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Biomedical subjects

A W Tolcher

Publications and source records attributed to A W Tolcher.

At least 19 recordsLinked to original sources
PubMed2005

A phase I, pharmacokinetic and biologic correlative study of oblimersen sodium (Genasense, G3139) and irinotecan in patients with metastatic colorectal cancer.

PURPOSE: To assess the feasibility and antitumor activity of oblimersen sodium, an antisense oligonucleotide directed to the Bcl-2 mRNA, combined with irinotecan in patients with advanced colorectal carcinoma, characterize the pharmacokinetic behavior of both oblimersen sodium and irinotecan, and examine Bcl-2 protein inhibition in peripheral blood mononuclear cells (PBMC). PATIENTS AND METHODS: Patients were treated with escalating doses of oblimersen sodium administered by continuous intravenous infusion (CIVI) days 1-8, and irinotecan administered intravenously on day 6 once every 3 weeks. RESULTS: Twenty patients received a total of 84 courses at doses ranging from 3 to 7 mg/kg/day for oblimersen sodium and from 280 to 350 mg/m2 for irinotecan. Febrile neutropenia and diarrhea limited escalation of oblimersen sodium and irinotecan to 5 mg/kg/day and 350 mg/m2, respectively. Other toxicities included nausea, vomiting, fever and fatigue. Steady-state plasma concentrations were achieved within 48 h of beginning oblimersen sodium treatment and the agent was undetectable 24 h after the discontinuation of the infusion. Reduction in levels of Bcl-2 protein in PBMC was documented following treatment with oblimersen sodium. One patient experienced a partial response and 10 additional patients had stable disease lasting 2.5-10 months. CONCLUSIONS: The combination is well tolerated at the recommended phase II oblimersen sodium dose of 7 mg/kg/day CIVI days 1-8 with irinotecan 280 mg/m2 intravenously on day 6 every 3 weeks.

Adult↗
PubMed2004

Phase I trial of a murine antibody to MUC1 in patients with metastatic cancer: evidence for the activation of humoral and cellular antitumor immunity.

BACKGROUND: BrevaRex mAb-AR20.5 is a murine anti-MUC1 monoclonal antibody generated to induce MUC1 antigen-specific immune responses through the formation of immune complexes with circulating MUC1 and/or MUC1-expressing tumor cells that may target these immune complexes (IC) to receptors on dendritic cells (DCs). PATIENTS AND METHODS: A phase I study focusing on safety and immunology evaluated 1, 2 and 4-mg doses. Seventeen patients with MUC1-positive cancers received intravenous infusions of the antibody over 30 min on weeks 1, 3, 5, 9, 13 and 17 of treatment. RESULTS: mAb-AR20.5 was well-tolerated, not associated with dose-limiting toxicity, and did not induce hypersensitivity reactions. Overall, five of 15 evaluable patients developed human anti-mouse antibodies (HAMA), five developed anti-idiotypic antibodies (Ab2) and seven developed anti-MUC1 antibodies. Immune responses were most prominent in the 2-mg dose cohort for all parameters tested, and treatment-emergent MUC1-specific T-cell responses were detected in five of 10 evaluable patients treated with mAb-AR20.5. CONCLUSIONS: The injection of a murine antibody to MUC1 induces MUC1-specific immune responses in advanced cancer patients. Anti-MUC1 antibody increases correlated with decrease or stabilization of CA15.3 levels (P=0.03). The 2-mg dose of mAb-AR20.5 showed strongest biological activity, and will be evaluated in future efficacy trials.

Adult↗
PubMed2003

Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedules.

Temozolomide, an oral DNA methylator that inactivates the DNA repair enzyme O(6)-alkylguanine-DNA alkyltransferase (AGAT), has demonstrated anticancer activity on protracted schedules. Protracted schedules may lead to an 'autoenhancement' of temozolomide's inherent cytotoxic potential by cumulative reduction of the cell's capacity for AGAT-mediated DNA repair and resistance. This study was undertaken to characterise AGAT inactivation and regeneration in the peripheral blood mononuclear cells (PBMCs) of patients treated on two protracted temozolomide schedules. O(6)-alkyl guanine-DNA alkyltransferase activity was measured in the PBMCs of patients treated on two phase I protracted temozolomide studies. Patients were treated daily for either 7 days every 2 weeks (Schedule A) or 21 days every 4 weeks (Schedule B). The effects of various temozolomide doses (75-175 mg m(-2)), treatment duration (7-21 days), and temozolomide plasma levels on AGAT inactivation and regeneration, as well as the relation between AGAT inactivation and toxicity, were studied. O(6)-alkyl guanine-DNA alkyltransferase activity in PBMCs was measured serially in 52 patients. Marked inactivation of AGAT occurred following 7 days of temozolomide treatment, with mean AGAT activity decreasing by 72% (P<0.0001). Similarly, mean AGAT activity decreased by 63 and 73% after 14 and 21 days of treatment, respectively (P<0.001 for both comparisons). O(6)-alkyl guanine-DNA alkyltransferase inactivation was greater after 7 days of treatment with higher doses of temozolomide than lower doses and remained markedly reduced 7 days post-treatment. However, AGAT inactivation following temozolomide treatment for 14 and 21 days was similar at all doses. On the continuous 21-day schedule, AGAT inactivation was significantly greater in patients who experienced severe thrombocytopenia than those who did not (90.3+/-5.5 vs 72.5+/-16.1%, P<0.045). In conclusion, protracted administration of temozolomide, even at relatively low daily doses, leads to significant and prolonged depletion of AGAT activity, which may enhance the antitumour activity of the agent.

Antineoplastic Agents, Alkylating↗
PubMed2001

Phase I and pharmacokinetic study of NSC 655649, a rebeccamycin analog with topoisomerase inhibitory properties.

PURPOSE: To assess the feasibility of administering NSC 655649, a water-soluble, rebeccamycin analog with topoisomerase inhibitory properties, as a brief intravenous (IV) infusion once every 3 weeks and to determine the maximum-tolerated dose (MTD) of NSC 655649, characterize its pharmacokinetic behavior, and seek preliminary evidence of antitumor activity. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of NSC 655649 administered over 30 to 60 minutes IV once every 3 weeks. An accelerated dose-escalation method was used to guide dose escalation. After three patients were treated at the first dose level, doses were escalated in increments that ranged up to 150% using single patient cohorts until moderate toxicity was observed, when a more conservative dose-escalation scheme was invoked. MTD was defined as the highest dose level at which the incidence of dose-limiting toxicity did not exceed 20%. MTD was determined for both minimally pretreated (MP) and heavily pretreated (HP) patients. Plasma and urine were sampled to characterize the pharmacokinetic and excretory behavior of NSC 655649. RESULTS: Forty-five patients were treated with 130 courses of NSC 655649 at doses ranging from 20 mg/m(2) to 744 mg/m(2). Myelosuppression was the principal toxicity. Severe neutropenia, which was often associated with thrombocytopenia, was unacceptably high in HP and MP patients treated at 572 mg/m(2) and 744 mg/m(2), respectively. Nausea, vomiting, and diarrhea were common but rarely severe. The pharmacokinetics of NSC 655649 were dose dependent and fit a three-compartment model. The clearance and terminal elimination half-lives for NSC 655649 averaged 7.57 (SD = 4.2) L/h/m(2) and 48.85 (SD = 23.65) hours, respectively. Despite a heterogeneous population of MP and HP patients, the magnitude of drug exposure correlated well with the severity of myelosuppression. Antitumor activity was observed in two HP ovarian cancer patients and one patient with a soft tissue sarcoma refractory to etoposide and doxorubicin. CONCLUSION: Recommended phase II doses are 500 mg/m(2) and 572 mg/m(2) IV once every 3 weeks for HP and MP patients, respectively. The absence of severe nonhematologic toxicities, the encouraging antitumor activity in HP patients, and the unique mechanism of antineoplastic activity of NSC 655649 warrant further clinical development.

Adult↗
PubMed2001

Other novel agents: Rationale and current status as chemopreventive agents.

Several novel targets are currently being evaluated both preclinically and clinically for the prevention of prostate cancer. Four divergent and novel approaches were discussed at the National Cancer Institute-sponsored workshop entitled, "New Clinical Strategies in Prostate Cancer Prevention." These interventions are further categorized into soy protein-based serine-protease inhibitors that reduce superoxide-induced DNA damage, and molecularly targeted approaches that are directed toward endothelin-1 expression/overexpression, peroxisome proliferator-activated receptor ligands, and insulinlike growth factors. Understanding each of these approaches has offered insights into the process of malignant transformation of prostatic epithelium, and further illustrates the difficulties of developing new agents in the treatment and prevention of prostate cancer. Close scrutiny of the clinical data emerging with these approaches, including validation of biologic endpoints, is required before large-scale prevention studies with these novel agents and targets can be considered.

Anticarcinogenic Agents↗
PubMed2001

Preliminary phase I results of G3139 (bcl-2 antisense oligonucleotide) therapy in combination with docetaxel in hormone-refractory prostate cancer.

The transition from androgen-dependent to androgen-independent prostate cancer is accompanied by a number of molecular genetic changes, including overexpression of the bcl-2 gene. Overexpression of Bcl-2 protein decreases the pro-apoptotic response to such cellular insults as irradiation, chemotherapy, and androgen withdrawal. Reduction of Bcl-2 expression in hormone-refractory prostate cancer (HRPC) preclinical models markedly increases the antitumor efficacy of docetaxel both in vitro and in vivo. Thus, a phase I/II pharmacokinetic and biologic correlative study has been initiated in patients with HRPC to examine whether docetaxel therapy can be enhanced with a therapeutic antisense oligodeoxynucleotide (G3139) directed at bcl-2 gene expression. Semin Oncol 28 (suppl 15):67-70.

Aged↗
PubMed2001

Novel compounds in the therapy of breast cancer: opportunities for integration with docetaxel.

Increasingly, novel agents are being developed specifically at inhibition of growth factor receptors and events within the signal transduction pathway. These agents include the epidermal growth factor tyrosine kinase inhibitors, the farnesyl transferase inhibitors, and bcl-2 antisense oligonucleotides. Along with these new approaches to molecular targeting, it will be necessary to develop new study designs for drug evaluation. Target validation in both normal surrogate tissues and tumor tissue becomes increasingly relevant in early clinical trials. Furthermore, antitumor efficacy may no longer correlate with normal hematological or nonhematological toxicity, and it may be more appropriate in phase I trials to identify the maximum target inhibition dose rather than the maximum tolerated dose. Moreover, measures of cytoreduction, such as complete and partial response, may be less relevant than disease stabilization for some of these novel agents which have limited cytotoxic effects and would be considered cytostatic agents. Assessment of single-agent activity and the future role in conjunction with cytostatic agents represents the single most important challenge facing the clinical development of these molecular targeted therapies.

Antineoplastic Agents, Phytogenic↗
PubMed2001

A phase I dose-finding study of combined treatment with an antisense Bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormone-refractory prostate cancer.

PURPOSE: Bcl-2 is a negative prognostic indicator in prostate cancer, implicated in the development of androgen independence and treatment resistance, and is overexpressed in hormone-refractory prostate cancer (HRPC). Genasense is a phosphorothioate antisense oligonucleotide complementary to the bcl-2 mRNA open reading frame that in preclinical studies has shown significant activity in inhibiting expression of Bcl-2, delaying androgen independence, and improving chemosensitivity in prostate and other cancer models. In this dose escalation study, we evaluated the combination of Genasense and mitoxantrone, a standard chemotherapy for patients with HRPC. DESIGN: Twenty-six patients with HRPC were treated at seven dose levels receiving Genasense at a dose ranging from 0.6 to 5.0 mg/kg/day and mitoxantrone from 4 mg/m(2) to 12 mg/m(2). Genasense was administered as a 14-day i.v. continuous infusion every 28 days with mitoxantrone given as an i.v. bolus on day 8. RESULTS: No dose-limiting toxicities were observed. Hematological toxicities were transient and included neutropenia, thrombocytopenia, and lymphopenia. Nonhematological toxicities included fatigue, fever, nausea, arthralgias, myalgias, and transient elevations in serum creatinine, none of which were severe. Two patients had >50% reductions in prostate-specific antigen. One patient, who received six cycles of Genasense at 1.2 mg/kg/day and a low dose (4 mg/m(2)) of mitoxantrone, also had symptomatic improvement in bone pain. Peripheral blood lymphocyte Bcl-2 protein expression decreased in five of five patients given Genasense at 5mg/kg/day (mean change from baseline, -12.8%; SD, 16.4%) as assessed by flow cytometry. Serum concentrations of Genasense given at doses of 3 mg/kg/day and greater, exceeded 1 microg/ml. CONCLUSIONS: Genasense and mitoxantrone are well tolerated in combination, and mitoxantrone can be delivered at a standard dose with biologically active doses of Genasense without significant additional toxicity. This observation allays concerns about trials that combine Genasense with full doses of other cytotoxic agents seeking greater evidence of activity.

Aged↗
PubMed2000

A phase I study of rhizoxin (NSC 332598) by 72-hour continuous intravenous infusion in patients with advanced solid tumors.

BACKGROUND: Rhizoxin (NSC 332598) is a novel macrolide antitumor antibiotic that inhibits microtubule assembly and also depolymerizes preformed microtubules. In preclinical evaluations, rhizoxin demonstrated broad antitumor activity in vitro and in vivo including both vincristine- and vindesine-resistant human lung cancers. Prolonged exposure schedules in xenograft models demonstrated optimal efficacy indicating schedule-dependent antitumor activity. The early phase I and II evaluations a five-minute bolus infusion schedule was studied, however, only modest anti-tumor activity was noted, possibly due to rapid systemic clearance. To overcome these limitations and to exploit the potential for schedule-dependent behavior of rhizoxin, the feasibility of administering rhizoxin as a 72-hour continuous intravenous (i.v.) infusion was evaluated. PATIENTS AND METHODS: Patients with advanced solid malignancies were entered into this phase I study, in which both the infusion duration and dose of rhizoxin were increased. The starting dose was 0.2 mg/m2 over 12 hours administered every 3 weeks. In each successive dose level, the dose and infusion duration were incrementally increased in a stepwise fashion. Once a 72-hour i.v. infusion duration was reached, rhizoxin dose-escalations alone continued until a maximum tolerated dose (MTD) was determined. RESULTS: Nineteen patients were entered into the study. Rhizoxin was administered at doses ranging from 0.2 mg/m2 i.v. over 12 hours to 2.4 mg/m2 i.v. over 72 hours every 3 weeks. The principal dose-limiting toxicities (DLT) were severe neutropenia and mucositis, and the incidence of DLT was unacceptably high at rhizoxin doses above 1.2 mg/m2, which was determined to be the MTD and dose recommended for phase II studies. At these dose levels, rhizoxin could not be detected in the plasma by a previously validated and sensitive high-performance liquid chromatography assay with a lower limit of detection of 1 ng/ml. No antitumor responses were observed. CONCLUSIONS: Rhizoxin can be safely administered using a 72-hour i.v. infusion schedule. The toxicity profile is similar to that observed previously using brief infusion schedules. Using this protracted i.v. infusion schedule the maximum tolerated dose is 1.2 mg/m2/72 hours.

Adult↗
PubMed1999

Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer.

PURPOSE: BMS-182248-1 (BR96-doxorubicin immunoconjugate) is a chimeric human/mouse monoclonal antibody linked to approximately eight doxorubicin molecules. The antibody is directed against the Lewis-Y antigen, which is expressed on 75% of all breast cancers but is limited in expression on normal tissues. Preclinical xenograft models demonstrated significant antitumor activity, including cures. A randomized phase II design was chosen to estimate the activity of the BR96-doxorubicin conjugate in metastatic breast cancer in a study population with confirmed sensitivity to single-agent doxorubicin. PATIENTS AND METHODS: Patients with measurable metastatic breast cancer and immunohistochemical evidence of Lewis-Y expression on their tumor received either BR96-doxorubicin conjugate 700 mg/m2 IV over 24 hours or doxorubicin 60 mg/m2 every 3 weeks. Patients were stratified on the basis of prior doxorubicin exposure, visceral disease, and institution. Cross-over to the opposite treatment arm was allowed with progressive or persistently stable disease. RESULTS: Twenty-three patients who had received a median of one prior chemotherapy regimen were assessable. There was one partial response (7%) in 14 patients receiving the BR96-doxorubicin conjugate and one complete response and three partial responses (44%) in nine assessable patients receiving doxorubicin. No patient experienced a clinically significant hypersensitivity reaction. The toxicities were significantly different between the two treatment groups, with the BR96-doxorubicin conjugate group having limited hematologic toxicity, whereas gastrointestinal toxicities, including marked serum amylase and lipase elevations, nausea, and vomiting with gastritis, were prominent. CONCLUSION: The BR96-doxorubicin immunoconjugate has limited clinical antitumor activity in metastatic breast cancer. The gastrointestinal toxicities likely represent binding of the agent to normal tissues expressing the target antigen and may have compromised the delivery of the immunoconjugate to the tumor sites.

Adult↗
PubMed1997

Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma.

The prognostic significance of Bcl-2 protein expression and bcl-2 gene rearrangement in diffuse large cell lymphomas (DLCL) is controversial. Bcl-2 protein expression prevents apoptosis and may have an important role in clinical drug resistance. The presence of a bcl-2 gene rearrangement in de novo DLCL suggests a possible follicle center cell origin and perhaps a distinct clinical behavior more akin to low-grade non-Hodgkin's lymphoma (NHL). The purpose of this study was to determine the impact of Bcl-2 protein expression and bcl-2 gene rearrangement (mbr and mcr) on survival of a cohort of patients with DLCL who were uniformly evaluated and treated with effective chemotherapy. Patients included the original MACOP-B cohort (n = 121) and the initial 18 patients treated with the VACOP-B regimen (total = 139). All patients had advanced-stage disease, were 16 to 70 years old, and corresponded to Working Formulation categories F, G, or H. No patients had prior treatment, discordant lymphoma, or human immunodeficiency virus seropositivity. Paraffin sections from diagnostic biopsies were analyzed for bcl-2 gene rearrangement including mbr and mcr breakpoints by polymerase chain reaction and Bcl-2 protein expression by immunohistochemistry. With a median follow-up of 81 months, overall (OS), disease-free (DFS), and relapse-free survival (RFS) were measured to determine the prognostic significance of these parameters. Analyzable DNA was present in 118 of 139 (85%) cases, with 14 demonstrating a bcl-2 rearrangement (11 mbr, 3 mcr). All 14 of these bcl-2 gene rearrangement-positive cases were found in the 102 patients with a B-cell immunophenotype, but the presence of this rearrangement had no significant influence on survival. Bcl-2 protein expression was interpretable in 116 of 139 (83%) cases, with immunopositivity detected in 54 of 116 (47%). Using a cut-off of greater than 10% Bcl-2 immunopositive tumor cells for analysis, positive Bcl-2 protein expression was seen in 28 of 116 (24%) patients and the presence of this expression correlated with decreased 8-year OS (34% v 60%, P < .01), DFS (32% v 66%, P < .001), and RFS (25% v 59%, P < .001). Bcl-2 protein expression remained significant in multivariate analysis that included the clinical international prognostic index factors and immunophenotype (P < .02). In conclusion, although bcl-2 gene rearrangement status could not be shown to have an impact on outcome, Bcl-2 protein expression is a strong significant predictor of OS, DFS, and RFS in DLCLs.

Adolescent↗
PubMed1997

Validation of a high-performance liquid chromatographic assay method for quantification of total vincristine sulfate in human plasma following administration of vincristine sulfate liposome injection.

The validation of a high performance liquid chromatographic (HPLC) assay method for quantitation of total vincristine sulfate (VINC) in human plasma is described. VINC was extracted from plasma using BondElut CBA solid phase cartridges with vinblastine as the internal standard. Chromatography was accomplished using a Waters Symmetry C8 (250 mm x 4.6 mm i.d.) analytical column, a Waters Delta-Pak ODS guard column with a mobile phase of 34.9% water-0.1% diethylamine (pH 7.0)-40% acetonitrile-25% methanol pumped isocratically at 1.0 ml min(-1) with ultraviolet detection at 297 nm. Above the limit of quantitation of 28.6 ng ml(-1), the area ratio precision (R.S.D. range 3.33-11.6%) and accuracy of predicted values (R.S.D. range 8.56-23.8% with the limit of quantitation being the only value above 20%) were acceptable. The assay was linear from 28.6-2860 ng ml(-1) VINC in plasma. Recovery of VINC from plasma and VINC from plasma spiked with vincristine sulfate liposome injection ranged from 74.9-87.1%. Stability of VINC in plasma stored at -20 degrees C for at least 49 days and of extracted plasma samples was demonstrated. Potential interference in quantitation of VINC from commonly co-administered drugs was evaluated along with day-to-day variability. The assay procedure was found suitable for evaluation of VINC clinical pharmacokinetics in plasma following administration of vincristine sulfate liposome injection prepared using distearoylphosphatidylcholine (DSPC)/cholesterol liposomes for injection.

Chromatography, High Pressure Liquid↗
PubMed1997

A phase I study of topotecan followed sequentially by doxorubicin in patients with advanced malignancies.

Inhibitors of topoisomerase I and topoisomerase II have demonstrated synergy when administered sequentially in several tumor models while having a diminished antitumor effect when given concurrently. To explore the potential for clinical sequence-dependent synergy, we instituted a Phase I study of topotecan (a topoisomerase I inhibitor) followed by doxorubicin (a topoisomerase II inhibitor) in patients with advanced malignancies. Thirty-three patients with advanced malignancies or malignancies for whom no standard therapy exists were entered into the study. Topotecan was administered in escalating doses by 72-h continuous infusion on days 1, 2, and 3, followed by a bolus of doxorubicin given on day 5. To explore the hematological toxicity associated with this sequence, bone marrow aspirates were obtained both prior to the topotecan infusion and immediately prior to the doxorubicin in 10 patients to determine by fluorescence-activated cell sorting analysis whether CD34+ cell synchronization was occurring using this sequential schedule. Dose-limiting hematological toxicity occurred at the first dose-level in three of six patients. Therefore, we defined the maximum-tolerated dose (MTD) below our starting dose-level. Further dose-escalation and a new MTD were defined with the addition of granulocyte-colony stimulating factor (G-CSF). The MTD was, therefore, topotecan 0.35 mg/m2/day continuous i.v. infusion on days 1, 2, and 3, followed by doxorubicin 45 mg/m2 on day 5 without G-CSF, whereas the MTD with G-CSF was topotecan 0.75 mg/m2/day by 72-h continuous i.v. infusion, followed by doxorubicin 45 mg/m2 i.v. bolus on day 5. Ten patients with paired bone marrow aspirates obtained before topotecan and before doxorubicin administrations were available for evaluation. In 7 of 10 patients, there was an increase (16.6 +/- 2.9% to 25.0 +/- 3.5%; P < 0.02) in the proportion of CD34+ cells in S-phase 24 h after the topotecan infusion and prior to doxorubicin compared to the pretreatment values, whereas 1 patient had a decrease in the proportion of CD34+ cells in S phase and 2 patients had no change. Topotecan and doxorubicin with this sequence and schedule can be given safely; the dose-limiting toxicity is hematological toxicity. Alterations in the fraction of hematopoietic progenitor CD34+ cells in S-phase may account for the increased granulocytopenia and thrombocytopenia observed at relatively low dose levels of the combination with and without G-CSF.

Adult↗
PubMed1996

Phase I study of paclitaxel in combination with cyclophosphamide and granulocyte colony-stimulating factor in metastatic breast cancer patients.

PURPOSE: In vitro data suggest that prolonged exposure to paclitaxel enhances breast cancer cytotoxicity. Our objective in this phase I study was to determine the tolerability of paclitaxel administered by 72-hour continuous intravenous (i.v.) infusion (CIVI) in combination with high-dose cyclophosphamide and granulocyte colony-stimulating factor (G-CSF) in the ambulatory setting to metastatic breast cancer patients. PATIENTS AND METHODS: Paclitaxel was administered over 72 hours by CIVI and cyclophosphamide was given daily by i.v. bolus on days 1, 2, and 3, followed by G-CSF every 21 days. The availability of ambulatory infusion pumps and paclitaxel-compatible tubing permitted outpatient administration. RESULTS: Fifty-five patients with metastatic breast cancer who had been previously treated with a median of two prior chemotherapy regimens were entered onto the study. Dose-limiting toxicity of grade 4 neutropenia for longer than 5 days and grade 4 thrombocytopenia occurred in three of five patients treated with paclitaxel 160 mg/m2 CIVI and cyclophosphamide 3,300 mg/m2 followed by G-CSF. The maximum-tolerated dose (MTD) was paclitaxel 160 mg/m2 CIVI and cyclophosphamide 2,700 mg/m2 in divided doses with G-CSF. Nonhematologic toxicities were moderate and included diarrhea, mucositis, and arthalgias. Although hemorrhagic cystitis developed in six patients, recurrence was prevented with i.v. and oral mesna, which permitted continued outpatient delivery. One hundred seventy-four cycles were safely administered in the ambulatory setting using infusional pumps and tubing. Objective responses occurred in 23 (one complete and 22 partial) of 42 patients with bidimensionally measurable disease (55%; 95% confidence interval, 38% to 70%), with a response rate of 73% (11 of 15) seen at the highest dose levels. CONCLUSION: Paclitaxel by 72-hour CIVI with daily cyclophosphamide followed by G-CSF can be administered safely in the ambulatory setting, has acceptable toxicity, and is an active regimen in the treatment of metastatic breast cancer.

Adult↗
PubMed1996

Phase I crossover study of paclitaxel with r-verapamil in patients with metastatic breast cancer.

PURPOSE: We conducted a phase I crossover study of escalating doses of both paclitaxel (Taxol; Bristol-Myers, Squibb, Princeton, NJ) and r-verapamil, the less cardiotoxic stereoisomer, in heavily pretreated patients with metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine patients refractory to paclitaxel by 3-hour infusion were treated orally with r-verapamil every 4 hours starting 24 hours before the same-dose 3-hour paclitaxel infusion and continuing for a total of 12 doses. Once the maximum-tolerated dose (MTD) of the combination was determined, seven additional patients who had not been treated with either drug were evaluated to determine whether the addition of r-verapamil altered the pharmacokinetics of paclitaxel. Consenting patients had tumor biopsies for P-glycoprotein (Pgp) expression before receiving paclitaxel and after becoming refractory to paclitaxel therapy. RESULTS: The MTD of the combination was 225 mg/m2 of r-verapamil every 4 hours with paclitaxel 200 mg/m2 by 3-hour infusion. Dose-limiting hypotension and bradycardia were observed in three of five patients treated at 250 mg/m2 r-verapamil. Fourteen patients received 32 cycles of r-verapamil at the MTD as outpatient therapy without developing cardiac toxicity. The median peak and trough serum verapamil concentrations at the MTD were 5.1 micromol/L (range, 1.9 to 6.3), respectively, which are within the range necessary for in vitro modulation of Pgp-mediated multidrug resistance (MDR). Increased serum verapamil concentrations and cardiac toxicity were observed more frequently in patients with elevated hepatic transaminases and bilirubin levels. Hematologic toxicity from combined paclitaxel and r-verapamil was significantly worse compared with the previous cycle of paclitxel without r-verapamil. In the pharmacokinetic analysis, r-verapamil delayed mean paclitaxel clearance and increased mean peak paclitaxel concentrations. CONCLUSION: r-Verapamil at 225 mg/m2 orally every 4 hours can be given safely with paclitaxel 200 mg/m2 by 3-hour infusion as outpatient therapy and is associated with serum levels considered active for Pgp inhibition. The addition of r-verapamil significantly alters the toxicity and pharmacokinetics of paclitaxel.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Phase I/II trial of biweekly paclitaxel and cisplatin in the treatment of metastatic breast cancer.

PURPOSE: To determine the maximum-tolerated dose of escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb, Princeton, NJ) administered biweekly with a fixed dose of cisplatin, to assess the toxicity, and to evaluate the activity of this combination in a phase I/II trial in metastatic breast cancer. PATIENTS AND METHODS: Twenty-nine women with metastatic breast cancer were enrolled; 27 were assessable for response and 29 for toxicity. All but two of the women had received prior adjuvant chemotherapy, with 23 receiving anthracyclines and six previous cisplatin. RESULTS: The initial starting dose of paclitxel 90 mg/m2 and cisplatin 60 mg/m2 became the phase II dose due to dose-limiting neutropenia. Responses were seen in 85% of assessable patients, with three patients (11%) achieving a complete response (CR) and 20 patients (14%) a partial response (PR), for an overall response rate of 85% (95% confidence interval [CI], 66% to 96%). The time to disease progression for patients who achieved a CR was 110 to 200 days, and for those with a PR, it was 96 to 377+ days, with a median time to progression of 7.1 months and a median response duration of 7.9 months. Sites of CR were skin, soft tissue, and lung, and all occurred in women with previous exposure to anthracyclines. Septic events were rare, with two grade 3 infections (7%), only one of which required hospital admission. There were no grade 4 nonhematologic toxicity and minimal grade 3 toxicity. A total of 251 chemotherapy cycles were given -- 16 with paclitaxel alone in five patients. Forty-five percent of patients required dose reductions, while 52% had delays due to neutropenia. CONCLUSION: Biweekly paclitaxel and cisplatin is an active combination in the treatment of metastatic breast cancer, including for patients with previous exposure to anthracyclines.

Adult↗
PubMed1996

Paclitaxel couplets with cyclophosphamide or cisplatin in metastatic breast cancer.

Determining active combinations containing paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) to treat metastatic breast cancer has been the focus of recent clinical development. Paclitaxel combined with either cyclophosphamide or cisplatin has several potential advantages: cisplatin and cyclophosphamide are active single agents against previously untreated metastatic breast cancer, colony-stimulating factors can modulate overlapping toxicities like myelosuppression, and no mechanisms of cross-resistance between paclitaxel and these agents are yet known. Major questions include the optimal schedule of administration and the sequence dependence of toxicities with these combinations. Paclitaxel schedules with cisplatin include either two dose levels using the 24-hour infusion or a novel biweekly 3-hour infusion. The sequence in the three available studies was paclitaxel followed by cisplatin. Hematologic toxicities were dose limiting with the biweekly and low-dose 24-hour paclitaxel/cisplatin combinations; with granulocyte colony-stimulating factor, neurotoxicity became a prominent cumulative toxicity of the high-dose paclitaxel/cisplatin combination. Response rates in the first-line treatment of metastatic breast cancer ranged from 49% to 85%. In the three completed studies with cyclophosphamide, paclitaxel has been administered over either 72, 24, or 3 hours. Paclitaxel followed by cyclophosphamide had greater hematologic toxicity than the opposite schedule or concurrent administration. Pharmacokinetic factors do not seem to account for this sequence-dependent toxicity. As expected, dose-limiting toxicity in all studies has been hematologic. However, granulocyte colony-stimulating factor has ameliorated myelosuppression and allowed considerable dose escalation of cyclophosphamide. This combination has demonstrated activity in previously treated patients with metastatic breast cancer, including the anthracycline-refractory subpopulation that will be reviewed.

Antineoplastic Agents↗