A phase I and pharmacokinetic study of indisulam in combination with carboplatin.

Indisulam (E7070) is an anticancer agent that is currently being evaluated in phase II clinical studies. A significant reduction in glutathione synthetase and glutathione reductase transcripts by indisulam provided a molecular basis for its combination with platinum agents. Indisulam demonstrated high anti-tumour activity in various preclinical cancer models. The objectives of this study were (1) to determine the recommended dose of indisulam in combination with carboplatin in patients with solid tumours and (2) to evaluate the pharmacokinetics of the combination. Patients with solid tumours were treated with indisulam in combination with carboplatin. Indisulam (350, 500, or 600 mg m(-2)) was given as a 1-hour intravenous infusion on day 1 and carboplatin (5 or 6 mg min ml(-1)) as an intravenous infusion over 30 min on day 2 of a three-weekly cycle. Sixteen patients received study treatment and were eligible. Thrombocytopenia was the major dose limiting toxicity followed by neutropenia. Both drugs contributed to the myelosuppressive effect of the combination. Indisulam 500 mg m(-2) in combination with carboplatin 6 mg min ml(-1) was identified not to cause dose limiting toxicity, but a delay of re-treatment by 1 week was required regularly to allow recovery from myelosuppression. The recommended dose and schedule for an envisaged phase II study in patients with non-small cell lung cancer is indisulam 500 mg m(-2) in combination with carboplatin 6 mg min ml(-1) repeated four-weekly. Patients who do not experience severe thrombocytopenia at cycle 1 will be permitted to receive an escalated dose of indisulam of 600 mg m(-2) from cycle 2 onwards.

Phase I/II study of oral etoposide plus GM-CSF as second-line chemotherapy in platinum-pretreated patients with advanced ovarian cancer.

The aim of this phase I/II study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities of chronic oral etoposide given on days 1-10 followed by rescue with subcutaneous (s.c.) granulocyte-macrophage colony-stimulating factor (GM-CSF) on days 12-19 as second-line chemotherapy in platinum-pretreated patients (pts) with advanced ovarian carcinoma. Cohorts of three to six pts were treated with doses of oral etoposide from 750 mg m(-2) cycle(-1) escalated to 1250 mg m(-2) cycle(-1) over 10 days, every 3 weeks. Subcutaneous GM-CSF, 400 mug once daily, days 12-19, was added if dose-limiting granulocytopenia was encountered. In total, 18 pts with a median Karnofsky index of 80% (range, 70-100%) and a median time elapsed since the last platinum dose of 10 months (range, 1-24 months), 30% of whom showed visceral metastases, were treated at four dose levels (DLs) of oral etoposide on days 1-10 of each cycle as follows: DL 1, 750 mg m(-2) cycle(-1), without GM-CSF, three pts; DL 2, 1000 mg m(-2) cycle(-1), without GM-CSF, three pts; DL 3, 1000 mg m(-2) cycle(-1), with GM-CSF, six pts; and DL 4, 1250 mg m(-2) cycle(-1), with GM-CSF, six pts. All pts were assessable for toxicity and 16 pts for response. Dose-limiting toxicity (DLT) was reached at DL 4 by three of six pts, showing World Health Organization (WHO) toxicity grade 4. One patient died from gram-negative sepsis associated with granulocytopenia grade 4. Two more pts developed uncomplicated granulocytopenia grade 4. Thus, we recommend that DL 3 can be used for further phase II evaluation (i.e. oral etoposide 1000 mg m(-2) cycle(-1), days 1-10, followed by s.c. GM-CSF 400 mug, days 12-19). The clinical complete or partial responses in each patient cohort were: DL 1, one of three pts; DL 2, one of three pts; DL 3, three of five pts; and DL 4, two of five pts. In conclusion, in this phase I/II study, we defined the MTD and the dose recommended for the therapy with oral etoposide given over 10 days followed by s.c. GM-CSF in platinum-pretreated patients with advanced ovarian cancer. Our data demonstrate encouraging activity of this regimen and strongly support its further investigation in a phase II study.