and non-small-cell lung cancer. The dose-limiting toxicity was myelosuppression, with thrombocytopenia greater than neutropenia, seen at a dose level of 0.70 mg mi-2 day-' administered as a continuous 21-day infusion every 28 days (Hochster et al, 1994). Of 21 platinum-pretreated ovarian cancer patients receiving continuous 21-day infusional topotecan at a starting dose of 0.4 mg in-2 day-', nine patients responded (43%), including one complete responder (5%).…”

mentioning

confidence: 99%

Continuous infusional topotecan in advanced breast and non-small-cell lung cancer: no evidence of increased efficacy

Mainwaring

Mc²,

Hickish³

et al. 1997

Summary Two open, phase 11 studies were performed to evaluate the activity and toxicity of infusional topotecan in patients with advanced non-small-cell lung carcinoma (NSCLC) and advanced breast cancer who had not received previous chemotherapy for metastatic disease. Twenty-five patients with an ECOG performance score < 2 were treated with infusional topotecan administered as a daily, continuous intravenous infusion starting at 0.6 mg m-2 day-' (NSCLC) and 0.5 mg m-2 day-1 (breast cancer) for 21 days every 4 weeks. Three patients achieved a partial response as defined by WHO criteria: one with NSCLC (8%; 95% Cl 0-39%) and two with advanced breast cancer (15%; 95% Cl 2-45%). The major toxicities were neutropenia and thrombocytopenia, with one episode of neutropenic sepsis. These data suggest that topotecan delivered as a continuous intravenous infusion over 21 days as single-agent therapy does not appear to offer a clinical advantage over conventional 5-day schedules against advanced NSCLC and advanced breast cancer.