Search PubMed⌕ Search

Biomedical subjects

D R Budman

Publications and source records attributed to D R Budman.

At least 55 records · Page 3Linked to original sources
PubMed1994

c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer.

BACKGROUND: The role of molecular markers in predicting the response to treatment of breast cancer is poorly defined. The Cancer and Leukemia Group B (CALGB) conducted a randomized adjuvant-chemotherapy trial (CALGB 8541) comparing three doses (high, moderate, and low) of cyclophosphamide, doxorubicin, and fluorouracil in 1572 women with node-positive breast cancer. This study (CALGB 8869) was designed to determine whether the DNA index, the S-phase fraction, c-erbB-2 expression, or p53 accumulation could be used as a marker to identify a subgroup of patients more likely than others to benefit from high doses of chemotherapy. METHODS: Tissue blocks were obtained from 442 patients randomly selected from the larger CALGB trial. Paraffin sections from the primary lesions were analyzed for DNA content, S-phase fraction, c-erbB-2 expression, and p53 accumulation. RESULTS: Patients randomly assigned to the high-dose regimen of adjuvant chemotherapy had significantly longer disease-free and overall survival if their tumors had c-erbB-2 overexpression. No further information was gained by adding the data on S-phase fraction or p53 accumulation to the analysis. There was no clear evidence of a dose-response effect in patients with minimal or no c-erbB-2 expression. CONCLUSIONS: There is a significant dose-response effect of adjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil in patients with overexpression of c-erbB-2 but not in patients with no c-erbB-2 expression or minimal c-erbB-2 expression. Overexpression of c-erbB-2 may be a useful marker to identify the patients who are most likely to benefit from high doses of adjuvant chemotherapy.

Adult↗
PubMed1994

Combination trial of subcutaneous recombinant alpha 2 b interferon and oral cyclophosphamide in follicular low-grade non-Hodgkin's lymphoma.

The follicular non-Hodgkin's lymphomas (NHL) have been among those tumors demonstrated to show frequent responses to alpha interferon in phase I and II clinical trials. In addition, there are data suggesting that alpha interferon demonstrates synergistic antitumor activity with alkylating agents in animal models for a number of tumors. Based on these data, Cancer and Leukemia Group B (CALGB) undertook a phase II pilot study of the combination of interferon rIFN alpha 2b (2 x 10(6) IU/m2 s.c. tiw) and cyclophosphamide (100 mg/m2 per day orally) with the ultimate purpose of examining this combination as long-term therapy of follicular lymphoma in comparison to oral cyclophosphamide alone. One hundred five advanced stage III or IV eligible patients with pathologically diagnosed International Working Formulation B or C histology were entered on CALGB 8553 to determine toxicity and response rates to the combination. Both previously chemotherapy-treated patients (32) and patients without prior chemotherapy (73) were entered on study. For patients without prior chemotherapy the overall response rate to the combination regimen was 86% with 58% of chemotherapy-treated patients achieving complete response. Chemotherapy-treated patients had a total response rate of 62% with only 25% complete responders. Complete responses in patients without prior chemotherapy were positively correlated with absence of B symptoms, and good performance status and negatively correlated with the histological subtype of follicular mixed small-cleaved and large cell histology (IWF C); only performance status was significantly correlated with response in patients who had previously had chemotherapy. Survival at 5 years is estimated to be 63% for those without chemotherapy and 39% for those previously treated with chemotherapy patients. The maximum toxicities experienced during therapy with the combination regimen of cyclophosphamide and interferon alpha were primarily related to myelosuppression. Sixty-seven percent of patients without prior chemotherapy and 65% of patients receiving prior chemotherapy experienced severe leukopenia while severe thrombocytopenia and anemia occurred in 6-31% of these patients. Non-myelosuppressive toxicities were less frequently seen. These response rates are similar to those achieved in a previous CALGB trial with oral cyclophosphamide as a single agent, although severe myelotoxicity was increased to approximately 60% of patients from less than 10% with the single-agent therapy. The combination of alpha interferon and cyclophosphamide administered in this fashion is safe when peripheral counts are carefully monitored. Randomized studies of this regimen in comparison to oral cyclophosphamide are currently in progress.

Administration, Oral↗
PubMed1994

Prospective analysis of colorectal carcinoma. Determination of an age-site and stage relationship and the correlation of DNA index with clinicopathologic parameters.

PURPOSE: A prospective study of colorectal cancer (1987-1991) using flow cytometry was performed to determine the relationship of age with DNA index (DNA-I), sites of disease, Dukes stage, grade, and survival. METHODS: The flow cytometry was performed on 138 fresh, unfixed, surgical specimens using 4',6'-diamidino-2-phenylindole, a DNA fluorochrome. RESULTS: The mean age was 66.9 (42.8 percent > or = 70; range, 22-92; median, 68) years, and 48.6 percent were female. The patients' stages were (in percent): A, 4.4; B, 53.0; C, 38.2; D, 4.4. Tumor grades of differentiation (in percent) were well, 14.4; moderate, 68.9; poor, 16.7; and sites (in percent) were: rectum, 19.6; sigmoid/left, 50.7; transverse/right, 29.0. Aneuploidy (DNA-I not equal to 1.0; CV, 3.5 percent) was found in 58.8 percent. Age (by decade of presentation) was compared with site and Dukes stage. Older patients had more transverse/right-sided lesions (P = 0.003). Patients with Dukes C and D tumors had a lower age (by decade of presentation) than patients with B2 lesions (P = 0.03). Age was not related to DNA-I or grade or DNA-I with sex, grade, site, stage, or survival (P > 0.05). CONCLUSIONS: This prospective study suggests that colorectal cancer tends to present at an earlier stage and in the more proximal colon in the older population. Because right-sided lesions are beyond the reach of sigmoidoscopy, these findings have prognostic and screening implications.

Adult↗
PubMed1994

Phase I evaluation of a water-soluble etoposide prodrug, etoposide phosphate, given as a 5-minute infusion on days 1, 3, and 5 in patients with solid tumors.

PURPOSE: To determine the toxicities, maximum-tolerated dose (MTD), and pharmacology of etoposide phosphate, a water-soluble etoposide derivative, administered as a 5-minute intravenous infusion on a schedule of days 1, 3, and 5 repeated every 21 days. PATIENTS AND METHODS: Thirty-six solid tumor patients with a mean age of 63 years, performance status of 0 to 1, WBC count > or = 4,000/microL, and platelet count > or = 100,000/microL, with normal hepatic and renal function were studied. Doses evaluated in etoposide equivalents were 50, 75, 100, 125, 150, 175, and 200 mg/m2/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by high-performance liquid chromatography (HPLC). Eleven of 36 patients were treated with concentrated etoposide phosphate at 150 mg/m2/d. RESULTS: Grade I/II nausea, vomiting, alopecia, and fatigue were common. Leukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m2, with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reactions were not observed in the first 25 patients. The MTD due to leukopenia was determined to be between 175 and 200 mg/m2/d. In 11 patients treated with concentrated etoposide phosphate, no local phlebitis was noted, but two patients did develop allergic phenomena. The conversion of etoposide phosphate to etoposide was not saturated in the dosages studied. Etoposide phosphate had peak plasma concentrations at 5 minutes, with a terminal half-life (t1/2) of 7 minutes. Etoposide reached peak concentrations at 7 to 8 minutes, with a t1/2 of 6 to 9 hours. Both etoposide phosphate and etoposide demonstrated dose-related linear increases in maximum plasma concentration (Cmax) and area under the curve (AUC). CONCLUSION: Etoposide phosphate displays excellent patient tolerance in conventional dosages when administered as a 5-minute intravenous bolus. The suggested phase II dose is 150 mg/m2 on days 1, 3, and 5. The ability to administer etoposide phosphate as a concentrated, rapid infusion may prove of value both in the outpatient clinic and in high-dose regimens.

Adult↗
PubMed1993

Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: a Cancer and Leukemia Group B study.

BACKGROUND: Chemotherapy-induced myelosuppression often limits escalation of cancer chemotherapy doses. Cyclophosphamide, an alkylating agent, is an ideal candidate for dose escalation: A log-linear relationship between cell kill and dose has been demonstrated, and the drug spares hematopoietic stem cells. In addition, studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ability to achieve optimal dose intensity as well as ameliorating chemotherapy-induced myelosuppression. PURPOSE: The purpose of this study was to determine the maximum tolerated dose and the toxic effects of cyclophosphamide administered every 2 weeks with GM-CSF support. METHODS: For this trial by the Cancer and Leukemia Group B (CALGB), cohorts of patients were treated with cyclophosphamide as a 1-hour intravenous infusion every 14 days; GM-CSF was given subcutaneously on days 3-10. Four dose levels of cyclophosphamide (1.5, 3.0, 4.5, and 6.0 g/m2) and three dose levels of GM-CSF (2.5, 5.0, and 10.0 micrograms/kg per day) were evaluated. There was no dose escalation in individual patients. Fifty-one patients with solid tumors who had CALGB performance status 0 or 1 and minimal prior radiotherapy were eligible for analysis. Drug clearance and area under the curve for plasma drug concentration x time (AUC) were estimated at completion of the infusion and at 4 and 24 hours after the start of the infusion. RESULTS: Ninety-five courses of therapy were analyzed. Treatment with cyclophosphamide at 3.0 g/m2 or more resulted in neutropenia (absolute neutrophil counts < 100/microL) in all cycles of therapy. At those doses, blood cell count recovery adequate for re-treatment occurred in 67%-85% of cycles (median, 16 days). Doses of 6.0 g/m2 were associated with the greatest degree of myelosuppression and frequent hospitalization (88% of cycles); requirements for blood transfusion prohibited further dose escalation. Nonhematologic toxic effects were tolerable, with two episodes of reversible cardiotoxicity and four episodes of hemorrhagic cystitis that precluded further therapy. Degree of myelosuppression was not correlated with cyclophosphamide AUC or clearance. CONCLUSIONS: The recommended phase II dose of cyclophosphamide is 4.5 g/m2 administered every 2 weeks with GM-CSF given at 5.0 micrograms/kg per day of GM-CSF. Our results suggest that, with GM-CSF support, high cumulative doses of cyclophosphamide can be given to achieve optimal dose intensity, with reproducible blood cell count recovery and without the need for autologous bone marrow transplantation. IMPLICATIONS: Phase II studies of this intensive regimen in malignant diseases sensitive to alkylating agents are currently being done in CALGB.

Adult↗
PubMed1993

Phase II trial of etoposide and cisplatin in patients with refractory and relapsed non-Hodgkin's lymphoma: Cancer and Leukemia Group B study 8351.

A phase-II study was conducted by the Cancer and Leukemia Group B (CALGB) in patients with refractory and relapsed non-Hodgkin's lymphoma (NHL) to assess the activity of the combination of etoposide and cisplatin. Sixty-five patients were entered on study, and 51 patients were evaluated for this report. The treatment regimen consisted of etoposide, 80 mg/m2 IV daily times 5 and cisplatin 20 mg/m2 IV daily times 5, repeated every 21 days. All patients had failed 1-3 prior chemotherapeutic regimens, had measurable disease, and had a performance status of 0-2. In the 51 evaluable patients, there were 4 complete responses (8%) and 12 partial responses (23%), for an overall response rate of 31% (95% Cl: 19%, 46%). In addition, 15 patients (29%) had some improvement in disease and 6 (12%) had stable disease. Failure-free survival for the 51 eligible patients was 40% at 3 months, 23% at 6 months, and 15% at 1 year. Significant toxicity was observed with this regimen. Severe neutropenia occurred in 20 patients (39%), severe anemia in 8 patients (16%), and severe thrombocytopenia in 18 patients (35%). One patient died of infection. Severe neurotoxicity (1) and hemorrhage (3) were also seen. The etoposide, cisplatin combination is active in NHL; however, in this dose and schedule their combined activity is only minimally better than published reports of etoposide alone. Further studies of related combinations are under evaluation by the CALGB.

Adolescent↗
PubMed1993

Therapy of refractory/relapsed acute myeloid leukemia and blast crisis of chronic myeloid leukemia with the combination of cytosine arabinoside, tetrahydrouridine, and carboplatin.

Eight patients, of whom four had acute myeloid leukemia (AML) and four had chronic myeloid leukemia (CML) blast crisis, were treated with a combination of cytosine arabinoside (ARA-C: 1,600 mg/m2 in three patients, 1,200 mg/m2 in five patients), tetrahydrouridine (THU: 2,800 mg/m2 in two patients, 2,646 mg/m2 in one patient, 2,100 mg/m2 in five patients), and carboplatin (900 mg/m2 in four patients, 720 mg/m2 in one patient, 450 mg/m2 in three patients). As a result of this treatment, five of the eight patients became aplastic. Two of the four patients with CML blast crisis reverted to the chronic phase and two of the four patients with acute nonlymphocytic leukemia (ANLL) attained a remission (one partial remission and one complete remission). The major toxicities included myelosuppression, unacceptable hepatotoxicity, and diarrhea. Pharmacokinetics studies revealed that the addition of carboplatin did not significantly change the disposition of ARA-C. ARA-C levels were not significantly changed in comparison with those obtained in a prior study of ARA-C with THU (ARA-C plasma levels at 3 h, 2630 +/- 1170 ng/ml).

Acute Disease↗
PubMed1992

Cisplatin, doxorubicin, cyclophosphamide, and etoposide combination chemotherapy for small-cell lung cancer.

Because of potential synergistic interactions, we added 25 mg/m2 i.v. cisplatin (P) 25 given on days 1-5 to the combination of 45 mg/m2 i.v. doxorubicin (A) given on day 1, 800 mg/m2 i.v. cyclophosphamide (C) given on day 1, and 50 mg/m2 i.v. etoposide (E) given on days 1-5. The resulting PACE regimen was given every 21 days for the first three courses and then every 28 days for the next five courses. PACE was used in two trials: the first, for both limited and extensive disease, was conducted at the University of Maryland Cancer Center and North Shore University Hospital; and the second, for extensive disease, was carried out as a Cancer and Leukemia Group B pilot study. Chest irradiation was not used. Prophylactic cranial irradiation at a dose of 3,000 cGy was given to all patients achieving a complete response (CR). A total of 33 subjects were entered in the first study; 8 of the 15 (53%) presenting with limited disease and 7 of the 18 (39%) exhibiting extensive disease achieved a CR. A partial response (PR) was obtained in 27% and 33% of cases, respectively. Of the 34 patients entered in the second study, 25 were eligible; 8 (32%) achieved a CR and 6 (24%) showed a PR. Toxicity was severe in both studies, including greater than 90% severe or life-threatening leukopenia and thrombocytopenia. Serial creatinine-clearance evaluations in the first study indicated progressive deterioration, which required discontinuation of the cisplatin before the planned completion of treatment in most cases. Since the response rate was no higher than the historic data reported for the three-drug ACE combination and because the toxicity was severe, the studies were stopped and patients were followed for survival. After a follow-up period of greater than 6 years, the median survival was 24 months for limited disease, with 33% and 27% of the patients being alive at 3 and 6.5 years, respectively. The median survival for extensive disease was 15 and 11 months in the first and second studies, respectively. These pilot studies suggest that the addition of cisplatin may augment the activity of the ACE regimen, but at the cost of severe toxicity. Further studies seem warranted if the myelotoxicity can be better controlled.

Adult↗
PubMed1992

Phenotypic analysis of 1-B-D-arabinofuranosylcytosine deamination in patients treated with high doses and correlation with response.

Two phenotypes for 1-B-D-arabinofuranosylcytosine (ara-C) deamination corresponding to a ratio of distribution for "slow" (ratio, less than or equal to 14) vs "fast" (ratio, greater than 14) deaminators of 70%:30%, have been determined on the basis of studies on plasma ratios of 1-B-D-arabinofuranosyluracil/ara-C (ara-U/ara-C) in 56 subjects treated with high-dose ara-C (3 g/m2 infused i.v. over 3 h). A positive correlation of age with the concentration of ara-U was observed. In a subgroup of 36 patients with leukemia, the ara-U/ara-C pattern was similar to that observed for all 56 subjects. In these leukemic patients, who were treated with combinations of ara-C plus other conventional agents, a tendency toward a positive response (complete response + partial response) was found for those showing low ara-U/ara-C ratios (slow deaminators). The phenotypic effect of deamination in acute leukemia needs to be evaluated prospectively.

Adolescent↗
PubMed1992

New vinca alkaloids and related compounds.

The vinca alkaloids remain among the most useful classes of anticancer agents used in the clinic today. However, previous analogs of these agents have not realized either increased safety or an enhanced antitumor spectrum. Currently, three derivatives are in clinical trial: vinorelbine, vintripol, and vinxaltine. Vinorelbine has shown consistent antitumor activity in patients with breast carcinoma and is in phase III trials in the United States, Europe, and Japan. Vintripol and vinxaltine, vinca alkaloids conjugated to amino acids, are in early clinical trials in Europe. The dose-limiting toxicity of these agents is leukopenia. A similar agent with a different chemical structure, rhizoxin, is in early phase II clinical trials with initial activity noted in breast carcinoma. The ultimate role of these agents in treatment of human malignancy awaits the results of ongoing studies.

Animals↗
PubMed1991

A loading dose/continuous infusion schedule of fludarabine phosphate in chronic lymphocytic leukemia.

Using a loading dose/continuous infusion schedule, fludarabine phosphate was administered to 51 patients with previously treated chronic lymphocytic leukemia (CLL). All patients had evidence of active disease, and the majority had advanced Rai stages. Of the 42 patients assessable for response, 22 (52%) achieved a partial response, five (12%) had stable disease, and 15 (36%) progressed. Thirteen of the 22 responders improved their Rai stages with fludarabine therapy, including six patients who achieved stage 0. Response rates for pretreatment stages III and IV were 60% and 53%, respectively. Patients with final Rai stages 0 to II had better survival than those with stages III and IV. Patients who had undergone splenectomy before starting therapy were more likely to respond. Myelosuppression was the primary toxicity and did not appear to be cumulative. Severe leukopenia and thrombocytopenia, although infrequent, were associated with several deaths in the early cycles of treatment. Nonhematologic toxicity was mild with no serious neurotoxicity noted. Infections were common with 22 minor, 18 major, and 10 fatal episodes. Fludarabine phosphate by this alternative dosing schedule is effective in refractory advanced CLL and is well tolerated by the majority of patients.

Adult↗
PubMed1991

Therapy of refractory/relapsed acute leukemia with cytosine arabinoside plus tetrahydrouridine (an inhibitor of cytidine deaminase)--a pilot study.

Thirty two patients with refractory or recurrent acute leukemia or blast crisis of chronic myelocytic leukemia were treated with 1-beta-D-arabinofuranosylcytosine (Ara-C), 100 mg/m2 [group I (n = 15)] or 200 mg/m2 [group II (n = 18)], and tetrahydrouridine (THU) 350 mg/m2, given concurrently as a 3 h continuous intravenous infusion at 12 h interval for eight doses. Two of 13 (15.3%) evaluable patients in group I achieved a complete response, both of whom had acute myelocytic leukemia. In group II, seven of 14 evaluable patients (50%) obtained objective responses--six with complete responses (42.8%) and one with partial response (7%). Myelosuppression was seen in all patients with a median duration of 32.5 days (group I) and 36.3 days (group II), respectively. Non-hematologic toxicity consisted of nausea, vomiting, diarrhea, conjunctivitis, skin rash, hepatocellular toxicity, hemorrhage, and renal toxicity. Pharmacokinetic studies revealed, for group I, mean peak plasma Ara-C levels at 3 h (Cp3h) of 1254 ng/ml, area under the curve (AUC) 4651 ng x h/ml, total body clearance (TBC) 32.65 l/h/m2, renal clearance (RC) 7.04 l/h/m2 with a mean of 12.36% of the injected amount of Ara-C excreted unchanged in urine over the first 24 h. The corresponding mean values for group II are Cp3h 3305 ng/ml, AUC 15080 ng x h/ml, TBC 20.48 l/h/m2, RC 7.02 l/h/m2 and 26.23%. Ara-C 200 mg/m2 combined with THU gave serum Ara-C levels and response rates comparable to those achieved with high dose Ara-C (HiDAC) (greater than or equal to 1 g/m2). Central nervous system toxicity associated with HiDAC was not seen. Pharmacokinetics for uracil arabinoside (Ara-U) in patients treated with Ara-C 200 mg/m2 plus THU, were comparable to values seen with Ara-C for Cp3h, AUC and 24 h urine, amounting to 3160 ng/ml, 21717 ng x h/ml and 23.62% whereas TBC was significantly lower (p less than 0.001) for Ara-U than for Ara-C (3.02 versus 20.48 l/h/m2).

Adult↗
PubMed1991

Phase III trial of brief intensive treatment of adult acute lymphocytic leukemia comparing daunorubicin and mitoxantrone: a CALGB Study.

This paper reports a study of the Cancer and Leukemia Group B (CALGB) comparing daunorubicin (DNR) or mitoxantrone (DHAD) in induction followed by multidrug intensification over 8 months in adult patients with acute lymphocytic leukemia (ALL). A total of 164 newly diagnosed patients were randomly assigned to either DNR or DHAD plus vincristine, prednisone and methotrexate given intravenously (i.v.) and interthecally (i.t.). Patients received four more intensification courses of chemotherapy and then all therapy was stopped. Central nervous system (CNS) prophylaxis consisted of nine infusions of intermediate dose methotrexate (MTX) and intrathecal MTX. DHAD and DNR were equally effective in producing complete remissions (63 and 65%, respectively). The estimated median remission duration is 10.2 and 12.3 months for the DHAD and DNR arms, respectively (p = 0.56). This study was stopped earlier than planned when it became apparent that remission duration for both arms was shorter than seen in our prior study in which all patients received more than 1 year of maintenance therapy. The estimated median survival is 18.3 and 20.6 months for the DHAD and DNR arms, respectively (p = 0.90). Younger patients and patients with a pre-treatment white blood count of less than 30,000/microliters had a significantly longer remission duration and survival. Eleven per cent of patients who achieved a complete remission have had a CNS relapse to date, which is not different from the rate in our prior study using cranial irradiation and i.t. MTX, implying that intermediate dose MTX with i.t. MTX may be as effective as cranial irradiation and i.t. MTX. This study suggests that some form of maintenance chemotherapy is required for the eradication of residual leukemia cells.

Adolescent↗
PubMed1990

Phase II trial of etoposide and cis-diaminodichloro-platinum in patients with refractory and relapsed Hodgkin's disease: Cancer and Leukemia Group B (CALGB) Study 8353.

A phase II study was conducted by the Cancer and Leukemia Group B (CALGB) in patients with refractory and relapsed Hodgkin's disease (HD) to assess the activity of the combination of etoposide and cis-platin. Twenty-seven patients were entered; 22 were evaluated for this report. Treatment consisted of etoposide (VP-16), 80 mg/m2 IV over 1 hour and cis-platin, 20 mg/m2 IV over 1/2-1 hour; both agents were given daily for 5 days and repeated every 21 days. All patients had received at least 2 prior chemotherapy regimens, had measurable disease, and most (86%) had a performance status of 0-1. In the 22 evaluable patients, there were 4 complete responses (18%) and 4 partial responses, for an overall response rate of 36% (95% Cl: 17.2%, 59.3%). Response duration was from 2.1 to 31 months. Significant toxicity was observed with this regimen. Ten patients (45%) had leukopenia less than 1,000/microliters, and 11 patients (50%) had thrombocytopenia less than 25,000/microliters. Serum creatinine levels reached greater than 2.0 in 14% of patients. Seven patients (32%) had severe nausea and vomiting. VP-16, cis-platin appears to be an active combination in HD; however, their combined activity is only marginally better than reported single-agent activity for VP-16 in the doses and schedule used. Further studies of related combinations in HD are currently under evaluation by the CALGB.

Adolescent↗
PubMed1990

Phase I trial of intravenous vinzolidine (LY 104208) given on a biweekly dosing schedule.

Vinzolidine (VZL) is a semisynthetic vinca alkaloid with broad antitumor activity in animal models of malignancy but had unpredictable toxic effects when given orally to humans. To minimize the toxic effects due to potential erratic gastrointestinal absorption, this drug was restudied in man as an intravenous preparation given as a rapid injection every two weeks. The maximum tolerated dose (MTD) on this schedule was 9.0 mg/m2 with unpredictable leukopenia (usually occurring 5-14 days post treatment but appearing erratically), constipation, paralytic ileus, and inappropriate ADH syndrome as major toxicities. Nonhematologic toxicities were dose-limiting. Repetitive dosing at two week intervals was associated with leukopenia at D 14-15 in some but not all patients treated above 5.0 mg/m2 precluding further treatment on schedule. In contrast, the oral MTD of this agent in our prior studies was 45 mg/m2 with no evidence of delayed leukopenia. Intrapatient variability of toxicity was small; interpatient variability of toxicity was substantial and did not correlate with prior therapy. Because of the presence of delayed hematologic toxicity on repetitive dosing schedules, intravenous VZL should be given on a dosing schedule longer than 14 days. No antitumor activity was seen in this study.

Adult↗
PubMed1990

Clinical pharmacokinetics of intravenously injected tritiated vinzolidine.

Vinzolidine (VZL), a novel, semi-synthetic vinca alkaloid showing evidence of oncolytic activity in phase I/II clinical trials, was studied in six patients for its pharmacokinetic and metabolic behavior. Following i.v. administration of [3H]-VZL at doses of 5, 6.7, and 9 mg/m2, blood and urine samples were collected and analyzed by sample oxidation and HPLC. Following a single i.v. dose, decay of total tritium in plasma was tetraphasic, with a rapid initial t1/2 alpha of 0.044 +/- 0.013 h, followed by a t1/2 beta of 0.54 +/- 0.22 h and a t1/2 gamma of 9.48 +/- 4.89 h; the terminal t1/2 gamma was 219 +/- 57 h. The mean plasma clearance of total tritium was 0.054 +/- 0.044 l.kg/h, and the mean volume of distribution was 14.3 +/- 5.4 l/kg; mean urinary excretion was 13.6% +/- 4.3% of the delivered radioactivity. Qualitative analysis of plasma and urine revealed the predominance of unchanged VZL plus two unidentified metabolites with different elution times. In comparison with oral VZL, as previously reported, i.v. injected VZL showed comparable values with respect to the volume of the central compartment (VC), plasma clearance (Clp), and terminal t1/2 for total tritium. Qualitatively, the metabolites observed in plasma and urine were comparable in number and quantity with values obtained in analyses after oral administration.

Antineoplastic Agents, Phytogenic↗