Phase I/II study of 72-hour infusional paclitaxel and doxorubicin with granulocyte colony-stimulating factor in patients with metastatic breast cancer.

PURPOSE: We conducted a phase I/II trial of concurrently administered 72-hour infusional paclitaxel and doxorubicin in combination with granulocyte colony-stimulating factor (G-CSF) in patients with previously untreated metastatic breast cancer and bidimensionally measurable disease. PATIENTS AND METHODS: We defined the maximum-tolerated dose (MTD) of concurrent paclitaxel and doxorubicin administration and then studied potential pharmacokinetic interactions between the two drugs. Forty-two patients who had not received prior chemotherapy for metastatic breast cancer received 296 total cycles of paclitaxel and doxorubicin with G-CSF. RESULTS: The MTD was determined to be paclitaxel 180 mg/m2 and doxorubicin 60 mg/m2 each by 72-hour infusion with G-CSF. Diarrhea was the dose-limiting toxicity (DLT) of this combination, with three of three patients developing abdominal computed tomographic (CT) scan evidence of typhlitis (cecal thickening) at the dose level above the MTD. All patients developed grade 4 neutropenia (absolute neutrophil count [ANC] < 500 microL), generally less than 5 days in duration. This combination was generally safely administered at dose levels at or below the MTD. The overall response rate was 72% (28 of 39 patients; 95% confidence interval [CI], 55% to 85%), with 8% complete responses (CRs) (three of 39; 95% CI, 2% to 21%) and a median response duration of 9 months. The median overall survival time for all patients is 23 months, with a median follow-up duration of 28 months. Pharmacokinetic studies showed that administration of paclitaxel and doxorubicin together by 72-hour infusion did not affect the steady-state concentrations of either drug. CONCLUSION: Concurrent 72-hour infusional paclitaxel and doxorubicin can be administered safely, but is associated with significant toxicity. The overall response rate of this combination in untreated metastatic breast cancer patients is similar to that achieved with other doxorubicin-based combination regimens. The modest complete response rate achieved suggests that this schedule of paclitaxel and doxorubicin administration does not produce significant additive or synergistic cytotoxicity against breast cancer.

Combination paclitaxel (Taxol) and doxorubicin therapy for metastatic breast cancer.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is a very active agent for the treatment of breast cancer, with associated complete response rates of 12% in patients with minimally pretreated metastatic disease. Simultaneous paclitaxel and doxorubicin administration by 72-hour continuous infusion in patients with previously untreated metastatic breast cancer has yielded an overall response rate of 72% with 8% complete responses. No alterations in paclitaxel or doxorubicin pharmacokinetics were observed when the drugs were administered alone versus in combination. Two phase I studies from the M.D. Anderson Cancer Center (Houston, TX) and the University of Indiana (Indianapolis, IN) have shown that administration of a 24-hour paclitaxel infusion prior to doxorubicin results in a significantly higher incidence of mucositis than the reverse sequence. Preliminary pharmacokinetic studies from M.D. Anderson suggest that peak plasma concentration and clearance of doxorubicin are altered by pretreatment with 24-hour paclitaxel. In contrast, in an ongoing phase I study at the Istituto Nazionale Tumori in Milan, Italy, no differences in toxicities have been observed with the combination of intravenous bolus doxorubicin and 3-hour infusional paclitaxel administered by either sequence. Preclinical in vitro and in vivo studies suggest that the combination of paclitaxel and doxorubicin is associated with no or minimal additive antitumor effects. The modest complete response rates that have been observed in patients with metastatic breast cancer to date are in agreement with these observations. A randomized study of paclitaxel versus doxorubicin versus intravenous bolus doxorubicin followed by 24-hour paclitaxel is now being conducted by the Eastern Cooperative Oncology Group.

Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103.

PURPOSE: To provide an investigational drug, paclitaxel, now commercially available, to women with refractory ovarian cancer and to evaluate response and toxicity in these patients. PATIENTS AND METHODS: Patients with platinum-refractory ovarian cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 3, at least three prior chemotherapy regimens, adequate hepatic and renal function, and no significant cardiac history were eligible. Patients were treated with paclitaxel 135 mg/m2 administered by 24-hour continuous intravenous infusion every 3 weeks. RESULTS: Leukopenia was the most frequent toxicity, with 78% of patients experiencing grade 3 or 4 toxicity. Other grade 3 and 4 toxicities were less common: fever (33%), infection (12%), thrombocytopenia (8%), vomiting (7%), cardiac (2%), neurologic (2%), and mucositis (1%). Fifteen treatment-related deaths (1.5%) were reported. The objective response rate was 22% (4% complete response [CR], 18% partial response; 95% confidence interval [CI] for overall response, 19% to 25%). The median time to progression from treatment initiation was 7.1 months in responding patients and 4.5 months for all patients. The median survival duration was 8.8 months. CONCLUSION: Paclitaxel has shown activity in women with platinum-refractory ovarian cancer, and it can be administered with an acceptable safety profile. Further research is needed to determine the optimal role of paclitaxel in the primary and salvage treatment of ovarian cancer.

Typhlitis resulting from treatment with taxol and doxorubicin in patients with metastatic breast cancer.

BACKGROUND: Typhlitis is being recognized with increasing frequency as a serious complication of aggressive chemotherapy for hematologic and solid malignancies. METHODS: In this report the authors describe two cases of typhlitis in patients with metastatic breast cancer treated with taxol and doxorubicin. RESULTS: Both cases occurred during the first cycle of treatment with taxol (180 mg/m2) and doxorubicin (75 mg/m2), being given simultaneously as 72-hour continuous intravenous infusions. CONCLUSION: Two cases of typhlitis have occurred after combined treatment with taxol and doxorubicin, while typhlitis has not been described after treatment with either drug alone.

Chloroquinoxaline sulfonamide: a sulfanilamide antitumor agent entering clinical trials.

Chloroquinoxaline sulfonamide (CQS) has been developed to the clinical trial stage based on its activity in the Human Tumor Colony Forming Assay (HTCFA). In the HTCFA, CQS demonstrated inhibition of colony formation against breast, lung, melanoma and ovarian carcinomas. The mechanism of action of CQS is unknown. It does not appear to inhibit folate metabolism as does the structurally similar sulfaquinoxaline. Preclinical toxicology studies in dogs and rats have shown that CQS is toxic to lymphoid organs, bone marrow, gastrointestinal tract, pancreas, CNS, adrenal glands and testes. Toxicity was generally reversible with the exception of testicular atrophy in dogs and rats which occurred late and was not reversible within the study time frame. The pharmacokinetic data indicate that CQS binds to serum proteins in a dose and species specific manner. Terminal half-lives appear to vary between species from 60 hours in mice, 15 hours in rats, and 45-132 hours in dogs. Preliminary data indicate a longer terminal half-life in humans. Two phase I trials are ongoing using a 60 min infusion schedule once every 28 days. The starting dose for each trial was 18 mg/m2.

Phase I study of Taxol, doxorubicin, plus granulocyte-colony stimulating factor in patients with metastatic breast cancer.

The objective of this phase I trial was to determine the maximal tolerated dose (MTD) of Taxol and doxorubicin administered as a simultaneous intravenous infusion over 72 hours every 21 days. Granulocyte-colony stimulating factor (G-CSF) 10 micrograms/kg, was administered on days 4-18 of each cycle. The treated population consisted of metastatic breast cancer patients previously untreated with chemotherapy for metastatic disease, who had not received doxorubicin in the adjuvant setting and who had bidimensionally measurable disease. The MTD was determined to be 75 mg/m2 of doxorubicin and 160 mg/m2 of Taxol. The dose-limiting toxicity of the combination was clinical typhlitis in three of three patients. Other significant toxicities included grade 3 diarrhea at the higher dose levels and grade 4 neutropenia in all patients. Eighteen patients were treated on this initial phase I study. The overall response rate was 62%, with 6% complete responses and 56% partial responses. The combination of doxorubicin and Taxol by 72-hour continuous infusion with G-CSF is an active regimen in patients with metastatic breast cancer.

Clinical development of Taxol.

Taxol is the first of a novel class of anticancer drugs, the taxanes. Taxol's unique effects include its ability to polymerize tubulin into stable microtubules in the absence of cofactors and to induce the formation of stable microtubule bundles. During its development, formidable challenges were overcome: a suitable formulation was developed, an adequate supply was ensured, severe hypersensitivity reactions were diminished in incidence and severity, and clinical efficacy was demonstrated. Phase II evaluation is still underway; to date, clinical efficacy has been demonstrated in ovarian, breast, non-small-cell lung, and head and neck cancer. Response rates were low in early studies in melanoma, prostate, colon, cervix, and renal cancer, but for these tumors, additional evaluation is ongoing with a higher Taxol dose or different schedule. In December 1992, Food and Drug Administration approval was granted for use of Taxol as second-line therapy in ovarian cancer patients. Nevertheless, important questions regarding optimal use of this important new drug remain. These include determination of optimal dose and schedule and development of suitable combination chemotherapy regimens. The clinical development of Taxol and current status of phase I, II, and III clinical trials are reviewed.

Terephthalamidine: past and future.

Terephthalamidine (NSC 57155) is one of 800 terephthalanilides and related compounds which were synthesized and tested preclinically in the late 1950's and early 1960's. Based upon their activity against murine leukemias, some of these agents were tested briefly in clinical trials at that time. Despite the observation of responses, the compounds were dropped because of severe and unusual neurotoxicity. More recently, terephthalamidine has been screened for antitumor activity and chosen for further clinical investigation by the NCI's Project for the Review of Old Drugs (P.R.O.D.) because of its novel structure and spectrum of preclinical activity. The current availability of a plasma assay for the drug permits further study of its clinical pharmacokinetics and pharmacodynamics and, perhaps, the development of improved scheduling strategies.

Cardiac disturbances during the administration of taxol.

The clinical development of taxol, a new antimicrotubule agent with a unique mechanism of cytotoxic action, has proceeded slowly due to serious hypersensitivity reactions (HSRs) and shortages in its supply. Nevertheless, large-scale phase II trials have been initiated as taxol has recently demonstrated impressive activity in advanced and cisplatin-refractory ovarian carcinoma. Furthermore, the incidence of HSRs has been reduced substantially with premedications and modifications in the administration schedule. However, various manifestations of potential cardiotoxicity have been observed in several patients who participated in four phase I and II studies of taxol. Asymptomatic bradycardia has occurred in a high proportion of patients, including 29% of ovarian cancer patients who were treated with maximally tolerated doses of taxol in a phase II study. More profound cardiac disturbances, including a range of atrioventricular conduction blocks, left bundle branch block, ventricular tachycardia (VT), and manifestations of cardiac ischemia, have been observed in seven of 140 patients (5%) who received taxol. Descriptions of these events are presented in this report to alert investigators to the potential for these adverse effects. Although these disturbances did not result in serious sequelae in most patients, investigators should continue to maintain a high degree of caution until precise risk factors, frequency, and clinical significance of these adverse cardiac effects are determined.