Activity of pirarubicin (4'-0-tetrahydropyranyladriamycin) in malignant mesothelioma

Eight patients with diffuse malignant mesothelioma of the pleura or peritoneum, previously untreated with chemotherapy, were treated with a new anthracycline 4'-0-tetrahydropyranyladriamycin (pirarubicin). Pirarubicin was given intravenously at the rate of 5 mg per minute, at doses ranging from 35 to 70 mg/m2 once every 21 days. On clinical evaluation, one patient had complete response lasting 4 months. On second-look laparotomy residual tumor was found and she was labelled a partial responder and changed to alternate chemotherapy. Another patient had a partial response of recurrent chest wall tumors lasting 11 months. A third patient had a partial response lasting 4+ months of a pleural-based tumor and resolution of pleural effusion. After the fifth course of chemotherapy, he developed severe granulocytopenia, pseudomonas sepsis, shock, and renal failure. Despite recovery of blood counts to normal within 3 days, renal failure proved fatal. Autopsy revealed only fibrosis and no gross or microscopic evidence of malignant mesothelioma. A fourth patient had improvement in evaluable disease lasting about 4 months; and the remaining four had stable disease for at least 2 months each. The authors conclude that, whenever feasible, noninvasive clinical assessment of tumor response should be supplemented by surgical-pathologic evaluation. Pirarubicin is active in malignant mesothelioma. This is the first report documenting complete tumor eradication after chemotherapy in an adult with malignant mesothelioma.     

A clinical trial of transarterial chemoembolization for hepatocellular carcinoma using 4'-0-tetrahydropyranyladriamycin]

A clinical trial of transarterial chemoembolization for hepatocellular carcinoma using pirarubicin (4'-0-tetrahydropyranyladriamycin, THP) was performed. Although adriamycin has been widely utilized for chemoembolization on the hepatocellular carcinoma, myocardial toxicity has been occasionally observed as its serious side effect. THP has an advantage that myocardial and gastrointestinal complications are less frequent than adriamycin. Ten patients with hepatocellular carcinoma were included in this study. Emulsion of 30-60 mg of THP and lipiodol was administered through a catheter inserted into the right or left hepatic artery, and thereafter, transarterial embolization was performed. PR was observed in seven of the ten patients and MR in two. Only one patient showed NC. Serum alpha-fetoprotein levels decreased in nine of the ten patients, and PIVKA II in the peripheral blood disappeared in all five patients that had been positive before the chemo-embolization four weeks after the treatment. Side effects included nausea in two patients just after administration of THP, but leukopenia below 2,000/cmm, was not observed in any of the patients. No other serious side effect was observed. From these results, THP was suggested to be a useful chemotherapeutic agent for hepatocellular carcinoma.     

A phase II study of (2'R)-4'-0-tetrahydropyranyladriamycin (THP) in patients with hematological malignancies. THP Study Group

A Phase II study of a new anthracycline, (2'R)-4'-0-tetrahydropyranyladriamycin (THP), was conducted in 162 patients with various hematological malignancies in a multi-institutional cooperative study. THP was given intravenously at a dose of either 10-30 mg/body for 3-5 consecutive days or 40-60 mg/body at 3-week intervals. Of 22 patients with AML, complete remission (CR) was observed in 2 patients and partial remission (PR) in 2. Of 18 patients with ALL, CR was observed in 5 and PR in 3. Of 68 patients with NHL, CR was observed in 11 and PR in 22. Of 8 patients with HD, CR was observed in 4 and PR in 2. One CML case showed CR and one ATL case showed PR. PR was noted in one of 2 patients with mycosis fungoides. Overall remission rate was 43.1% (CR 23 cases and PR 33 cases). The predominant toxicity was myelosuppression. Leukopenia (less than 4,000/mm3) was noted in 67 (77.6%) and thrombocytopenia (less than 10 X 10(4)/mm3) in 24 (27.0%). Nausea/vomiting and anorexia were common, and were observed in 61 (43.3%) and 65 (46.1%) cases, respectively. Hair loss and cardiotoxicity were mild and recovered quickly on discontinuation of THP. Thus, THP was found to be effective for various hematological malignancies including acute leukemia and malignant lymphoma.     

Phase II trial of 4'-0-tetrahydropyranyladriamycin (pirarubicin) in head and neck carcinoma.

BACKGROUND. 4'-0-tetrahydropyranyladriamycin (Pirarubicin, Meiji Seika (USA) Inc., New York, NY) may be less toxic than doxorubicin. METHODS. A Phase II trial of Pirarubicin was done in 26 patients who had not previously had chemotherapy and who had measurable and incurable head and neck carcinoma. All patients received an intravenous bolus dose of 60 mg/m2 Pirarubicin in the first cycle without any prophylactic antiemetic. The cycles were repeated every 3 weeks. Based on tumor response, nadir counts, or complications of myelosuppression, the doses were escalated or de-escalated by 10 mg/m2, if necessary, in the second cycle to achieve mild leukopenia (3000-4000 leukocytes/microliters). RESULTS. Leukopenia was mild, moderate (2000-2999 leukocytes/microliters), severe (1000-1999 leukocytes/microliters), and life threatening (less than 1000 leukocytes/microliters) in 13%, 31%, 27%, and 9% of the first two courses, respectively. The median interval to nadir leukopenia was 13 days (range, 7-21 days), with a median of 8 days (range, 5-13 days) to recover to normal. One patient with a leukocyte count of 800/microliters and an absolute granulocyte count (AGC) of 488/microliters died of sepsis 15 days after the first course. All patients had at least one course that resulted in leukopenia. One episode each of mild (100,000-150,000 platelets/microliters) and severe (25,000-49,999 platelets/microliters) thrombocytopenia occurred in the first two courses. Leukocyte, granulocyte, and platelet counts were not done routinely after the second cycle. Six patients who received four or more courses with cumulative doses of 310, 610, 340, 260, 660, and 550 mg/m2 had decrements of 0%, 1%, 7%, 10%, 12%, and 13%, respectively, in radionuclide left ventricular ejection fraction (LVEF). All other toxic effects were mild. CONCLUSIONS. In the 24 patients with disease evaluable for response to Pirarubicin therapy, 1 had a complete response that lasted 5 months and 4 had a partial response of 2, 3, 6, and 8 months. The median survival time in patients with disease that responded to Pirarubicin therapy was 27 months; in patients with disease that did not respond to Pirarubicin therapy, the median survival time was 4 months, and in the total cohort, it was 5 months. Pirarubicin was well tolerated and was an active agent in head and neck squamous cell carcinoma.     

Phase II study of (2'R)-4'-0-tetrahydropyranyladriamycin (THP) in gastrointestinal cancer

A phase II study of a new anthracycline, (2'R)-4'-0-tetrahydropyranyladriamycin (THP) was performed on 37 patients with gastrointestinal cancer in 6 co-operative study institutions. Twenty-five patients out of 37 were evaluable for response according to the Koyama-Saito's criteria. THP was administered weekly at doses of 10 to 30 mg/body or every 3 to 4 weeks at doses of 40 to 60 mg/body intravenously. Of the 14 patients with gastric cancer, we obtained one complete response and 3 partial responses (response rate 28.6%), and of the 6 patients with rectal cancer, we obtained one partial response (16.7%). Leukopenia of less than 3 X 10(3)/mm3 and erythrocytopenia of less than 300 X 10(4)/mm3 were seen in 48% and 26% of cases. Neither cardiotoxicity nor hair loss were seen. These results suggest that THP is useful in the treatment of patients with gastrointestinal cancer.     

A phase I and pharmacokinetics study of prolonged ambulatory-infusion carboplatin

A total of 18 patients received 6-week ambulatory infusions of carboplatin in groups at dose levels of 14, 28, 35 and 42 mg/m² per day. The dose-limiting toxicity was myelosuppression. At 42 mg/m², three of four patients had WHO grade 4 and one of four had grade 3 neutropenia, whereas two patients had grade 3 thrombocytopenia. At 35 mg/m², two of five patients had grade 3 neutropenia, whereas one had grade 4 and two had grade 3 thrombocytopenia. Non-hematological toxicities were predominantly gastrointestinal, with 3 of 18 patients experiencing grade 3 emesis. Total and ultrafiltrable platinum (UFPt) were assayed by flameless atomic absorption spectrometry in weekly and post-infusion plasma and urine samples. In plasma, levels of total platinum increased throughout the infusion, and the protein binding slowly increased from 60% platinum bound at week 1 to 90% bound by week 4. Although the UFPt level reached a steady state within 1 week, the concentration did not increase with the dose level, remaining at a mean value of 0.58±0.24 M. Renal excretion of platinum accounted for 70±12% of the dose at steady state. There was a high inter-patient variability in both total body clearance of UFPt (range, 83–603 ml/min) and renal clearance (range, 67–390 ml/min). A terminal elemination half-life of 13–27 h was noted for post-infusion UFPt. Neutropenia was linearly related to the total daily carboplatin dose, but neither neutropenia nor thrombocytopenia could be related to steady-state UFPt or the UFPt area under the concentration-time curve (AUC). The recommended dose for phase II studies is 28 mg/m² per day.     

Phase II collaborative study of (2'R)-4'-0-tetrahydropyranyladriamycin (THP) for urological malignancies--Urological Co-operative THP Study Group

A Phase II clinical trial of a new anthracycline, (2'R)-4'-0-tetrahydropyranyladriamycin (THP), was performed in 137 patients with urological malignancies. Out of them, 111 patients were evaluated for tumor responses and 125 patients were evaluated for adverse effects. In cases of intravenous administration, overall response rate was 18.5% (22.2% for bladder cancer, 30.0% for tumors of the renal pelvis and ureter, and 6.7% for prostatic cancer). In the case of intra-arterial administration, overall response rate was 42.9% (50.0% for bladder cancer). For 50 patients with superficial bladder cancer intravesical chemotherapy with THP was performed. Sixteen patients showed complete disappearance of the tumor, 2 patients showed more than 90% tumor regression and 12 patients showed more than 50% tumor regression, respectively. Overall response rate was 60%. Cardiotoxicity was minimal. Alopecia was noted in a total of 16 patients, but this was minimal. Leukocytopenia was the major adverse effect among patients undergoing systemic THP administration. In conclusion, THP was most effective against transitional cell carcinoma of the urinary tract.     

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.     

A phase I and pharmacology study of an oral platinum complex,JM216: dose-dependent pharmacokinetics with single-dose administration

JM216 [bis-acetato-ammine-dichloro-cyclohexylamine-platinum (IV)] is an oral platinum complex with in vivo activity against murine and human tumor models and a lack of nephro- and neurotoxicity in rodents. During a phase I study of a single-dose schedule, JM216 was given in dry-filled hard gelatin capsules by mouth without hydration or diuresis. In all, 37 patients were given a total of 88 courses at doses ranging from 60 to 700 mg/m². The study was stopped before the MTD was reached because of nonlinear pharmacokinetics. Myelosuppression was manifest by leucopenia or thrombocytopenia and showed marked variability at 420–700 mg/m². Vomiting was mild and controllable by antiemetics in approximately 50% of courses. The onset of vomiting was delayed to 4 h after during ingestion. There was no nephro-, oto- or neurotoxicity. A partial response was recorded in a patient with recurrent ovarian cancer, and significant falls in plasma tumour markers (CA125) were seen in two further cases. Plasma pharmacokinetics were linear and showed moderate interpatient variability at dose levels of 120 mg/m². At dose levels of 200 mg/m², C_max and AUC increased less than proportionally to dose. This was associated with greater interpatient pharmacokinetic variability and reduced urinary platinum recovery. A significant sigmoidal relationship existed between ultrafilterable plasma AUC and the percentage of reduction in platelet count (r ²=0.78). Nonlinear absorption was a limitation to this single-dose schedule of oral NM216; however, little nonhaematological toxicity was seen at doses associated with myelosuppression and antitumour activity. Clinical studies of divided dose schedules using doses within the range of pharmacokinetic linearity (120 mg/m²) are now being investigated.Abbreviations AUC Area under the plasma concentration versus time curve - C _max peak plasma concentration - cxs courses - FAAS flameless atomic absorption spectrophotometry - Gd CTC toxicity severity grade - JM216 bis-acetato-ammine-dichloro-cyclohexylamineplatinum(IV) - MRT mean residence time - MTD maximally tolerable dose - pts patients - T _max time of peak plasma concentration     

A randomized phase II study of (2'R)-4'-0-tetrahydropyranyladriamycin and adriamycin in combination with vincristine and ACNU in small cell lung cancer--THP-ADM, VCR, ACNU vs ADM, VCR, ACNU

Between April 1984 and March 1988, a comparative randomized phase II study was performed to compare the effects of (2'R)-4'-0-Tetrahydropyranyl-adriamycin (THP) and adriamycin in combination with vincristine (VCR) and ACNU in 60 previously untreated and evaluable patients with small cell lung cancer (SCLC). Arm AVA was constituted by adriamycin, VCR and ACNU, and arm TAVA by THP, VCR, ACNU. Of the 30 patients treated with AVA, there were 20 partial responses, 7 with no change and 3 with progressive disease, for an overall response rate of 66.7%. On the other hand, of the 30 patients on TAVA, one complete response and 22 partial responses were observed, for an overall response rate of 76.7% Median survival time of AVA was 10.0 M, that, of TAVA was 9.3 M. But significant differences between the two arms was not found. During induction therapy, leukopenia was the main side effect. Over WHO Grade 3 leukopenia was seen in 53.3% of patients on AVA and 70.0% of those on TAVA. Moderate hair loss (Grade 2) was significantly less frequent with TAVA than AVA. In conclusion, the results indicated that THP is active in SCLC with the same level of adriamycin, and has less toxicity. THP is a suitable drug as a first line combination chemotherapy for SCLC.     

A phase I clinical, plasma, and cellular pharmacology study of gemcitabine

A novel deoxycytidine analog, gemcitabine (2',2'-difluorodeoxycytidine [dFdC]), has been studied in a phase I clinical and pharmacology trial. Doses ranging from 10 to 1,000 mg/m2 were administered over 30 minutes weekly times 3 weeks every 4 weeks. The maximum-tolerated dose (MTD) was 790 mg/m2. The dose-limiting toxicity was myelosuppression, with thrombocytopenia and anemia quantitatively more important than granulocytopenia. Nonhematologic toxicity was minimal. Two responses in patients with adenocarcinomas of the colon and lung were documented. The maximum dFdC plasma concentration, reached after 15 minutes of infusion, was proportional to the total dose administered. Elimination, due mainly to deamination, was rapid (terminal half-life [t1/2], 8.0 minutes) and dose independent. The deamination product 2',2'-difluorodeoxyuridine (dFdU) was eliminated with biphasic kinetics characterized by a long terminal phase (t1/2, 14 hours); it was the sole metabolite detected in urine. The concentration of dFdC 5'-triphosphate in circulating mononuclear cells increased in proportion to the dFdC dose at infusions between 35 and 250 mg/m2. No further increment in dFdC 5'-triphosphate (dFdCTP) was observed at higher doses, which resulted in plasma dFdC concentrations greater than 20 mumol/L (350 to 1,000 mg/m2), suggesting saturation of dFdC 5'-phosphate accumulation. The recommended dose for phase II clinical trials in solid tumors is 790 mg/m2/wk.     

Good tolerance of weekly oral idarubicin: (4-demethoxydaunorubicin): A phase I study with pharmacology

Summary Idarubicin (4-demethoxydaunorubicin) is an orally active anthracycline. We treated 26 patients with 37 courses of the drug on a schedule of oral administration weekly × 3 followed by a 3-week rest period. The maximum tolerated dose on this schedule was 22.5 mg/m² weekly × 3 every 6 weeks, with consistent myelosuppression being the dose-limiting toxicity; other toxicity was minimal. Pharmacologic studies showed a mean alpha half-life of 1.6 ± 0.3 h and a beta half-life of 39 ± 8.4 h for idarubicin. This schedule was well tolerated, with consistent toxicity patterns seen. Pharmacologic studies confirmed prolonged exposure to the drug and its active metabolite. In comparison with other schedules, this one may offer advantages in terms of consistent hematologic toxicity and prolonged exposure to both the parent compound and its active metabolite. Dose intensity was comparable with that on other schedules. Supported by a grant from Adria Labs (Columbus, Ohio) and the Kaplan Cancer Center (CA 16087) H. Hochster is a recipient of an American Cancer Society Career Development Award     

A phase I and pharmacology study of GR63178A,a water-soluble analogue of mitoquidone

Summary GR63178A is a water-soluble analogue of mitoquidone, a pentacyclic pyrroloquinone. This group of drugs exhibit a novel structure and activity against several murine solid tumours and xenografts. In the present phase I study the toxicity and pharmacokinetics of GR63178A given on 5 consecutive days of a 21-day cycle were examined. A total of 24 patients presenting with a wide range of tumours were treated at 5 doses escalated to reach the maximal tolerated dose (MTD). Linear pharmacokinetics was documented over the dose range studied, and there was no difference in parent drug handling between day 1 and day 4 of dosing. A number of metabolites were detected. The toxicity profile was unusual in that pain occurred in 20/24 patients, most often at the site of known disease. This was the dose-limiting toxicity. Other side effects included nausea and vomiting (23/24), phlebitis at the infusion site (6/24) and headache (7/24). No treatment response was seen in this study. The MTD was demonstrated to be 160 mg/m² daily (total, 800 mg/m² per treatment cycle). the drug has now entered phase II trials at 120 mg/m² daily x 5, repeated every 21 days.     

A phase I pharmacokinetics study of 9-nitrocamptothecin in patients with advanced solid tumors

Purpose

9-Nitrocamptothecin (9-NC) is a novel orally administered camptothecin analog. The purpose of this study is to evaluate the pharmacokinetics and safety of 9-nitrocamptothecin in patients with advanced solid tumors.

Methods

The 23 patients for a single-dose pharmacokinetic experiment were divided into 3 dosing cohorts. The dosage of 9-nitrocamptothecin capsule was 1.25, 1.5 and 1.75 mg/m², respectively. The 8 patients for a multiple-dose pharmacokinetic study were orally administered 9-nitrocamptothecin 1.5 mg/m² for 5 consecutive days. Determination of the plasma concentration of 9-nitrocamptothecin was performed by high-performance liquid chromatography-ultraviolet detector technique, and determination of plasma concentration of 9-aminocamptothecin was performed by high-performance liquid chromatography-fluorescence detector technique.

Results

In the single-dose pharmacokinetic study, the mean ± SD 9-nitrocamptothecin C _max were 94.49 ± 41.38, 115.56 ± 63.27 and 147.57 ± 38.19 ng/mL; AUC_0–36 were 877.14 ± 360.90, 961.33 ± 403.58 and 1,189.75 ± 405.80 ng h/mL, respectively; the mean ± SD 9-aminocamptothecin C _max were 12.85 ± 6.46, 10.72 ± 6.58 and 28.74 ± 31.94 ng/mL; AUC_0–36 were 157.61 ± 111.61, 88.71 ± 39.51 and 173.52 ± 122.19 ng h/mL, respectively. In the multiple-dose pharmacokinetic study, the mean ± SD 9-nitrocamptothecin AUC_ss was 907.04 ± 736.47 ng h/mL, C _max was 85.98 ± 47.52 ng/mL, C _min was 18.91 ± 22.50 ng/mL, C _av was 37.79 ± 30.69 ng/mL, DF was 2.16 ± 0.87; the mean ± SD 9-aminocamptothecin AUC_ss was 442.73 ± 308.39 ng h/mL, C _max was 34.83 ± 18.31 ng/mL, C _min was 10.32 ± 6.95 ng/mL, C _av was 18.45 ± 12.85 ng/mL, DF was 1.34 ± 0.42. Comparing single-dose 1.5 mg/m² group with multiple-dose 1.5 mg/m² group, no significant difference was observed in 9-NC pharmacokinetic parameters, but with respect to the metabolite, significant differences were observed in C _max and AUC. The toxicity of 9-NC varied from mild to moderate. No grade 3 or grade 4 toxicity was observed during the study. There was 2- to 13-fold variabilities in 9-NC and 9-AC exposure among different patients for any given dose of 9-NC.

Conclusions

All participants had good tolerance throughout the study. 9-NC and 9-AC exposure did not increase proportionally to the dose ranging from 1.25 to 1.75 mg/m². After 5-day continuous administration, accumulation was observed in the metabolite 9-AC, but not in 9-NC.     

A clinical pharmacokinetics study of carzelesin given by short-term intravenous infusion in a phase I study

We investigated the pharmacokinetic behavior of carzelesin in 31 patients receiving this drug by 10-min intravenous infusion in a Phase I clinical trial, which was conducted at institutions in Nijmegen (institution 1) and Brussels (institution 2). The dose steps were 24, 48, 96, 130, 150, 170, 210, 250, and 300 μg/m². Carzelesin is a cyclopropylpyrroloindole prodrug that requires metabolic activation via U-76,073 to U-76,074. The lower limit of quantitation (LLQ) of the high-performance liquid chromatography (HPLC) method used in this study was 1 ng/ml for the parent drug and its metabolic products. Carzelesin was rapidly eliminated from plasma (elimination half-life 23 ± 9 min; mean value ± SD). At all dose levels, U-76,073 was found as early as in the first samples taken after the start of the infusion. However, the concentration of U-76,074 exceeded the LLQ for only short periods and only at the higher dose levels. Although the plasma levels of all three compounds were well above the respective IC₅₀ values obtained by in vitro clonogenic assays, they were much lower than those observed in a preclinical study in mice. There was a substantial discrepancy in the mean plasma clearance␣observed between patients from institution 1 (7.9 ± 2.1 l h⁻¹ m⁻²) and those from institution 2 (18.4 ± 13.6 l h⁻¹ m⁻²; P = 0.038), probably reflecting problems with drug administration in the latter institution. The results recorded for patients in institution 1 indicated that the AUC increased proportionately with increasing doses. There was a good correlation between the maximal plasma concentration and the AUC, enabling future monitoring of drug exposure from one timed blood sample. Urinary excretion of carzelesin was below 1% of the delivered dose. Received: 6 May 1997 / Accepted: 5 September 1997     

Intrathecal mafosfamide: a preclinical pharmacology and phase I trial.

PURPOSE: Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. PATIENTS AND METHODS: In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. RESULTS: The cytotoxic target exposure for mafosfamide was 10 micromol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 micromol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. CONCLUSION: The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.     

Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study.

PURPOSE: Phase I clinical and in vitro studies of gemcitabine (2',2'-difluorodeoxycytidine; dFdC) have demonstrated that the accumulation rate of dFdC 5'-triphosphate (dFdCTP) in mononuclear and leukemia cells is saturated when plasma or extracellular dFdC levels exceed 15 to 20 mumol/L. Thus, we designed a phase I study to maximize the accumulation of dFdCTP by leukemia cells by administering dFdC at 10 mg/m2/min, a dose rate calculated to produce steady-state plasma dFdC levels that exceed 15 to 20 mumol/L. PATIENTS AND METHODS: The treatment intensity was increased in patients (n = 22) with relapsed or refractory acute leukemia or chronic myelogenous leukemia (CML) in blast crisis by prolonging the infusion duration but maintaining the same rate. Doses of dFdC between 1,200 mg/m2 and 6,400 mg/m2 were administered weekly for 3 weeks. RESULTS: The maximum-tolerated dose was 4,800 mg/m2 infused over 480 minutes. The mean steady-state dFdC level in plasma of all infusions was 26.5 +/- 9 mumol/L (n = 19). The accumulation rates of dFdCTP in circulating leukemia cells varied greatly among patients but remained linear in eight patients infused for 120 to 240 minutes, and up to or beyond 360 minutes in five of eight additional patients. Elimination of dFdCTP was significantly related to its cellular concentration: blasts with greater than 450 mumol/L dFdCTP exhibited biphasic elimination, whereas blasts with lower dFdCTP concentrations exhibited linear kinetics. Biphasic elimination was associated with higher dFdCTP areas under the concentration-times-time curve (AUCs) and greater inhibition of DNA synthesis. CONCLUSION: Studies of the cellular pharmacology and pharmacodynamics of dFdC may be useful in optimizing protocol designs for leukemia.     

Human alpha-lymphoblastoid interferon. A phase I study including pharmacokinetics and effects on hematologic stem cells (CFU-GMs)

Human alpha lymphoblastoid interferon (Wellferon) was administered to 33 patients in a phase I study. Patients received Wellferon intramuscularly every 12 hours for 14 doses in nine dosage levels ranging from 0.75 X 10(6) units to 50.0 X 10(6) units. Toxicity tended to be dose dependent and included fever/chills, malaise, hematologic toxicity, and digestive tract toxicity. Thirty X 10(6) u q 12 h was felt to be the maximum tolerated dose. Three partial responses (renal cell carcinoma, diffuse histiocytic lymphoma, Hodgkin's disease) were achieved. Interferon rapidly (2 to 3 hours after the initial injection) reached peak serum levels which varied generally with dose and exceeded 500 u/ml at the 30 and 50 X 10(6) u dosages. Multiple doses of interferon resulted in cumulative peak levels substantially higher than first dose levels (greater than 500 u/ml at dosages greater than 3 X 10(6) u/ml and greater than 1,500 u/ml at dosages greater than or equal to 18 X 10(6) u). Interferon given at high dosages persisted up to 10 days beyond the final injection. Despite hematologic toxicity, inhibition of CFU-GM was not seen.     

Zinostatin and doxorubicin. A combination phase I study

Because of encouraging single-agent activity for both zinostatin and doxorubicin in hepatocellular cancer, a phase I tolerance study with these drugs in combination was undertaken. The dose of zinostatin given daily for 5 consecutive days and repeated every 6 weeks was fixed at 2250 units/M2. The starting dose of doxorubicin was 45 mg/m2 on days 1 and 22 of every 6-week cycle, but this was escalated or deescalated by increments of 33% as tolerated. The occurrence of unpredictable severe and prolonged cumulative myelosuppressive toxicity in most patients resulted in considerable management difficulties. In addition, three patients developed congestive heart failure at cumulative doxorubicin doses ranging from 195 to 270 mg/m2 and two patients developed possible drug-related nephrotoxicity. Until reasons for the pharmacogenetic variability observed with zinostatin are defined, combination studies employing this drug are not recommended.     

A phase I and pharmacokinetic study of intraperitoneal topotecan.

PURPOSE: To evaluate the feasibility and pharmacology of intraperitoneal (IP) topotecan. PATIENTS AND METHODS: Fifteen patients with recurrent ovarian cancer in a phase I trial were treated with escalating IP topotecan doses (5-30 mg/m(2)) for pharmacokinetic analysis. RESULTS: Dose limiting toxicity (DLT) was acute hypotension, chills and fever at the 30 mg/m(2) dose level. Haematological toxicity and abdominal pain were mild for all dose levels studied. PHARMACOKINETICS: Peak plasma levels of total topotecan were reached at 2.7 +/- 1.1 h after IP instillation. The apparent V(ss) was 69.9 +/- 25.4 L/m(2), plasma clearance 13.4 +/- 2.5 L/h/m(2) and plasma T1/2 3.7 +/- 1.3 h. The plasma AUC was correlated with the dose (R = 0.95, P < 0.01). The plasma AUC ratio of lactone versus total topotecan (lactone + carboxy-forms) increased with the dose from 16% to 55%, (R = 0.84, P < 0.01). Peritoneal total topotecan was cleared from the peritoneal cavity at 0.4 +/- 0.3 L/h.m(2) with a T1/2 = 2.7 +/- 1.7 h. The mean peritoneal/plasma AUC ratio for total topotecan was 54 +/- 34. CONCLUSION: A substantial dose of topotecan can be delivered by the IP route, achieving cytotoxic plasma levels of topotecan, with acceptable toxicity. The recommended dose for further phase II trials is 20 mg/m(2) IP, which enables combination with active doses of other cytotoxic drugs, in view of its limited myelotoxicity when given by this route.