Ifosfamide continuous infusion without mesna. A phase I trial of a 14-day cycle

Twenty patients received 27 courses of ifosfamide administered as a 24-hour continuous infusion for 14 days without Mesna. The goal of the study was to deliver a dose rate and total cumulative dose of ifosfamide that would be comparable to standard bolus or short-term infusions administered with Mesna. Dose escalations proceeded from 200 to 300, 400, 450, 500, and 550 mg/m2/d. Four patients developed transient microscopic hematuria at 400, 450, and 500 mg/m2/d. There were no instances of macroscopic hematuria. At 550 mg/m2/d, three patients experienced nonurologic toxicity; confusion (1), nausea (1), and Grade 2 leukopenia (1). The recommended dose of 500 mg/m2/d delivers a total dose of 7 g/m2 per cycle, which is comparable to that delivered in clinical practice for bolus or short-term infusion. Because few patients received multiple courses over time, the cumulative effects are indeterminate in the present trial. The frequency and predictability of hematuria are not precise, and at least daily monitoring by urine Hematest is essential, adding Mesna to the infusate in patients with persistent hematuria. The protracted infusion schedule for ifosfamide permits convenient outpatient administration without Mesna and reduces the drug cost of clinical usage of this agent by up to $890 per cycle. Clinical activity was demonstrated in a single patient, but a comparative trial of standard bolus schedules with the protracted infusion schedule will be necessary to determine if the clinical effectiveness of the drug is maintained.     

Phase 1 study of carboplatin in patients with advanced cancer, intermittent intravenous bolus, and 24-hour infusion

We undertook a phase 1 study of Carboplatin (CBDCA) on an intermittent single intravenous (IV) bolus (schedule A) and a 24-hour continuous infusion schedule (schedule B). Hydration and forced diuresis were not performed. Patients were not premedicated for anticipated vomiting. Thirty-eight adult patients with solid tumors received a total of 71 courses. In schedule A, doses were escalated from 20 to 600 mg/m2. The dose-limiting toxicity was myelosuppression. At doses of 270 mg/m2 and higher, leukopenia and thrombocytopenia were reproducibly seen. The dose of 600 mg/m2 was the maximally tolerated dose, producing severe thrombocytopenia (platelet counts less than 30,000/microL). Other toxicities included a fall in hemoglobin levels and tolerable nausea and vomiting. Schedule B produced comparable hematologic and emetogenic toxicities to those in schedule A. In three patients audiograms became abnormal with high-frequency hearing loss without overt deafness. Two patients developed hypomagnesemia without irreversible renal dysfunction. Patients with poor performance status, preexisting renal dysfunction, a third fluid space, or bone metastases seemed to develop increased hematologic toxicity. The recommended phase 2 dose for good risk patients is 400 mg/m2 IV bolus and for poor risk patients 270 mg/m2 IV bolus. Responses were seen in one patient each with head and neck carcinoma (partial response), small cell lung cancer (minor response), and breast cancer (minor response).     

Constant infusion schedule for adriamycin: a phase I-II clinical trial of a 30-day schedule by ambulatory pump delivery system

Eighteen patients received a continuous intravenous infusion of adriamycin for 14-60 days in a phase I study in which the dose rates were escalated from 2 mg/sq m/day to 5 mg/sq m/day to establish the optimal dose to be delivered over a 30-day period. The drug was delivered via a tunneled subclavian catheter by a portable infusion pump (Cormed model ML-6) primed to provide a volume of diluted drug of 10 cc/day. Leukopenia and stomatitis were observed at 4 mg/sq m/day doses or greater in 50% of courses. At doses less than 4 mg/sq m/day, only 3/17 courses (18%) were associated with stomatitis. Partial alopecia developed in all patients, but less than 50% of scalp hair was affected. The cumulative dose of continuous infusion adriamycin at 30 days is comparable to the dose delivered by standard bolus intermittent schedules (60-90 mg/sq m g 21 days), but the adverse drug effects are eliminated or substantially reduced. Cardiac toxicity was assessed in selected patients treated to 450 mg/sq m or greater by cardiac biopsy and/or gated pool studies. No histopathologic lesions were noted in 3 patients receiving 450 mg/sq m or greater. The recommended daily dose rate of adriamycin in this protracted infusion regimen is 3 mg/sq m/day. The phase II study of this schedule and dose rate in 38 additional patients (a total of 52 evaluable patients) demonstrated objective responses in 1/9 soft tissue sarcoma, 1/3 mesothelioma, 1/3 hepatoma, and 2/13 breast cancer. Phase III studies of the protracted continuous infusion schedule for adriamycin are indicated in that clinical activity is demonstrated at a substantial reduction in toxicity. Pharmacologic studies expanding the existing data base are also necessary.     

Etoposide plus carboplatin admixture. Phase I study of five- or seven-day continuous infusion.

Thirty-five patients were entered in a Phase I trial of an admixture infusion of etoposide (VP-16) and carboplatin (CBDCA) administered continuously for 5 or 7 days. Because of the compatibility and solubility of the two agents, the treatment program could be administered on an outpatient basis. The dose rate of VP-16 was fixed at 30 mg/m2/day (total dose 150 mg/m2 for 5 days or 210 mg/m2 for seven days) for each cycle. Carboplatin was evaluated at three dose rates: 50, 60, and 75 mg/m2/day on the 5-day infusion and 40, 50, and 60 mg/m2/day on the 7-day infusion with cycles repeated at 28 to 42 days. The dose limiting toxicity was hematologic and followed a pattern typical for carboplatin, that is, delayed neutropenia and/or thrombocytopenia with a protracted leukocyte recovery. Renal toxicity was observed in three patients. The optimum total dose for the infusional carboplatin component was 300 mg/m2 (5-day) and 420 mg/m2 (7-day). The total etoposide dose was 150 mg/M2 and 210 mg/M2, which did not appear to contribute to the hematologic toxicity. Delivery of the admixture of VP-16 and CBDCA was feasible, although cumbersome, as a result of the portable delivery system. Extending the duration of infusion increases the total cumulative dose of carboplatin and etoposide that can be administered without increasing adverse effects.     

Pharmacokinetic study of two infusion schedules of irinotecan combined with cisplatin in patients with advanced gastric cancer

OBJECTIVE: Irinotecan (CPT-11) in combination with cisplatin (CDDP) has shown promising antitumor activity for advanced gastric cancer, but the optimal administration schedule of CPT-11 is still controversial. To clarify the pharmacokinetic effects of different CPT-11 administration schedules, we compared two different regimens (continuous infusion of CPT-11 for 24 h and CPT-11 infusion for 90 min) combined with CDDP in patients with advanced gastric cancer. PATIENTS AND METHODS: Five patients were treated with CPT-11 at a dose of 60 mg/m(2) delivered by continuous infusion for 24 h on day 1 and by a 90-min infusion on day 15, together with CDDP daily administered at a dose of 10 mg/m(2) on days 1-3 and days 15-17 for 4 weeks. The pharmacokinetics of CPT-11 and its metabolites, SN-38 and SN-38 glucuronide (SN-38G), were investigated, as well as the toxicity of therapy. RESULTS: Grade 3 leukopenia was observed in 1 patient after 24-hour infusion and in 1 patient after 90-min infusion of CPT-11. In addition, grade 3 thrombocytopenia was observed in 1 patient after the 90-min infusion. Other adverse reactions were mild, and the planned dose was delivered to all patients. The area under the plasma concentration-time curve of SN-38, the active metabolite from CPT-11, was increased by 24-hour infusion when compared with the 90-min infusion, and there was no increase in toxicity. CONCLUSION: Protracted infusional CPT-11 combined with CDDP is a practical regimen, and may be appropriate for a future phase II trial.     

Failure of allopurinol to provide clinically significant protection against the hematologic toxicity of a bolus 5-FU schedule

Allopurinol has been shown to ameliorate the myelotoxicity of 5-fluorouracil (5-FU) given as an infusion. To study the potential effectiveness of allopurinol in modifying the toxicity of 5-FU given as a bolus, 8 adult patients with metastatic malignancies were given 11 courses of bolus 5-FU with allopurinol. Allopurinol was administered at a dose of 900 mg/day orally beginning a week prior to the 5-FU therapy and continued a week after the last dose of 5-FU was administered. Three patients received a total of 5 courses of 600 mg/m2 of 5-FU via bolus injection for 4 consecutive days every 28 days. Six patients were given 6 courses of 800 mg/m2 of 5-FU via bolus injection in the same schedule. Gastrointestinal toxicity was mild and no significant neurotoxicity was documented. However, severe myelosuppression occurred at the 800 mg/m2 dosage which led to marked leukopenia in 5 of the 6 patient courses and thrombocytopenia in 1. Gram-negative sepsis developed in 3 of the leukopenic patients with 2 resultant deaths. Allopurinol does not appear to allow clinically significant dose escalation of bolus 5-FU given on this schedule.     

Granulocyte-macrophage colony-stimulating factor. Preliminary observations on the influences of dose, schedule, and route of administration in patients receiving cyclophosphamide and carboplatin.

BACKGROUND. In an attempt to learn how best to administer granulocyte-macrophage colony-stimulating factor (GMCSF), the authors performed a Phase I study of this agent. They were interested in the influences of dose, schedule, and route of administration on the effects of GMCSF in patients receiving standardized 1-day regimens of cyclophosphamide (CYCLO) and carboplatin (CBDCA). METHODS. Between June 1988 and March 1991, 57 patients with advanced cancer received GMCSF in association with CYCLO 1 g/m2 plus CBDCA 225-700 mg/m2. After the first dose escalation to 300 mg/m2 of CBDCA, patients who had previously received chemotherapy or radiation therapy were excluded. GMCSF was administered in three different doses, five different schedules, and by two different routes. Altogether, 17 different treatment groups were observed. In addition, 24-hour GMCSF serum concentration curves were charted in four patients. RESULTS. Using four sequential groups of three patients each who had received myelosuppressive treatment, treatment with CYCLO 1 g/m2 and CBDCA 225 mg/m2, the apparent superiority of daily subcutaneous injection over 30-minute daily IV infusion of GMCSF was demonstrated graphically. Subsequently, the authors observed apparent enhancement of GMCSF effects beyond those produced by the initially selected 20-day basic 10 micrograms/kg daily SC regimen beginning 2 days after chemotherapy. When administered SC every 12 hours for 14 days beginning the day after chemotherapy, GMCSF appeared to ameliorate the severity of both leukopenia and thrombocytopenia. These effects permitted escalation of the CBDCA dose to 700 mg/m2 (with 1 g/m2 of CYCLO) before cytotoxic tolerance limits were reached. Graphic small group comparisons suggest that GMCSF given SC in doses of 5 micrograms/kg twice daily may produce comparable leukocyte and platelet support after chemotherapy with lower toxicity than occurs from higher doses. Prechemotherapy priming with GMCSF twice daily for an additional 4 days (days -6 to -3) seems to ameliorate postchemotherapy cytopenias further but at the cose of some increased risk of GMCSF toxicity. Although most of the toxic effects of moderate-dose GMCSF are controlled by antihistamines and ibuprofen, oral glucocorticoids (e.g., prednisone, 10 mg twice daily during the second week of GMCSF administration) may be required in patients with serositis, pulmonary infiltrates, or severe skin eruptions. CONCLUSIONS. Our observations suggest that GMCSF should be administered SC in doses of approximately 5 micrograms/kg every 12 hours for 10-14 days beginning the day after chemotherapy. Prechemotherapy priming with these same doses for four additional days (days -6 to -3) may additionally ameliorate postchemotherapy leukopenia and thrombocytopenia, but with increased risk of toxicity.     

Combined 5-fluorouracil and floxuridine administered as a 14-day infusion. A phase I study

5-Fluorouracil (5-FU) and floxuridine (FUdR) were admixed in a single solution and administered via a central venous catheter on a continuous infusion schedule for 14 days. The Phase I trial design developed for admixture combinations was employed with starting doses for 5-FU at 250 mg/m2/day and for FUdR at 0.075 mg/kg/day. Twenty patients and 28 courses were studied. Dose rate limiting toxicity was pseudoregional enteritis with or without stomatitis experienced by five of ten of the courses administered at the highest dose rates of the admixture components. The simultaneous delivery of the two agents results in a modest compromise of the cumulative dose delivered for FUdR. Previous Phase I studies of single agent 5-FU and FUdR had demonstrated that the optimal dose rates for the individual agents in a 14-day continuous 24-hour infusion schedule is 350 mg/m2/d and 0.125 mg/Kg/day, respectively. The maximum dose rate of 5-FU at 350 mg/m2/day for 14 days is not restricted even with the addition of FUdR at up to 0.1 mg/kg/day. The optimal dose rates for Phase II trails should be as follows: 5-FU, 350 mg/m2/day; and FUdR, 0.1 mg/kg/day.     

Cyclophosphamide, methotrexate, and 5-fluorouracil in a three-drug admixture. Phase I trial of 14-day continuous ambulatory infusion

The compatibility and stability at room temperature for up to 7 days of a three-drug admixture of cyclophosphamide, methotrexate, and 5-fluorouracil (5-FU) (CMF) was established permitting the practical delivery of the combination as an infusion in an ambulatory setting. Fourteen patients received 20 courses of CMF administered on a continuous infusion schedule for 14 days of a 28-day cycle. The dose rates were fixed for 5-FU (300 mg/M2/day) and methotrexate (0.75 mg/M2/day). The cyclophosphamide dose was escalated from 25 to 50, 75, and 100 mg/M2/d. Leukopenia and thrombocytopenia were observed in two of five patients receiving the maximal dose of cyclophosphamide. No other toxicities were observed including alopecia, stomatitis or liver function abnormalities. This Phase I trial suggests that the cumulative doses of cyclophosphamide, methotrexate, and 5-FU are comparable to the maximum doses delivered as single agent infusions. Furthermore, when the infusion CMF is compared to the "standard" bolus schedule for CMF, the infusion schedule delivers 116%, 8%, and 350% of the respective three component drugs (cyclophosphamide, methotrexate, and 5-FU).     

A phase I study of menogaril in patients with advanced cancer

Menogaril (7-con-O-methylnogarol) is a semisynthetic anthracycline analogue of nogalamycin that has shown good activity against a variety of experimental tumor systems as well as decreased cardiac toxicity when compared with doxorubicin in preclinical studies. Forty-one patients with refractory solid tumors received menogaril during a phase I trial at The Johns Hopkins Oncology Center (Baltimore). Menogaril was administered as an intravenous (IV) infusion on days 1 and 8 of a 28-day cycle in doses of 8 to 140 mg/m2. Eastern Cooperative Oncology Group (ECOG) grade 3 and 4 leukopenia was the principle dose-limiting toxicity and was occasionally accompanied by thrombocytopenia. Both WBC and platelet nadirs occurred between days 15 and 22. Anemia requiring transfusion was occasionally seen. Nonhematologic toxicities observed included frequent anorexia and malaise that was not dose related and postinfusion phlebitis that was dose related and occasionally dose limiting. Gastrointestinal toxicity and alopecia were infrequent and mild in severity. Three patients with cumulative doses of menogaril greater than 1,400 mg/m2 had no significant changes in ejection fractions as determined by serial gated blood pool scans. Two patients had greater than 10% decrements in ejection fractions without clinical changes at total doses of 128 and 288 mg/m2. One patient with prior anthracycline therapy and chest irradiation decreased her left ventricular ejection fraction from 52% to 30% and developed respiratory failure after two cycles of therapy in the setting of disease progression. No responses to menogaril therapy were observed. The recommended phase II dose for menogaril on this day 1 and 8 schedule is 140 mg/m2. A starting dose of 90 mg/m2 should be considered for heavily pretreated patients. In comparing results of this phase I schedule with those of other schedules, evidence for schedule-dependent toxicity differences should be sought.     

Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma

This phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with O⁶-benzylguanine (O⁶-BG). Both TMZ and O⁶-BG were administered on days 1–5 of a 28-day treatment cycle. A bolus infusion of O⁶-BG was administered at 120 mg/m² over 1 h on days 1, 3, and 5, along with a continuous infusion of O⁶-BG at 30 mg/m²/day. TMZ was administered at the end of the first bolus infusion of O⁶-BG and then every 24 h for 5 days during the continuous infusion of O⁶-BG. Patients were accrued to one of three 5-day dosing regimens of TMZ. Twenty-nine patients were enrolled into this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for TMZ for the three different 5-day dosing schedules was determined as follows: schedule 1, 200 mg/m² on day 1 and 50 mg/m²/day on days 2–5; schedule 2, 50 mg/m²/day on days 1–5; and schedule 3, 50 mg/m²/day on days 1–5 while receiving pegfilgrastim. Thus, the 5-day TMZ dosing schedule that maximized the total dose of TMZ when combined with O⁶-BG was schedule 1. This study provides the foundation for a phase II trial of O⁶-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.     

Dose finding study of paclitaxel and carboplatin for ovarian cancer (JKTB)

We conducted a dose-finding study for combination therapy of paclitaxel (Taxol; TXL) and carboplatin (Paraplatin; CBDCA). TXL is a novel plant-derived anticancer agent that is a diterpene derivative possessing the taxane ring. The subjects were patients with ovarian carcinoma, who were evaluated by a modified Fibonacci method. The dosage of TXL was 150 to 180 mg/m2. CBDCA was administered by dose escalation from AUC = 4 to 7. The administration schedule was as follows. Pre-medication was administered before TXL was given. TXL was then administered by intravenous infusion over 3 hours, followed by CBDCA. The dose of CBDCA was determined using the Calvert formula: [AUCX (GFR + 25)]. GFR was calculated with the Jelliffe equation. The non-hematological toxicities observed in 15 eligible cases were mainly grade 1, with no grade 3 or above, and no increase in severity was observed with stepping up. The hematological toxicities were grade 3 leukopenia in 5 of 15 cases, neutropenia in 5 cases and thrombocytopenia in 0 cases. No grade 4 toxicity was observed. The lowest counts of leukocytes and neutrophils were reached after 10.8 and 11.7 days, respectively. The toxicities were reversible in most cases with subsequent recovery. The above findings indicate that the recommended dosages for TJ therapy for Japanese ovarian cancer patients should be TXL 180 mg/m2 and CBDCA at a target of AUC = 6.     

Combined chemotherapy with weekly paclitaxel and carboplatin for recurrent and refractory epithelial ovarian cancer--phase I study

The current initial standard chemotherapy for advanced ovarian cancer is a regimen with a combination of platinum and taxane. However, the 5-year survival rate remains at 40% or lower, and the recurrence rate is as high as 70-80%. Second-line chemotherapy for recurrent cases has not yet been established. We conducted a phase I study of combined chemotherapy with paclitaxel (TXL) and carboplatin (CBDCA) administered weekly for recurrent and refractory ovarian cancer. The subjects were patients with a histopathologically confirmed diagnosis of malignant epithelial ovarian cancer, with recurrent or refractory disease after the initial chemotherapy. TXL was administered at escalating concentrations up to 60-100 mg/m(2), while the dose of CBDCA was fixed at an AUC of 2. In regard to the dosing schedule, premedication was performed as defined before TXL administration, and TXL and CBDCA were administered, in that order, by intravenous infusion for over at least 1 hour. The 4-week period, including the administration of both drugs on Day 1, 8, and 15, was regarded as one course of treatment. No cases developed grade 4 hematoxicity, but leukopenia and neutropenia occurred. All cases of leukopenia of step 4 and step 5 developed grade 3 leukopenia. Grade 2 thrombocytopenia was one example at a low rate. Non-hematological toxicity included neuropathy, arthralgia and muscle pain, but none of the patients developed grade 3 or 4. The response rate was 41.7% (5/12). The response rate of cases administered over TXL 80 mg was 66.7% (4/6). Based on these results,the following dose schedule was recommended for planning and designing a phase II study in the future: CBDCA AUC 2+TXL 80 mg/m(2) (Days 1, 8, and 15 q 4 weeks).     

A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study

One hundred seventy-nine patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid-Atlantic Oncology Program (MAOP) to compare two schedules of delivery for single-agent fluorouracil (5-FU). The "standard" treatment was a schedule commonly employed in clinical practice, namely, a daily bolus dose administered intravenously (IV) for five consecutive days and repeated at 5-week intervals. The investigational treatment was a continuous infusion of 5-FU administered 24 hours a day for a protracted time (10 weeks or more). Both treatments were continued until the development of disease progression or unless interrupted for toxicity. Using stringent objective criteria requiring independent confirmation of x-ray or scan-documented response, the tumor response rate reached 7% (six of 87) for the bolus arm and 30% (26 of 87) for the infusion arms (P less than .001). Toxicity was substantially different for the two arms with major leukopenia observed only on the bolus arm, 22% developing grade 3 (severe) or grade 4 (life-threatening) leukopenia with four sepsis-related deaths. Hand-foot syndrome was observed only in the infusional arm, requiring treatment interruptions and dose reductions in 24% of patients, but with little impact on quality of life. In spite of the major difference in objective response rate, overall survival for the two groups was comparable. Administration of 5-FU as a continuous infusion for protracted periods clearly improves the therapeutic index for this agent in patients with advanced colon cancer with respect to response rate and reduced toxicity. This schedule appears workable in the community setting and yields response rates similar to those reported for 5-FU with high-dose leucovorin, but without the gastroin testinal toxicity profile of the latter combination.     

A phase I study of chlorozotocin (NSC 178248).

Chlorozotocin was administered by rapid intravenous infusion to 35 patients with advanced cancer on either single-day of five-consecutive-day schedules. Total doses per course ranged from 12.5 to 200 mg/m2. On either administration schedule, dose limiting toxicities were thrombocytopenia and leukopenia at total doses of 150 mg/m2 to 200 mg/m2. Repetitive courses of drug may produce progressive impairment of renal and bone marrow function. Nausea and vomiting were infrequent and mild without definite relationship to dose. Minor reversible nondose related increases in SGOT and in serum creatinine occurred at all doses on both schedules. The plasma half-life of intact N-nitroso groups averaged 9.5 minutes after rapid intravenous administration of doses up to 40 mg/m2 and 12.5 minutes after doses of 150 or 200 mg/m2. No differences between plasma half-lives were seen between identical doses given on the first and fifth days of the five-day schedule. Objective tumor regression was noted in one patient with bronchogenic large cell carcinoma and one patient with metastatic melanoma.     

A phase I pharmacokinetic study of 21-day continuous infusion mitoxantrone

A phase I study of mitoxantrone given as a continuous infusion for 21 days using a venous access port and a portable pump was performed. The first dose step was 0.3 mg/m2/d for 21 days. Courses were repeated every 6 weeks. Dose increment per step was 0.1 mg/m2/d in the first three dose steps and 0.2 mg/m2/d in the latter dose steps. Twenty-five patients entered the study and received a total of 50 courses, with a median of two courses (range, one to five). Up to 0.5 mg/m2/d, no toxicity (according to the World Health Organization [WHO] criteria) occurred. At 0.7 mg/m2/d, one patient experienced grade 2 leukocytopenia and at the 0.9 mg/m2/d dose step, one patient experienced grade 2 leukocytopenia, grade 1 thrombocytopenia, and grade 1 hair loss. At 1.1 mg/m2/d, two of six patients had grade 3 leukocytopenia, and in one patient treatment was discontinued after two days because of myocardial infarction. In both patients receiving 1.3 mg/m2/d, treatment was discontinued after 2 weeks because of grade 3 leukocytopenia. Three patients at the 1.1 mg/m2/d, dose step and two patients at the 1.3 mg/m2/d dose step experienced some nausea in the last week of the infusion period. One patient developed subclavian vein thrombosis. No infectious complications occurred. Pharmacokinetic studies were performed by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Plasma steady-state was reached after 35 hours. During steady-state there was a linear relationship between the mitoxantrone dose administered and the level of mitoxantrone in plasma (r = .93, P less than .005). The mitoxantrone level in leukocytes increased significantly during the infusion period at the 0.9 mg/m2, the 1.1 mg/m2, and the 1.3 mg/m2 dose steps. The area under the curve (AUC) in leukocytes was higher with continuous infusion of 1.1 mg/m2/d for 21 days compared with bolus injection of 12 mg/m2. Mitoxantrone could be detected in plasma for at least five days after the end of the 21-day infusion period and in leukocytes for at least 14 days. Continuous infusion mitoxantrone may increase intracellular drug uptake as expressed by intracellular AUC. We recommend a dose of 1.1 mg/m2/d for 3 weeks for evaluation of antitumor efficacy in phase II studies.     

A phase I clinical and pharmacokinetic study of the camptothecin glycoconjugate, BAY 38-3441, as a daily infusion in patients with advanced solid tumors.

BACKGROUND: The aim of this study was to define the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of the camptothecin glycoconjugate BAY 38-3441, administered as an infusion for 30 min on two separate schedules every 3 weeks. PATIENTS AND METHODS: A total of 81 patients with advanced solid tumors were treated with BAY 38-3441 either at doses of 20, 40, 67, 100, 140, 210, 315, 470 and 600 mg/m2/day for 1 day every 3 weeks (single-dose schedule), or at doses of 126, 189, 246, 320 and 416 mg/m2/day once daily for three consecutive days every 3 weeks (3-day schedule). Plasma sampling was performed to characterize the pharmacokinetics of BAY 38-3441 and camptothecin with these schedules. RESULTS: DLTs included renal toxicity, granulocytopenia and thrombocytopenia on the single-day schedule at doses > or = 470 mg/m2/day, and diarrhea and thrombocytopenia on the 3-day schedule at doses > or = 320 mg/m2/day. Other non-DLTs were gastrointestinal, dermatological and hematological. Pharmacokinetics of BAY 38-3441 and camptothecin appear to be dose-dependent, but not linear. CONCLUSIONS: Renal toxicity was dose-limiting for BAY 38-3441 using 30-min infusions on the single-dose schedule. Dose escalation to 470 mg/m2/day is feasible using a 2-h infusion. However, because of the superior safety profile, we recommend the 3-day schedule for BAY 38-3441 at a dose of 320 mg/m2/day as 30-min infusions for further phase II studies.     

A phase I and pharmacology study of continuous-infusion low-dose methotrexate administration

Continuous intravenous infusion of methotrexate (MTX) was evaluated in a Phase I study designed to establish the optimal dose rate to provide a minimum of 28 days of constant 24-hour drug exposure. Twenty-six courses were administered to 21 patients at dose rates of 0.75 mg/M2/day to 3 mg/M2/day. Dose-limiting toxicity was predominantly stomatitis at the highest dose rates. Thrombocytopenia (platelet count less than 100,000) without leukopenia developed in 8 of 26 courses at the lower dose rates, with or without stomatitis, and was rapidly reversible. Serial blood levels revealed detectable serum MTX concentrations at all dose rates delivered with mean MTX concentrations varying from 12.8 nM at 0.75 mg/M2/day to 140 nM at 2.5 mg/M2/day. Total-body clearance of MTX approximated renal creatinine clearance. The recommended dose rate for continuous infusion of methotrexate is 0.75 mg/M2/day for 28 days, and for shorter durations (less than or equal to 14 days), the optimal dose rate is 1.5 mg/M2/day. The continuous-infusion schedule for MTX, therefore, results in a substantial decrease in the delivered dose compared with that achieved with a bolus schedule.     

Phase I and pharmacokinetic study of irinotecan administered as a low-dose, continuous intravenous infusion over 14 days in patients with malignant solid tumors.

PURPOSE: To evaluate the feasibility of administering irinotecan as a continuous intravenous infusion for 14 to 21 days. PATIENTS AND METHODS: Patients with solid tumors refractory to standard therapy received continuous infusions of irinotecan by means of an ambulatory infusion pump. The starting dosage was 12.5 mg/m(2)/d for 14 days every 3 weeks. After identification of the maximum-tolerated dose for the 14-day infusion schedule, the protocol was amended to prolong the infusion duration to 17 and 21 days. Pharmacokinetics of irinotecan and SN-38 and its glucuronide were determined using high-performance liquid chromatography and noncompartmental modeling. RESULTS: Thirty-three patients received 85+ courses. At the first dose level (12.5 mg/m(2)/d), cumulative grade 3 or 4 diarrhea and grade 3 or 4 neutropenia occurred in three of five patients. At a dosage of 10 mg/m(2)/d, 14-day administration resulted in grade 4 diarrhea in two of six patients and one episode of grade 4 vomiting occurred, whereas with 17-day administration, one episode of grade 3 nausea and two episodes of grade 3 or 4 diarrhea were observed in six patients. Increasing the number of days of infusion to 21 days was not feasible because of cumulative diarrhea. Hematologic toxicity was rare. The mean metabolic SN-38 area under the curve/irinotecan area under the curve ratio was 16% +/- 6% compared with 3% to 5% after short infusion schedules involving therapeutic dosages. Partial responses were observed in two patients with extraovarian and colorectal cancer. CONCLUSION: The recommended dosage is 10 mg/m(2)/d for 14 days, repeated every 3 weeks. Enhanced metabolism of irinotecan to SN-38 may explain in part the low recommended dose for this schedule.     

A phase I-II study of continuous 5-day infusion mitomycin-C

A phase I-II study was undertaken to establish the maximum-tolerated dose of a continuous 5-day infusion of mitomycin-C and its efficacy in patients with advanced metastatic drug-resistant breast and gastrointestinal malignancies. The dose-limiting toxicity was myelosuppression, predominantly thrombocytopenia, and was severe and cumulative. Nonhematologic toxicity was infrequent, and no renal or cardiac toxicity was seen. For patients with breast cancer who had received extensive prior therapy, 3 mg/m2/day for 5 days repeated every 6-8 weeks were well-tolerated doses; and for patients with gastrointestinal cancer, the maximum-tolerated dose was 4 mg/m2/day. One patient with breast cancer had a partial response lasting 4 months, and no responses were observed in patients with gastrointestinal cancer. The administration of mitomycin-C by continuous infusion did not appear to have improved its therapeutic index.