Search

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.

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.

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.

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.

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.