John A. Hohneker

Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer.

PURPOSE This prospective multicenter randomized trial was performed to compare the effectiveness and safety of intravenous (i.v.) vinorelbine tartrate (Navelbine [NVB]; Burroughs Wellcome Co, Research Triangle Park, NC) with i.v. melphalan (Alkeran [ALK]; Burroughs Wellcome Co) in a heavily pretreated population of patients with anthracycline-refractory advanced breast cancer (ABC). Efficacy end points included time to disease progression (TDP), time to treatment failure (TTF), survival, tumor response rates, and quality of life (QL) and relief of cancer-related symptoms. PATIENTS AND METHODS Between August 24, 1990, and December 1, 1992, 183 patients were randomized (2:1) to treatment with NVB (30 mg/m2 weekly) or ALK (25 mg/m2 every 4 weeks) i.v. Patients were stratified by measurable or nonmeasurable-assessable disease and by treatment center. RESULTS Time to disease progression was significantly longer with NVB than with ALK, with a median 12 weeks versus 8 weeks, respectively (P < .001). NVB patients also had significantly longer time to treatment failure than ALK patients, with a median 12 weeks versus 8 weeks, respectively (P < .001). The effect of NVB on survival was also statistically significant (P = .034): 1-year survival rates were 35.7% with NVB and 21.7% with ALK and the median survival rate was 35 weeks and 31 weeks, respectively. In total, 46.5% of NVB patients and 28.2% of ALK patients achieved an objective response or stabilization of disease (P = .06). No intergroup differences were noted in patient-assessed QL and cancer-related symptoms. The most common toxicities were hematologic, including granulocytopenia with NVB and thrombocytopenia and granulocytopenia with ALK. Both drugs were generally well tolerated, and no septic deaths were reported. CONCLUSION This randomized trial demonstrates a survival benefit in anthracycline-refractory ABC. NVB was well tolerated and demonstrated activity superior to ALK in anthracycline-refractory ABC, without compromising QL. Based on activity of single-agent NVB in this difficult-to-treat patient population, investigations of NVB in combination with other anticancer drugs are warranted.

Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer.

PURPOSE To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. PATIENTS AND METHODS Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. RESULTS Sixty-five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5-FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. CONCLUSION 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmacokinetics.

Allopurinol: Intravenous Use for Prevention and Treatment of Hyperuricemia

PURPOSE To tabulate data obtained over a 21-year period to determine the efficacy and safety of an intravenous (IV) allopurinol preparation. PATIENTS AND METHODS IV allopurinol was provided on a compassionate plea basis to patients of any age in whom xanthine oxidase inhibitor therapy was indicated as an adjunct to chemotherapy and for whom oral intake was restricted. Three hundred twenty-seven investigators at multiple hospitals in the United States treated 1,172 patients with IV allopurinol. The vast majority of these patients had a malignancy and were in danger of developing tumor lysis syndrome (TLS) and subsequent acute uric acid nephropathy (AUAN) and were unable to take oral allopurinol. Data referable to the time period of IV allopurinol administration were collected, collated, and analyzed retrospectively. There was no randomization. RESULTS In patients initiating treatment for an elevated serum uric acid (SUA), the SUA normalized or improved in 87% of adult patients and normalized or improved in 95% of pediatric patients. IV allopurinol, administered prophylactically to patients at high risk of developing hyperuricemia and TLS, prevented an increase in SUA levels in 93% of adults and 92% of children. Toxicities caused by IV allopurinol were minimal and consisted of 10 instances of mild to moderate skin or allergic reactions. CONCLUSION IV allopurinol is as efficacious and safe as oral allopurinol and will be of significant benefit to patients at risk of TLS and AUAN and unable to take oral medication.

Pharmacokinetic, bioavailability, and feasibility study of oral vinorelbine in patients with solid tumors.

PURPOSE The feasibility of administering vinorelbine (Navelbine, Burroughs Wellcome Co, Research Triangle Park, NC), a semisynthetic vinca alkaloid with broad activity, as a liquid-filled gelatin capsule was evaluated in a bioavailability (F) and pharmacokinetic study. PATIENTS AND METHODS Each of 17 cancer patients had pharmacokinetic studies performed after receiving vinorelbine 30 mg/m2 intravenously (IV), which is the maximum-tolerated dose (MTD) for weekly IV administration, and twice after receiving the oral formulation at a nominal dose of 100 mg/m2. Subsequently, these patients and 10 other subjects received the oral formulation at a dose of 100 mg/m2/wk to evaluate the feasibility of chronic oral administration. RESULTS Plasma drug disposition was well described by a triphasic model. Mean central volume of distribution and steady-state volume of distribution (Vss) were large (0.66 +/- 0.46 L/kg and 20.02 +/- 8.55 L/kg, respectively); the mean harmonic terminal half-life (t1/2) was long (18 hours); and the high mean clearance (CI) rate (0.80 +/- 0.68 L/h/kg) approached hepatic blood flow. F was low (0.27 +/- 12), and absorption was rapid (mean time of maximum plasma concentration [Tmax], 0.91 +/- 0.22 hours). Absorption parameters after the first and second oral doses were similar, with mean F values of 0.27 +/- 0.14 and 0.25 +/- 0.11, respectively. Coefficients of variability (CVs) for F, maximum plasma concentration (Cmax), and Tmax were 32%, 42%, and 78%, respectively, indicating moderate intraindividual variability. The pharmacologic profile of this oral formulation indicates that there is a large first-pass effect. Neutropenia was the principal toxicity of oral vinorelbine. Grade 3 or 4 neutropenia occurred in 63% of patients, but only 11% developed neutropenia and infection. Nausea, vomiting, and diarrhea were also common with oral administration, but these effects were rarely severe and could be ameliorated by using a divided-dose schedule and/or prophylactic antiemetic and antidiarrheal agents. The mean nominal oral dose was 82 mg/m2, and the mean percentage of intended dose that was received was 92%. Although dose escalations were permitted for negligible toxicity, doses were not escalated to greater than 100 mg/m2/wk in any patient. Vinorelbine given as a liquid-filled gelatin capsule at 100 mg/m2 provided equivalent pharmacologic exposure as 30 mg/m2 IV. CONCLUSION The oral administration of vinorelbine, specifically as a liquid-filled, soft gelatin capsule, is a feasible route of administration. Weekly oral dosing at 100 mg/m2 induces a consistent degree of myelosuppression, but the high frequency of grade 3 or 4 neutropenia, albeit brief and uncomplicated, warrants the recommendation of a slightly lower starting dose, ie, 80 mg/m2/d, for subsequent phase II evaluations, especially in heavily pretreated patients.

Multicenter Phase II Study to Evaluate a 28-Day Regimen of Oral Fluorouracil Plus Eniluracil in the Treatment of Patients With Previously Untreated Metastatic Colorectal Cancer

PURPOSE To determine the efficacy of fluorouracil (5-FU) plus eniluracil when administered to patients with previously untreated metastatic colorectal cancer. PATIENTS AND METHODS In this single-arm phase II study, patients with previously untreated metastatic colorectal cancer received oral eniluracil plus 5-FU (10:1 dose ratio), at 5-FU doses of 1.00 mg/m(2) or 1.15 mg/m(2) twice daily (every 12 hours) for 28 consecutive days repeated every 5 weeks (one cycle). Treatment continued until there was documented disease progression or unacceptable toxicity. RESULTS Thirty and 25 patients were enrolled at a starting dose of 1.00 mg/m(2) and 1.15 mg/m(2), respectively. Fourteen (25%) of 55 patients (95% confidence interval, 15% to 39%) had a partial response, and 20 patients (36%) had stable disease. The median durations of the partial responses and stable disease were 23.9 weeks (range, 12.3 to 52.1+ weeks) and 24.1 weeks (range, 17.1 to 55.6+ weeks), respectively. The median durations of progression-free and overall survival were 22.6 weeks (range, 21.0 to 29.0 weeks) and 59 weeks (range, 4 to 84+ weeks), respectively. The response rate in the 1.15 mg/m(2)-dose group was similar to the 1.00 mg/m(2)-dose group (28% v 23%, respectively). Severe (grade 3/4) nonhematologic treatment-related toxicity included diarrhea (nine patients), nausea/vomiting (one patient each), mucositis (two patients), and anorexia (one patient). Severe hematologic toxicities were rare. At the 1.15 mg/m(2)-dose level, two patients exhibited grade 3 granulocytopenia, and two patients had grade 3 anemia. CONCLUSION The response rate with oral 5-FU plus eniluracil is comparable with that observed with infusional 5-FU or bolus 5-FU and leucovorin. The toxicity profile of this oral regimen is acceptable for use in an outpatient home-based setting.

Multicenter phase II study of weekly oral vinorelbine for stage IV non-small-cell lung cancer.

PURPOSE We initiated a large multicenter phase II trial in stage IV non-small-cell lung cancer (NSCLC) to evaluate the activity and safety of an oral gelatin-based formation of vinorelbine. PATIENTS AND METHODS Twenty-three centers participated in this uncontrolled phase II study, which accrued patients between August 1991 and March 1992. Eligible patients had previously untreated measurable or assessable stage IV NSCLC, age more than 18 years, and Karnofsky performance status > or = 70%. The treatment plan initially was to administer 100 mg/m2/wk of oral vinorelbine or 80 mg/m2/wk for patients who had received prior radiation therapy. After the observation of grade IV granulocytopenia in six of the first 25 patients, subsequent doses were reduced by 40 mg (one capsule) in all patients. RESULTS One hundred sixty-two patients were treated: 138 with measurable and 24 with assessable disease. One hundred two patients were men and 60 women. The mean age was 62 years (range, 36 to 83). The overall response rate was 14.5% for patients with measurable disease (95% confidence interval, 9.3% to 21.7%). The median time to treatment failure (TTF) for all patients was 9 weeks. The median survival time was 29 weeks; the 1-year survival rate was 22%. Toxicities included grade 3 or 4 neutropenia in 40%, which was dependent on the vinorelbine dose. Other toxicities included mild to moderate nausea/vomiting, diarrhea, and stomatitis. The mean dose intensity of vinorelbine was 53 mg/m2. CONCLUSION Oral vinorelbine administered once weekly is an active agent in stage IV NSCLC. The median survival time of 29 weeks is similar to that achieved with single-agent intravenous vinorelbine and more aggressive cisplatin-based combinations. Further studies of this compound in the palliative-intent care setting appear to be indicated.

The effects of food and divided dosing on the bioavailability of oral vinorelbine

Abstract The effects of food and divided dosing on the bioavailability of a liquid-filled gelatin capsule formulation of vinorelbine (Navelbine), a semisynthetic vinca alkaloid with broad clinical activity, was evaluated in patients with advanced solid tumors. A group of 13 patients were randomized to treatment with the oral formulation at the recommended phase II dose of 80 mg/m2 per week either in the fasting state or after ingestion of a standard meal. Patients were treated 1 week later in the alternate state relative to their first dose. The effects of divided dosing were assessed during the 3rd week, at which time vinorelbine was administered in two divided doses. After the completion of pharmacokinetic and bioavailability studies, patients received the oral formulation at a dose of 80 mg/m2 per week in two divided doses to evaluate the feasibility of chronic oral drug administration. Both manipulations resulted in small, albeit statistically significant, reductions in the relative bioavailability of this oral formulation. The relative bioavailability decreased by 22±28% when treatment followed the ingestion of a standard meal, possibly due to a delay in gastrointestinal transit time. The mean time of maximum plasma concentration (Tmax) increased from 1.3±1.6 h in the fasting state to 2.5±1.6 h in the fed state, although this difference was not statistically significant. Similarly, the relative bioavailability declined by 16±51% when vinorelbine was administered in two divided doses. An analysis of dose proportionality revealed disproportionate increases in dose-normalized Cmax and AUC values with single oral doses above 120 mg, which may account for this phenomenon. The high clearance of vinorelbine, which approaches hepatic blood flow, and the lack of dose proportionality after oral administration, indicate that there is a large first-pass effect which may be saturable, or nonlinear, above single doses of 120 mg. In addition, the toxicological and pharmacological characteristics of oral vinorelbine indicate that treatment after a standard meal or on a divided dosing schedule is safe. Chronic oral administration of the agent in two divided doses was also well tolerated. However, the small reduction in the relative bioavailability following the ingestion of a standard meal and with divided dosing suggest the need for further pharmacodynamic studies to determine if reductions in drug exposure of this magnitude may portend diminished antitumor activity.

Clinical development of eniluracil/fluorouracil: an oral treatment for patients with solid tumors.

Eniluracil (776C85, GW776) inactivatesdihydropyrimidine dehydrogenase (DPD), the principal enzyme of5-fluorouracil (5-FU) catabolism. Inactivation of DPD eliminatesa potential mechanism for tumor 5-FU resistance and permitsachievement of reliable and predictable pharmacokincticsfollowing oral 5-FU administration. Eniluracil/5-FU hasdemonstrated efficacy as monotherapy in patients with a varietyof solid tumors when given on a 5 or 28-day dosing schedule. Theprimary and dose-limiting toxicity is myelosuppresion with the5-day schedule and diarrhea with the 28-day schedule. Thefrequency of hand-foot syndrome is minimal with either schedule.Phase III pivotal registration-directed studies witheniluracil/5-FU given by the 28-day schedule are ongoing orplanned for the near future in patients with advanced colorectal,breast and pancreatic cancer.

A phase I trial of vinorelbine in combination with mitoxantrone in patients with refractory solid tumors

Vinorelbine (Navelbine®) is a unique semi-synthetic vinca-alkaloid with a favorable safety profile that has demonstrated significant antitumor activity in patients with non-small cell lung cancer, advanced breast cancer, advanced ovarian cancer and Hodgkins disease. The most common dose-limiting toxicity is neutropenia, while other reported toxicities are minimal. Mitoxantrone (Novantrone®) is an anthracene derivative that has demonstrated antitumor activity in patients with breast cancer, ovarian cancer, acute leukemia, and lymphoma. Mitoxantrone also has a very favorable toxicity profile with significantly less nausea and vomiting, alopecia, and stomatitis as compared with anthracyclines. The dose-limiting toxicity for mitoxantrone is leukopenia. The study was designed to determine the safety and maximally tolerated dose of IV vinorelbine used in combination with a fixed dose of mitoxantrone for the treatment of patients with refractory solid tumors. Vinorelbine was administered on days 1 and 8 of the treatment regimen as a short IV infusion. The starting dose was 15 mg/m2. Mitoxantrone was administered as a 20-min infusion on day 1 only at a fixed dose of 10 mg/m2. Seventeen patients with solid malignancies were entered in the study. For personal reasons, one patient decided to discontinue the treatment after day 1 of cycle 1. Therefore, 16 patients were evaluable for toxicity. The main toxicity was myelosuppression which was dose-limiting and resulted in dose reductions and delays. The use of G-CSF had a minimal overall impact on this regimen. Stable disease was observed in three cases. In patients previously treated with chemotherapy, the maximally tolerated dose was defined as vinorelbine 20 mg/m2 on days 1 and 8 and mitoxantrone 10 mg/m2 on day 1 without growth factor support. These doses can be recommended for phase II study of the regimen as salvage treatment.

Inability to escalate vinorelbine dose intensity using a daily x3 schedule with and without filgrastim in patients with metastatic breast cancer.

Purpose: Vinorelbine (Navelbine) is a semisynthetic vinca alkaloid with documented activity in breast cancer. The major dose-limiting toxicity (DLT) when given weekly is myelosuppression with minimal neurologic toxicity. This phase I study attempted to define the maximally tolerated dose (MTD) and the DLT of vinorelbine on a daily ×3 schedule with and without filgrastim support. Methods: A total of 19 patients with stage IV breast cancer were enrolled in separate studies at Duke University Medical Center (DUMC) and the Dana-Farber Cancer Institute (DFCI). Eligible patients could have received up to two prior chemotherapy regimens in the metastatic setting and had to have an ANC >1500/mm2, PLT >100 000 m3, creatinine <2.0 mg/dl, bilirubin <2.0 mg/dL, SGOT not more than three times normal, and performance status 0–1. Vinorelbine was administered using a daily ×3 schedule every 3 weeks. The protocols were designed to study dose escalation with and without growth factor support. At DUMC, in the initial phase of the study, the starting dose was 15 mg/m2 per day and dose escalations of 5 mg/m2 were planned until DLT developed and the MTD was defined. DLT was defined as granulocytopenia <500/mm3 for >7 days, grade IV thrombocytopenia, febrile neutropenia, or grade III or greater nonhematologic toxicity. In the second phase of the study, growth factor support was given with vinorelbine at the MTD. Filgrastim at a dose of 5 g/kg was started on day 4 of the 21-day cycle and was continued until the neutrophil count exceeded 10 000 cells/mm3. At DFCI, all patients received growth factor starting on day 4 and the starting dose of vinorelbine was 25 mg/m2. Results: At DUMC, DLT was seen at 20 mg/m2 in three of three patients and included febrile neutropenia, grade IV neutropenia >7 days, grade III neurotoxicity, and grade III vomiting. Despite the addition of filgrastim, DLT was again seen at 20 mg/m2 and included grade III neurotoxicity (jaw pain, abdominal pain, constipation, ileus) and grade IV mucositis. Three patients at DFCI were treated with vinorelbine at a dose of 25 mg/m2 with growth factor support, and two developed DLT including febrile neutropenia, neutropenia >7 days, and grade III stomatitis. Conclusions: Our effort to escalate the dose intensity of vinorelbine on this schedule was not successful and was complicated by hematologic and nonhematologic toxicity. A daily ×3 schedule of vinorelbine should not be pursued as an alternative treatment regimen in patients with previously treated metastatic breast cancer.