Phase I trial of intravenous cisplatin-topotecan chemotherapy for three consecutive days in patients with advanced solid tumors: parallel topotecan escalation in two fixed platinum dosing schemes.

PURPOSE: We performed a phase I study of two fixed dosing schemes of cisplatin, a DNA cross-linker, with intravenous escalating topotecan, a DNA-topoisomerase I inhibitor. EXPERIMENTAL DESIGN: 40 patients with advanced solid tumors received intravenous cisplatin at a fixed dose of either 25 mg/m2 (schedule A) or 20 mg/m2 (schedule B) daily for 3 days with standard hydration. Topotecan escalation proceeded in 0.75, 0.90, 1.0, 1.15 mg/m2 cohorts in schedule A and 1.0, 1.1, 1.2, 1.3 mg/m2 cohorts in schedule B, administered intravenously at the end of cisplatin infusion daily for 3 days, repeated every 3 weeks. Dose-limiting toxicity (DLT) consisted of protracted grade IV neutropenia, febrile neutropenia, grade IV thrombocytopenia and any grade III/IV non-hematological toxicity. Epoetin and granulocyte colony-stimulating factor support was allowed on severe myeloablation. Endpoints were the identification of maximal tolerated dose (MTD), DLT and other toxicity. RESULTS: The MTD was reached in cohort 25/1.15 mg/m2 in schedule A and 20/1.2 mg/m2 in schedule B. All DLT seen consisted of three episodes of febrile neutropenia and two of grade IV thrombocytopenia in schedule A, with three episodes of febrile neutropenia and one of protracted neutropenia in schedule B. Myelosuppression was substantial in all cohorts despite granulocyte colony-stimulating factor and epoetin support, peaked on the third week of treatment and resulted in administration of chemotherapy at a median of every 4 weeks. Non-hematologic toxicity was mild. The response rate was 51% with seven complete responses occurring in patients with ovarian cancer, small cell and non-small cell lung cancer and cancer of unknown primary. The recommended dose was 20/ 1.1 mg/m2 for cisplatin and topotecan on schedule B, as the number of responses and administered topotecan dose were higher in schedule B recommended dose with lower cisplatin dose, minimizing problems of nephrotoxicity and vomiting. CONCLUSIONS: The schedule B daily cisplatin-topotecan x 3 combination with secondary cytokine support is associated with promising activity and schedule convenience. However, substantial myelosuppression undermines its applicability in the palliative setting, stressing the need for less toxic regimens.

Biweekly administration of 24-h infusion of irinotecan followed by a 1-h infusion of docetaxel: a phase I study.

We developed a chemotherapy combination regimen based on preclinical data suggesting synchronization of cancer cells in G2/M phase when exposed to irinotecan over a protracted period. This phase I study aimed to determine the toxicity spectrum, and define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended optimal dose (ROD) of irinotecan infused over 24 h and followed by a 1-h infusion of 30 mg/m2 docetaxel. Starting dose for irinotecan was 30 mg/m2 and escalation proceeded at 30 mg/m2 increments, in cohorts of three to six patients until the MTD was reached. A dose between the MTD and the previous level was explored to further define the ROD. Thirty-two patients with advanced refractory cancers (median age 64, 19 male) received 190 treatment courses at five dosing levels of irinotecan: 30 mg/m2 (n=6 patients), 60 (n=3), 90 (n=7), 120 (n=8) and 105 (n=8). The MTD and ROD was 120/30 and 105/30 mg/m2. DLTs were diarrhea and neutropenia. Antitumor activity was modest. The ROD of biweekly administration of 24-h irinotecan followed by 1-h docetaxel is 105 and 30 mg/m2, respectively. The low hematological toxicity and modest activity observed leave questions concerning the optimal timing of this combination.

Weekly paclitaxel combined with pegylated liposomal doxorubicin (CaelyxTM) given every 4 weeks: dose-finding and pharmacokinetic study in patients with advanced solid tumors.

BACKGROUND: We aimed to define the maximum tolerated dose (MTD) and characterize the toxicity of the combination of pegylated liposomal doxorubicin (PLD; Caelyx trade mark ) and weekly paclitaxel (wPTX), and to investigate pharmacokinetics of PLD in this combination. METHODS: A phase I study was performed with an initial dose of 50 mg/m(2) wPTX and 30 mg/m(2) PLD. The paclitaxel dose was escalated in increments of 10 mg/m(2) and PLD in increments of 5 mg/m(2) until the MTD was reached. The pharmacokinetics of PLD were studied at the highest achieved dose levels. RESULTS: Forty-four cancer patients were enrolled. The MTD was 30/90 and 35/80 mg/m(2) for PLD/wPTX. Dose-limiting toxicities included treatment delay for neutropenia grade 3, febrile neutropenia, palmar-plantar erythrodysesthesia and deep venous thrombosis. Toxicity below the MTD was mild: skin toxicity grade 1-2 developed at high cumulative doses and vascular thrombotic events occurred in two patients with predisposing factors. No cardiotoxicity or clinically relevant peripheral neuropathy was seen. Nausea/vomiting and alopecia were negligible. Three complete responses and nine partial responses were documented among 34 evaluable cases. PLD plasma concentrations were evaluated in seven patients treated at subMTD. Paclitaxel produced a median 53.5% increase of PLD area under the concentration curve (range 4.4%-219%). CONCLUSIONS: The combination of PLD/wPTX constitutes an active chemotherapy regimen with mild toxicity that merits investigation in phase II at 30/80 or 35/70 mg/m(2). Patients should be monitored for a potentially increased risk of thromboembolic events.

Phase I trial of 6-hour infusion of glufosfamide, a new alkylating agent with potentially enhanced selectivity for tumors that overexpress transmembrane glucose transporters: a study of the European Organization for Research and Treatment of Cancer Early Clinical Studies Group.

PURPOSE: To determine the maximum-tolerated dose (MTD), the principal toxicities, and the pharmacokinetics of 6-hour infusion of glufosfamide (beta-D-glucosylisophosphoramide mustard; D-19575), a novel alkylating agent with the potential to target the glucose transporter system. PATIENTS AND METHODS: Twenty-one patients (10 women and 11 men; median age, 56 years) with refractory solid tumors were treated with doses ranging from 800 to 6,000 mg/m(2). Glufosfamide was administered every 3 weeks as a two-step (fast/slow) intravenous infusion over a 6-hour period. All patients underwent pharmacokinetic sampling at the first course. RESULTS: The MTD was 6,000 mg/m(2). At this dose, two of six patients developed a reversible, dose-limiting renal tubular acidosis and a slight increase in serum creatinine the week after the second and third courses of treatment, respectively, whereas three of six patients experienced short-lived grade 4 neutropenia/leukopenia. Other side effects were generally mild. Pharmacokinetics indicated linearity of area under the time-versus-concentration curve against dose over the dose range studied and a short elimination half-life. There was clear evidence of antitumor activity, with a long-lasting complete response of an advanced pancreatic adenocarcinoma and minor tumor shrinkage of two refractory colon carcinomas and one heavily pretreated breast cancer. CONCLUSION: The principal toxicity of 6-hour infusion of glufosfamide is reversible renal tubular acidosis, the MTD is 6,000 mg/m(2), and the recommended phase II dose is 4, 500 mg/m(2). Close monitoring of serum potassium and creatinine levels is suggested for patients receiving glufosfamide for early detection of possible renal toxicity. Evidence of antitumor activity in resistant carcinomas warrants further clinical exploration of glufosfamide in phase II studies.

Weekly docetaxel in minimally pretreated cancer patients: a dose-escalation study focused on feasibility and cumulative toxicity of long-term administration.

BACKGROUND: Docetaxel is an agent with impressive clinical activity but a rather poor profile of toxicity when given every three weeks. Therefore, optimisation of its clinical use is highly warranted. This is a dose-escalation study of weekly docetaxel particularly focused on the feasibility of long-term administration and characterisation of cumulative toxicity. PATIENTS AND METHODS: Twenty-six patients (11 female/15 male, median age 56, range 23-73) were treated over the range of 25-50 mg/m2/week. Dose-limiting toxicity for this schedule was defined as any grade > 2 antiproliferative toxic effect resulting in a > 2-week delay for re-administration of the drug, or any grade > 2 organ-specific toxicity. Patients were monitored clinically and electrophysiologically for neurotoxicity. No prolonged corticosteroid co-medication or prophylactic haematopoietic growth factors were given. RESULTS: A median/mean number of 8.5/8.7 consecutive weekly courses were given per patient. The maximum tolerated dose that prevented on-schedule administration of the drug was 50 mg/m2. The main cumulative toxicities were a mild fluid retention and dacryorrhea which became evident as the number of treatment courses increased. Grade 2 alopecia and fatigue were observed only at 45 mg/m2 and higher. Activity was seen at all of the dose levels studied. CONCLUSIONS: Long-term weekly administration of docetaxel is feasible at doses up to 45 mg/m2/week with acceptable toxicity. Further clinical evaluation is justified at this schedule and 40 mg/m2/week of docetaxel is proposed for phase II studies as an active dose with minimal toxicity.