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 semi-synthetic 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 x3 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 > 100000 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 x3 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 microg/kg was started on day 4 of the 21-day cycle and was continued until the neutrophil count exceeded 10000 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 x3 schedule of vinorelbine should not be pursued as an alternative treatment regimen in patients with previously treated metastatic breast cancer.

Continuous infusion 5-fluorouracil as first-line therapy for metastatic breast cancer.

Previous phase II studies of continuous infusion Fluorouracil (5-FU) (CI 5-FU) in refractory metastatic breast cancer have shown modest activity with low toxicity. Its activity in a first-line setting has not been formally tested. Patients were eligible if they fulfilled the following criteria: metastatic breast cancer; measurable or evaluable disease, no prior chemotherapy in the metastatic setting; ECOG performance status of 0, 1, or 2: adequate bone marrow and liver function. Patients were treated with 5-FU 250 mg/m2 per day by continuous intravenous infusion for 5 weeks in a 6-week cycle. Treatment was continued until disease progression or unacceptable toxicity. In addition to the traditional endpoints of response, survival, and toxicity, quality of life was assessed with the Functional Living Index-Cancer (FLIC) and the Symptom Distress Scale (SDS). Twenty-one patients were enrolled. Among the 16 patients with measurable disease, the objective response rate was 44% (95% CI 20%, 68%) with CR rate 13% and PR rate 31%. The median duration of response was 37 weeks. Responses were not observed in patients with visceral (lung or liver) disease. Among all 21 patients in the study, the median time to disease progression was 12 weeks, and median overall survival was 64 weeks. Grade 1 or 2 mucosal and cutaneous toxicity were common. Only 4 patients (19%) had toxicity greater than grade 2; three patients had grade 3 mucositis, and 1 patient developed an indwelling catheter infection requiring its removal. Among responding patients, mean FLIC scores improved from 114.3 at baseline to 128.7 at week 8 (p = 0.11). Symptoms reported on the SDS generally improved in responding patients. Continuous infusion 5-FU as a first-line therapy for metastatic breast cancer has moderate activity and low toxicity. Its use should be considered in the first-line setting when toxicity needs to be minimized.

Deoxyspergualin: phase I clinical, immunologic and pharmacokinetic study.

Deoxyspergualin (DSG) is an analog of the polyamine spergualin with preclinical evidence of activity in murine and human tumor models. This phase I study examined a 120 h continuous infusion schedule in 56 patients with refractory solid tumors at doses ranging from 80 to 2792 mg/m2/day. Dose-limiting toxicity was reversible hypotension and appeared to be associated with plasma levels of DSG > 4 micrograms/ml. Other dose-dependent effects noted were pruritus and circumoral paresthesias. Myelosuppression and gastrointestinal toxicities were mild and sporadic. Two patients with refractory head and neck cancer had minor responses. The recommended phase II dose on this schedule is 1800 mg/m2. Additional monitoring to identify immunologic properties included immunophenotyping of peripheral lymphocytes and cytotoxic activity by means of standard 51Cr-release assays. These studies revealed a non-dose-dependent increase in the number of cells expressing T cell antigens predominantly the T suppressor (CD8) phenotype posttreatment. In three patients, a mild increase in LAK activity was noted post-treatment without a consistent relationship to dose or change in cell surface antigens. Pharmacokinetic studies were completed on 26 patients ranging from doses of 80 to 2792 mg/m2. The average plasma concentration ranged from 0.07 to 7 micrograms/ml. DSG was rapidly cleared from the plasma with a mean terminal half-life of 1.9 h. Mean total body clearance was 25.24 l/h/m2. Further in vivo immunologic studies should be pursued while the agent is studied in fixed dosage phase II clinical trials.

Etoposide in gastric cancer.

Etoposide has modest single-agent activity (21% partial response rate) in patients with previously untreated metastatic gastric carcinoma. The use of etoposide in combination with agents like doxorubicin, cisplatin, and 5-fluorouracil with or without leucovorin has been of increasing interest to oncologists. Such combinations have been reported to produce overall response rates as high as 60% to 70%, with complete response rates as high as 20%, in patients with advanced measurable gastric carcinoma. Etoposide-containing regimens have also been used preoperatively in potentially resectable patients. In these studies, approximately 60% of treated patients may be rendered disease-free following resection. Preoperative (neoadjuvant) therapy has not yet been shown in phase III studies to be superior to surgery alone. Significant myelosuppression is the major toxicity of etoposide-based chemotherapy. Such chemotherapy deserves further evaluation in the treatment of gastric cancer.

A phase I clinical and pharmacokinetic trial of hepsulfam.

Hepsulfam (1,7-heptanediol-bis-sulfamate) is one of a series of bis-sulfamate acid esters that was synthesized in an attempt to improve the antitumor efficacy of busulfan. Hepsulfam has shown broad antineoplastic activity in preclinical studies. This Phase I trial evaluated hepsulfam given as a single i.v. dose every 21-35 days. Twenty-nine patients with refractory solid tumors participated in this study. Twenty-six of these patients had had either prior chemotherapy or radiation therapy. Fifty-two courses of treatment were given at doses ranging from 30 to 360 mg/m2/day. The dose limiting toxicity was prolonged thrombocytopenia and granulocytopenia. This toxicity was cumulative with Grade 3 or 4 thrombocytopenia occurring in 3 of 15, 4 of 9, and 2 of 2 patients in the first, second, and third courses of greater than or equal to 210 mg/m2, respectively. This toxicity was noted in patients with less than or equal to 1 prior chemotherapeutic regimen, as well as in patients with greater than 1 prior chemotherapeutic regimens. Nonhematological toxicities included Grade 1 or 2 nausea and vomiting and fatigue. There was no evidence of pulmonary toxicity. Plasma levels of hepsulfam were quantified by gas chromatography in 12 patients. The plasma and blood half-lives were 15.9 +/- 4.6 and 90 +/- 13 h, respectively. No objective tumor responses were seen. We conclude that the maximally tolerated dose when hepsulfam is given as a single dose every 35 days is 210 mg/m2, but that there is significant risk of cumulative hematological toxicity at this level.

Phase I evaluation of 773U82.HCl, a member of a new class of DNA intercalators.

The arylmethylaminopropanediols (AMAPs) are a new class of DNA intercalators. 773U82.HCl is the second of these compounds to enter clinical trial. Significant antitumor activity for 773U82.HCl was documented in a variety of murine and human tumor models. This phase I study examined a 1-, 2- and 6-hour infusion given every 28 days. Thirty-six patients received 58 courses of drug at doses ranging from 15 mg/m2 to 980 mg/m2. The dose-limiting toxicity of 773U82.HCl was hemolysis noted at 980 mg/m2. Change in color of the plasma and decreases in haptoglobin were correlated with drug concentrations of the infusate greater than or equal to 3 mg/ml. Clinically significant changes in hemoglobin levels requiring blood transfusions did not occur. Neurologic toxicity occurred at 720 mg/m2 with the most severe neurologic toxicity occurring in a patient with the highest peak plasma concentration (4.1 micrograms/ml). With an increase in duration of the infusion and amount of fluid administered, the neurologic toxicity resolved. Other toxicities included mild nausea and vomiting and a dose-related phlebitis. Pharmacokinetic studies were completed in 22 patients. The mean terminal t1/2 beta was 4.4 h with a mean apparent volume of distribution at steady state (Vdss) of 314 l/m2. The mean total body clearance was 72 l/h/m2. Peak plasma levels ranged from 0.04 to 4.14 micrograms/ml. Further studies with 773U82.HCl on this schedule at the doses studied are not recommended. Hematologic monitoring for evidence of intravascular hemolysis should be included in future studies with 773U82.HCl.

Phase I clinical and pharmacokinetic trial of flavone acetic acid.

Flavone acetic acid is a synthetic benzopyrone derivative with an unknown mechanism of action. Thirty-eight patients (30 men and 8 women) were treated once a week for 4 weeks every 5 weeks with doses of flavone acetic acid ranging from 0.33 to 12.5 g/m2. At doses less than or equal to 3.9 g/m2, the drug was administered intravenously over 1 hour; at doses greater than or equal to 5.28 g/m2, the infusion period was lengthened to 6 hours. Treatment of all patients included hydration before and after treatment and alkalization to maintain urine pH at greater than or equal to 6.5. A dose-limiting toxic effect was hypotension at 10 g/m2. Pharmacokinetic studies revealed linear behavior in the eight patients studied, beginning at 3.9 g/m2. Peak plasma levels ranged from 125 to 630 micrograms/mL, with a mean terminal half-life of 22.4 hours. Immunologic monitoring was performed in three patients at 10 g/m2. A transient increase in CD16- and/or Leu-19-positive cells was noted in all three patients. In one patient, this increase correlated with a 10-fold increase in K562 cell killing. There were no objective tumor responses seen in this trial. The recommended phase II dose on this schedule is 8 g/m2. Further studies to elucidate the drug's mechanism of action and to define its immunologic properties are recommended.

Phase I evaluation of crisnatol (BWA770U mesylate) on a monthly extended infusion schedule.

Crisnatol is an arylmethylaminopropanediol derivative that has shown promise as an antitumor agent in preclinical testing. In a phase I trial using a monthly six-hour infusion schedule the recommended dose for future phase II trials was found to be 388 mg/m2. Neurologic toxicity was dose-limiting in that trial and correlated with the attainment of a threshold plasma concentration of greater than 4.5 micrograms/ml. In this study we treated 15 patients with escalating doses of crisnatol from 450 mg/m2 to 900 mg/m2 administered at a rate of 50 mg/m2/hr over 9, 12, 15, and 18 hours. Toxicity was mild to moderate at all dose levels. However, serious central nervous system effects were noted in one patient at 900 mg/m2 over 18 hours whose plasma level was 6.5 micrograms/ml. This study has demonstrated higher total doses of crisnatol can be given if the drug is administered as a prolonged infusion in an attempt to avoid high plasma levels of the agent.

Phase I and clinical pharmacology trial of 502U83 using a monthly single dose schedule.

502U83 is an arylmethylaminopropanediol derivative exhibiting significant antineoplastic activity in a number of murine and human tumor models. In this Phase I trial, a 1-h or 4-h infusion of the agent was administered i.v. in 250 ml of 5% dextrose in water every 28 days. Fifty-three courses at doses of 25 to 2000 mg/m2 were administered to 36 patients with refractory solid tumors. Prolongation of the PR, QRS, and QT intervals on electrocardiograms was dose limiting at 2000 mg/m2. This prolongation appeared dose related and was reversible upon discontinuation of the infusion. No hematological toxicity was observed. Other toxicities included only sporadic and mild to moderate nausea and vomiting. No tumor responses were noted. 502U83 plasma concentrations were determined by high-pressure liquid chromatography. Complete pharmacokinetic profiles were obtained for 21 of the 36 patients. After infusion, plasma concentrations declined in a biexponential or in a triexponential manner with a harmonic mean terminal t 1/2 of 8.83 h. Using a three-compartment model, the mean apparent volume of distribution at steady state and total-body clearance were 195 liters/m2 and 42.5 liters/h/m2, respectively, indicative of extensive tissue distribution. No correlation could be found between the pharmacokinetic parameters and prolongation of the cardiac conduction intervals. Because of the cardiac effects with the drug, the schedule of administration of 502U83 used in this study cannot be recommended.

Induced proteins in human peripheral mononuclear cells over a range of clinically tolerable doses of interferon-gamma.

This study assessed biologic response modification at three different dose levels (0.15, 1.5, and 15 mg/m2) of interferon-gamma (IFN-gamma) administered by intravenous bolus three times weekly. A final total of 24 patients were evaluable. Dose-limiting toxicity occurred at the highest dose level (15 mg/m2) and included fatigue, leukopenia, and hepatotoxicity. Evaluation of biologic response modification included assessment of 2',5'-oligoadenylate (2-5A) synthetase activity in peripheral mononuclear cells, measurement of serum beta 2-microglobulin and expression of beta 2-microglobulin on monocytes, measurement of monocyte HLA Class II expression (HLA-DR, HLA-DQ), and measurement of hydrogen peroxide generation by monocytes 24 h after the first and fourth IFN-gamma treatments. Significant increases (p less than 0.05) from baseline were seen at 24 h with all parameters except H2O2 generation. Except for enhancement of HLA-DR, even the lowest dose (0.15 mg/m2) augmented synthesis of 2-5A synthetase and HLA proteins. A dose-response effect was noted for changes in serum and monocyte beta 2-microglobulin levels but not for 2-5A synthetase levels or HLA Class II antigen expression on monocytes. After 4 doses administered over 9 days, most parameters remained increased when compared to pretreatment, but were not further enhanced when compared with levels attained after the first dose. The results of this study document the efficacy of IFN-gamma for biological activation over a wide dose range and are consistent with the postulate that immunoregulatory effects of biological therapeutics can be obtained in man at doses substantially less than those that are maximally tolerated. Further documentation of biologic response parameters by IFN-gamma at low doses will be necessary to determine the importance of biologic activation in relation to antitumor activity.

High-dose cisplatin for locally advanced or metastatic head and neck cancer. A phase II pilot study.

High-dose cisplatin (40 mg/m2 every day X5) was administered to 14 patients (11 men, three women) with locally advanced or metastatic head and neck cancer not curable by surgery or refractory to previous chemotherapy and/or radiation therapy. All 14 patients were evaluable for toxicity; one patient was inevaluable for response due to early death. A total of 24 courses of therapy were administered. The dose-limiting toxicity was myelosuppression with 73% of patients experiencing Grade III or IV neutropenia. Grade II or above thrombocytopenia occurred in 30% of the patients. Renal and neurologic toxicity was minimal. Two patients experienced laryngeal edema from vigorous hydration with one of them requiring a tracheostomy for respiratory compromise. Partial responses were seen in six patients (46%). Two of the six patients had received previous treatment with standard dose cisplatin. Two patients achieved long-term responses (54+, 44+ months, respectively). Both of these patients were previously untreated, inoperable (T4N3M0, T3N1M0), and subsequently received radiation therapy after two cycles of chemotherapy. Median duration of response in the remaining responders was 3 months (range, 3-10 months). High-dose cisplatin may benefit selected patients with inoperable, advanced head and neck tumors. However, further randomized trials need to be conducted before firm conclusions can be established.

Lack of interferon production by dipyridamole.

Dipyridamole, previously reported to be an interferon (IFN) inducer in mice, was evaluated in 43 normal volunteers or cancer patients. At doses ranging from 150 mg orally to 887 mg intravenously, no serum antiviral activity suggesting IFN induction was observed.