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© 2000 American Society for Clinical Oncology Phase I and Pharmacokinetic Study of the Differentiating Agent Vesnarinone in Combination With Gemcitabine in Patients With Advanced CancerFrom the Institute for Drug Development, Cancer Therapy and Research Center, and The University of Texas Health Science Center at San Antonio, San Antonio, TX; and Otsuka America Pharmaceutical, Inc, Palo Alto, CA. Address reprint requests to Amita Patnaik, MD, Institute for Drug Development, Cancer Therapy and Research Center, 8122 Datapoint Dr, Suite 250, San Antonio, TX, 78229; email apatnaik{at}saci.org
PURPOSE: To evaluate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic profile of vesnarinone given once daily in combination with gemcitabine. PATIENTS AND METHODS: Twenty-six patients were treated with oral vesnarinone once daily on a continuous schedule at doses of 60, 90, 120, 150, and 180 mg in combination with intravenous (IV) gemcitabine at a dose of 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks. To determine whether biologically relevant concentrations were being achieved, predose concentrations (Cmin) of vesnarinone were obtained weekly. Plasma gemcitabine and 2',2'-difluorodeoxyuridine concentrations were obtained during courses 1 and 2. RESULTS: Twenty-six patients were treated with 92 courses of vesnarinone/gemcitabine. The principal toxicities of the regimen consisted of neutropenia and thrombocytopenia, which were dose-limiting in two of eight heavily pretreated new patients treated at the 90 mg/1,000 mg/m2 dose level and one of 10 minimally pretreated new patients at the 120 mg/1,000 mg/m2 dose level. None of three patients treated with 15 courses at the vesnarinone/gemcitabine dose levels of 60 mg/1,000 mg/m2 experienced DLT. Pharmacokinetic studies of vesnarinone revealed significant interpatient variability at any given dose level. There was evidence of a linear relationship between vesnarinone dose and mean Cmin at dosages of vesnarinone less than 150 mg, with plateauing of mean Cmin values at higher dosages. There was no impact of vesnarinone on gemcitabine concentrations, and the vesnarinone pharmacokinetics did not change with gemcitabine between weeks 1 and 2. Two partial responses occurred in patients with refractory breast and non–small-cell lung carcinoma. CONCLUSION: When combined with gemcitabine, the recommended dose of vesnarinone for phase II evaluations is 90 mg orally once daily with gemcitabine 1,000 mg/m2 IV on days 1, 8, and 15 every 4 weeks. There is no evidence of pharmacokinetic interaction between vesnarinone and gemcitabine. Further studies of vesnarinone as a single agent or in combination with gemcitabine and other antineoplastic agents are warranted.
VESNARINONE (OPC-8212; Otsuka America Pharmaceutical Inc, Palo Alto, CA; 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone; Fig 1), a novel quinolinone originally developed for its inotropic properties to treat cardiac failure, has demonstrated a unique spectrum of intriguing biologic effects, including tumor cell differentiating and proapoptotic properties.1-3 It was the observation of agranulocytosis in clinical cardiac studies of vesnarinone that prompted further exploration of its potential antiproliferative effects.3-5 Although vesnarinone is not directly cytotoxic, it inhibits proliferation and induces cellular differentiation and apoptosis in transformed cell lines, human tumor xenografts, and primary tumor specimens.6-9 Additionally, studies of the combination of vesnarinone and gemcitabine have demonstrated additive and synergistic antitumor effects, prompting this phase I and pharmacologic study of the combination (report on file, Otsuka America Pharmaceutical Inc).
Vesnarinone inhibits cell growth in vitro, which is accompanied by morphologic changes consistent with cellular differentiation and apoptosis. Treatment of HSG-AZA3 salivary carcinoma cells with vesnarinone at a concentration of 30 µg/mL for 8 days induced differentiation to chondrocyte-like cells and morphologic evidence of apoptosis.3 Additionally, vesnarinone at concentrations of 5 to 50 µg/mL for 6 days induced acinar cell differentiation and apoptosis in the human salivary gland tumor cell line TYS. Interestingly, the expression of p21WAF1 mRNA in TYS cells was markedly enhanced by vesnarinone treatment and increased in a time-dependent manner, suggesting that the expression of p21WAF1 mediates cell growth inhibition and differentiation in TYS cells.10 Recent studies have also revealed that vesnarinone inhibits the production of cytokines such as tumor necrosis factor alpha, interleukin-6, and interferon gamma in lipopolysaccharide-stimulated peripheral-blood mononuclear cells, indicating that other mechanisms such as immune modulation may contribute to the antiproliferative actions of vesnarinone.11-13 The induction of cellular differentiation and apoptosis by vesnarinone has been associated with impressive antitumor activity against a broad spectrum of human solid tumor and hematopoietic cancer cell lines.8,9,14,15 In a preliminary screening of 64 human tumor cell lines treated with vesnarinone concentrations ranging from 5 to 60 µg/mL for 7 days, prominent growth-inhibitory effects were noted in 32 cell lines, of which 12 were inhibited more than 50% at the highest concentration of 60 µg/mL. The tumor cell lines showing the greatest degree of sensitivity included lymphoid, lung, brain, melanoma, ovarian, renal, prostate, breast, and squamous cell carcinoma.16 In addition, pancreatic cancer cell lines demonstrated dose-dependent growth inhibition in the presence of vesnarinone, with 50% inhibitory concentration values of 21.0, 18.0, and 10.0 µg/mL for PANC-1, MIAPaCa-2, and BxPC-3, respectively.15 Treatment of HSG-AZA3 salivary carcinoma cells with vesnarinone at concentrations of 3 and 30 µg/mL for 8 days resulted in inhibition rates of 65.9% and 92.7%, respectively.3 The combination of vesnarinone and gemcitabine was also studied in the MIAPaCa-2 cell line using a clonogenic assay in which tumor cells were treated with gemcitabine for 1 hour, washed, and subsequently incubated with vesnarinone for 7 days. The interactions between vesnarinone and gemcitabine were additive or synergistic (report on file, Otsuka America Pharmaceutical Inc). In support of this, [3H]thymidine incorporation was inhibited by vesnarinone (35%, 60%, and 95% at 10, 30, and 100 µg/mL, respectively) in peripheral-blood mononuclear cells, suggesting that the potentiation of antitumor effects by vesnarinone and gemcitabine may be due in part to dual effects on ribonucleotide pools.17 The antiproliferative effects of vesnarinone have also been demonstrated in human tumor xenografts (lung, colorectal, salivary gland, melanoma, and pancreas). The effects of oral vesnarinone were assessed in the BxPC-3 and Spa-1 human pancreatic cancer xenograft models at doses of 5 and 50 mg/kg/d for 21 days. Tumor growth inhibition against BxPC-3 for the 5 and 50 mg/kg levels were 36% and 42%, respectively; tumor growth inhibition against Spa-1 for the 5 and 50 mg/kg levels were 8% and 29%, respectively.15 Xenograft studies performed with the TYS cell line with administration of 200 mg/kg of vesnarinone orally for 35 days resulted in 50% tumor growth inhibition, with histopathologic features of terminal differentiation and apoptosis.8,18 Clinical studies of vesnarinone in patients with heart disease, cancer, or human immunodeficiency virus infection have suggested a tolerable toxicity profile. Adverse events, including leucopenia, skin rash, thyroid function abnormalities, increased liver enzymes, and prolongation of the corrected QT interval, have generally been infrequent and modest in severity. In United States clinical trials of vesnarinone, 0.3% of cases of nonfatal torsades de pointes were observed, which resolved on withdrawal of vesnarinone.3 In a phase I study of vesnarinone in advanced cancer patients at doses ranging from 60 to 240 mg daily, no instances of either hematologic or nonhematologic toxicity occurred, and in clinical trials in patients with cardiac disease, the incidence of reversible neutropenia ranged from 0.2% to 2.5%.3-5 Pharmacologic studies of vesnarinone have revealed dose-independent elimination and dose-proportional pharmacokinetics in the dosing range of 7.5 to 240 mg. The mean half-life was 44.7 ± 1.2 hours, and clearance averaged 4.49 ± 0.28 mL/h/kg.19 Studies on the effects of inhibition of the CYP3A hepatic isoenzyme by erythromycin after vesnarinone administration revealed a 1.5-fold increase in the area under the concentration-time curve (AUC) of vesnarinone along with a decrease in clearance, suggesting involvement of this isoenzyme in vesnarinone metabolism.20 The rationale supporting the current study was based on the novel mechanism of action of vesnarinone, the demonstration of in vitro synergy when combined with gemcitabine, and the nonoverlapping toxicities of both compounds. The major objectives of this phase I and pharmacologic study were to (1) characterize the principal toxicities of vesnarinone administered once orally daily with standard doses of intravenous (IV) gemcitabine (1,000 mg/m2 on days 1, 8, and 15 every 4 weeks) in patients with advanced solid tumors, (2) determine the maximum-tolerated dose (MTD) of vesnarinone in combination with gemcitabine on this schedule, (3) describe the pharmacokinetic and pharmacodynamic behavior and the presence of any interactions between vesnarinone and gemcitabine, and (4) seek preliminary evidence of antitumor activity in patients with advanced cancers.
Eligibility Patients with histologically confirmed solid malignancies, in whom no effective therapy existed, were candidates for this study. Eligibility criteria also included (1) age of 18 years or older; (2) Eastern Cooperative Oncology Group performance status of 2 or less (ambulatory and capable of self-care); (3) a minimum life expectancy of 12 weeks; (4) no major surgery or treatment with chemotherapy within 21 days (42 days for mitomycin or nitrosoureas); (5) measurable or nonmeasurable but assessable disease; (6) adequate hematopoietic (WBC count of  3,000/µL, absolute neutrophil count [ANC] of 1,500/µL, platelet count of 100,000/µL, and hemoglobin 9.0 g/dL), hepatic (total bilirubin less than 1.6 mg/dL; AST and ALT levels < two times the upper limit of normal, unless the elevation was caused by hepatic metastases, in which case elevations of five times the upper normal limits were permitted), and renal (serum creatinine level of < 2.0 mg/dL) functions; (7) no severe gastrointestinal disturbance that could preclude oral administration or gastrointestinal absorption; (8) no active neoplastic involvement of the CNS; (9) discontinuation of hematopoietic growth factors at least 3 weeks before study entry; (10) no concomitant use of drugs capable of inhibiting or inducing hepatic cytochrome p450 enzyme (CYP3A and CYP 2E1) metabolism within 2 weeks of study entry; (11) no prior treatment with doxorubicin or daunorubicin at cumulative doses exceeding 350 mg/m2 or mitoxantrone exceeding 140 mg/m2 unless left ventricular ejection fraction 40%; (12) QTc interval less than 450 ms on pretreatment ECG; (13) no clinically significant atrial or ventricular arrhythmia; and (14) no coexisting cardiac or medical problems of sufficient severity to limit compliance with the study. All patients gave informed written consent before treatment. Initially, patients were treated without stratification according to the extent of prior therapy; however, consistent hematologic toxicity in heavily pretreated patients led to the consideration of treatment on the basis of prior myelotoxic therapy. Patients were considered heavily pretreated with myelotoxic therapy if they had previously received more than six courses of an alkylating agent as combination therapy, more than two courses of carboplatin or mitomycin, irradiation to more than 25% of bone marrow–bearing areas, any prior nitrosoureas, high-dose therapy requiring hematopoietic stem cells, and/or had widespread metastases to bone.
Dosage and Dose Escalation
Dose-Intensity
Drug Administration
Pretreatment and Follow-Up Studies
Plasma Sampling and Assay Vesnarinone and the internal standard (OPC-8192) were extracted from plasma using a liquid-liquid extraction. The extract was analyzed by reverse-phase high-performance liquid chromatography (HPLC) using a Spherisorb ODS-2 column (Waters Corporation, Milford, MA; 4.6 mm x 150 mm, 5-µm particle size) and an isocratic elution. The eluent was monitored using an ultraviolet absorbance detector set at 265 nm. The mobile phase consisted of 24% acetonitrile in a 50-mmol/L phosphate buffer (pH 2.2) solution. This method was modified form the original HPLC method to enhance sensitivity.21 The lower limit of quantitation was established as 0.20 µg/mL for 0.25 mL of plasma sample. Linearity was established in the range of 0.20 to 12.0 µg/mL. To determine possible interference with the vesnarinone assay by gemcitabine and its metabolite, dFdU, both compounds were injected into the system and neither agent was eluted or detected. Gemcitabine, dFdU, and two internal standards, 5-fluorouridine and 5-fluoro-5-deoxyuridine, were extracted from plasma using a liquid-liquid extraction procedure. The extract was analyzed by reverse-phase HPLC using a Cosmosil C-18 column (Nacalai Tesque, Japan, distributed in the United States by P.J. Cobert Associates, Inc, St. Louis, MO; 4.6 mm x 150 mm, 5-µm particle size) and a Beckman Ultrasphere ODS column (St. Louis, MI; 4.6 mm x 150 mm, 5-µm particle size) in tandem and a 40-minute gradient nonisocratic elution. The eluent was monitored using an ultraviolet absorbance detector set at 272 nm. The mobile phase for analyzing the samples consisted of solution A (1% acetonitrile and 3% methanol in a 50 mmol/L phosphate buffer [pH 2.9] solution) and solution B (acetonitrile and 50 mmol/L phosphate buffer [pH 2.9] 1/1 volume-to-volume ratio). The lower limit of quantitation was established as 40 ng/mL for 0.50 mL of plasma sample. Linearity was established in the range of 40 to 2,000 ng/mL. Specificity of this analytic method was established by the absence of interference peaks at the expected retention times of gemcitabine, dFdU, and the internal standards. Vesnarinone, OPC-8230, OPC-18136, and OPC-18137 were injected into the system and none of the four analytes showed peaks interfering with gemcitabine, dFdU, or the internal standards. The interday/intraday coefficients of variation for gemcitabine, dFdU, and vesnarinone were 0.2% to 9.1%/2.8% to 6.9%, 0% to 15.6%/11%, and 0% to 14.6%/4.2% to 9.3%, respectively.
Pharmacokinetic and Pharmacodynamic Analysis The mean plasma gemcitabine and metabolite (dFdU) EOI concentrations were calculated as the arithmetic means of the plasma EOI concentration values obtained for the first 8 weeks of treatment. The pharmacokinetic data were described using descriptive statistics. The Jonckheere-Terpstra test was used to determine whether vesnarinone pharmacokinetics were dose-independent.
The relationships between toxicity and pharmacokinetic parameters reflecting systemic exposure to vesnarinone and gemcitabine were explored. The percentage decrements in the ANC and platelet counts were related to the dose and mean Cmin of vesnarinone and to the EOI gemcitabine concentrations. The percentage decrement in the blood cell counts was calculated as follows:
Both simple and sigmoidal maximum effect models of drug effect were fit to these relationships using the nonlinear least-squares regression program, WinNonlin (Statistical Consultants, Inc., Apex, NC). Linear and nonlinear regression methods were used to assess the relationships between quantitative parameters of myelosuppression and relevant parameters of drug exposure. Statistical analysis was performed using Proc StatXact (Version 4.0, Cytel Software Corp, Cambridge, MA).
Twenty-six patients were accrued between November 1996 and August 1998 and received 92 total courses of treatment. The patient characteristics are listed in Table 1. Twenty-two of the 26 patients previously received chemotherapy, radiotherapy, or both. Eleven and 15 patients were classified as minimally or heavily pretreated, respectively, according to the criteria described previously. The total numbers of new patients treated at each dose level, number of fully assessable courses, and the dose-escalation scheme for vesnarinone, as well as the rates of DLTs as a function of dose level, are listed in Table 2.
The initial dose level of 60 mg vesnarinone was not associated with the occurrence of DLT during the first course of therapy in patients irrespective of the extent of prior treatment. Dose escalation of vesnarinone to the next level of 120 mg in heavily and minimally pretreated patients resulted in one DLT that consisted of prolonged (> 5 days) grade 4 neutropenia and concomitant grade 3 thrombocytopenia in a heavily pretreated patient. Brief grade 4 neutropenia was also observed in another heavily pretreated patient during a first course at the 120-mg dose level. Because hematologic toxicity was observed only in patients with heavy prior therapy at the 120-mg dose level as well as the requirement for gemcitabine dose reductions and omissions in the same patient population, a decision was made to stratify patients according to the extent of their prior myelotoxic therapy. A lower dose level of 90 mg was explored in heavily pretreated patients, and further dose escalations greater than 120 mg required stratification according to prior therapy. At the 90-mg dose level of vesnarinone, two hematologic DLTs consisting of prolonged (> 5 days) grade 3 thrombocytopenia were observed among eight patients. There were no DLTs at the higher dose levels of 150 and 180 mg vesnarinone, which consisted of only minimally pretreated patients. Although a formal MTD was not defined for minimally pretreated patients, the MTD and recommended phase II dose for heavily pretreated patients was vesnarinone 90 mg with gemcitabine 1,000 mg/m2.
Hematologic Toxicity
The first dose level of 60 mg of vesnarinone was not associated with the occurrence of any DLT; however, grade 3 neutropenia was observed in two of 15 courses (heavily pretreated, one course; minimally pretreated, one course), whereas grade 4 neutropenia was observed in three of 15 courses. All episodes of grade 4 neutropenia occurred in heavily pretreated patients and were brief (< 5 days), with the exception of one episode that occurred in association with fever requiring hospitalization for parenteral antibiotics during course 2. There were no instances of either grade 3 or 4 thrombocytopenia at the 60-mg dose level. The dose of vesnarinone was escalated to 120 mg daily in the next cohort of patients and one DLT was observed at this dose level. All occurrences of significant hematologic toxicities at the 120-mg dose level of vesnarinone were in heavily pretreated patients, with brief (< 5 days) grade 4 neutropenia in one (4%) of 28 courses, and dose-limiting grade 4 neutropenia (> 5 days) accompanied by grade 3 thrombocytopenia in one (4%) of 28 courses. At the 90-mg dose level, consisting only of heavily pretreated patients, there were no occurrences of dose-limiting neutropenia; however, there were two episodes of dose-limiting thrombocytopenia. Five (18%) of 28 courses were associated with grade 3 neutropenia, whereas three (11%) of 28 courses were associated with grade 4 neutropenia (< 5 days). Neutropenia and thrombocytopenia occurred independently, with the exception of one course at the 90-mg level, where grade 3 neutropenia occurred concomitantly with grade 3 thrombocytopenia. Although six (21%) of 28 courses were complicated by either grade 3 or 4 thrombocytopenia, five of the episodes occurred in a single patient who also experienced dose-limiting grade 3 thrombocytopenia (< 50,000/µL for > 5 days).
At the 150- and 180-mg dose levels of vesnarinone, consisting only of minimally pretreated patients, no significant grade 3 or 4 hematologic toxicity was observed in eight and three courses, respectively. Anemia resulting in
Nonhematologic Toxicity
Dose-Intensity of Gemcitabine
Antitumor Activity A partial response occurred in a patient with metastatic breast carcinoma involving lymph nodes, bone, and liver who had received two prior chemotherapy regimens (doxorubicin/cyclophosphamide, docetaxel/fluorouracil) in addition to high-dose chemotherapy and autologous stem-cell rescue and hormonal therapy (tamoxifen). This patient achieved complete resolution of her visceral and nodal metastases accompanied by a decreased intensity of radioisotope uptake in metastatic lesions on bone scan after two courses of vesnarinone and gemcitabine. The partial response lasted 4 months. Another partial response of 5 months’ duration was experienced by a patient with metastatic non–small-cell lung carcinoma involving brain and lymph nodes. This patient had received three prior chemotherapy regimens consisting of etoposide/carboplatin, single-agent vinorelbine, and single-agent docetaxel as well as whole-brain radiation. A 74% reduction in extent of nodal disease was recorded after two courses of treatment with vesnarinone and gemcitabine. Stable disease lasting from 2 to 8 months was observed in 11 patients with a variety of other solid tumors.
Pharmacokinetic Studies
To determine whether there was a linear relationship between mean vesnarinone Cmin and dose, the Jonckheere-Terpstra test using Proc StatXact Version 4.0 was used. Paired t tests were performed to determine whether there was any effect of gemcitabine on vesnarinone plasma concentrations. When examining only those patients who received a gemcitabine dose of 1,000 mg/m2, the plasma vesnarinone concentration increased linearly with vesnarinone doses less than 150 mg, with a P value approaching statistical significance (r2 = 0.1; P = .08). When examining all doses of gemcitabine, however, there was a statistically significant linear relationship between mean vesnarinone Cmin and doses less than 150 mg (r2 = 0.19; P = .01), as seen in Fig 2. Graphically, it can be seen that there was plateauing of concentrations at doses greater than 120 mg; however, there were insufficient data at the higher dose levels to make definitive conclusions. There were no significant differences in vesnarinone plasma levels with time, as shown in Fig 3. A paired t test comparison of vesnarinone Cmin between week 3 (gemcitabine present) and week 4 (gemcitabine absent) did not show a significant difference (P = .48). Similarly, paired t test comparisons of vesnarinone Cmin between week 7 and week 8 (with and without gemcitabine, respectively) revealed a P value of .56, confirming the absence of any effect of gemcitabine on vesnarinone plasma concentrations. Mean EOI gemcitabine and dFdU plasma concentrations for all dose levels of vesnarinone are represented in Figs 4 and 5, respectively. There was no significant difference in gemcitabine and dFdU levels between week 1, when vesnarinone plasma levels had not achieved steady-state, and the subsequent weeks. Mean EOI gemcitabine levels ranged between 1.97 and 28.96 µg/mL, whereas mean EOI dFdU levels ranged between 0.51 and 49.54 µg/mL.
Pharmacodynamic Studies Twenty-four patients were assessable for pharmacodynamic studies. The relationships between mean vesnarinone mean Cmin and the percentage decrement in either ANC or platelet count were not well described by either simple (r2 = 0.16 and 0.01, respectively) or sigmoidal (r2 = 0.18 and 0.02, respectively) maximum effect models or by linear (r2 = 0.24 and 0.003, respectively) models, as illustrated in Fig 6A and 6B. Similar results were observed between gemcitabine EOI values and percentage decrement in ANC and platelet counts.
Vesnarinone, a quinolinone derivative with antiproliferative, prodifferentiating, and proapoptotic properties, was selected for development as an anticancer agent given its broad spectrum of antitumor activities in preclinical models. The combination of this novel cytostatic agent with gemcitabine was attractive because of the broad and overlapping spectra of antitumor activities of both agents, the potential for synergy arising from the dual effects on ribonucleotide pools, the demonstration of in vitro synergy in studies of human pancreatic cell lines, and the prospects for nonoverlapping toxicities3,17 (report on file, Otsuka America Pharmaceutical Inc). This phase I and pharmacologic study was designed to evaluate the feasibility of administering oral vesnarinone continuously once daily in combination with IV gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks. This schedule was projected to result in exposure to biologically relevant concentrations of vesnarinone and to stimulate optimal conditions for synergy. Neutropenia and thrombocytopenia were the principal DLTs observed with the combination of vesnarinone and gemcitabine. Among five heavily pretreated patients at the 120-mg dose level of vesnarinone, there was one hematologic DLT in addition to substantial dose reductions and omissions of gemcitabine, thus prompting the exploration of the 90-mg/d dose of vesnarinone. The 90-mg/d dose level, although associated with the occurrence of hematologic DLT in two (25%) of eight patients, resulted in hematologic DLT in only two (7%) of 28 courses and is thus the recommended phase II dose in patients who have received heavy prior myelotoxic therapy. Among minimally pretreated patients, the doses of 150 and 180 mg/d of vesnarinone were well tolerated without hematologic DLT; however, consideration of the emerging safety data from vesnarinone cardiac trials as well as the preliminary pharmacokinetic data from this study resulted in the decision to complete this trial without further dose escalation. Although the MTD was not defined for minimally pretreated patients, a dose of 90 mg vesnarinone with 1,000 mg/m2 of gemcitabine may be recommended for subsequent disease-oriented studies of this combination in patients with minimal prior therapy. It is also possible that a dose of 120 mg of vesnarinone in minimally pretreated patients may be recommended for future phase II studies. This recommendation is based on the demonstration of biologically relevant plasma concentrations of vesnarinone at the 120-mg dose level and the lack of dose-limiting side effects as well as plateauing in the mean vesnarinone Cmin at doses greater than 120 mg.
The decision to not pursue doses of vesnarinone greater than 120 mg/d was partly justified by the results of studies of vesnarinone in patients with congestive heart failure.4,5 These studies raised the possibility of QTc prolongation and arrhythmogenic complications in patients with underlying left ventricular dysfunction receiving chronic oral therapy with vesnarinone at dosages In the present study, dose limiting myelosuppression was observed exclusively in patients with extensive prior therapy. Grades 3 and 4 neutropenia were each experienced by 23% of patients, whereas the combined incidence of grade 3 and 4 thrombocytopenia was 15%. Although dose reductions of vesnarinone occurred because of a priori definitions of DLT, the observed hematologic toxicity in this population is consistent with that reported in prior studies of gemcitabine in previously treated patients.22,23 In a single-agent phase II study of gemcitabine for patients with advanced metastatic breast cancer, 17 of 18 patients were receiving gemcitabine as either second- or third-line treatment. In this study, grade 3 and 4 neutropenia was experienced by 25% and 20% of patients, respectively.22 In another phase II study of gemcitabine in metastatic breast cancer in which 26 of 40 patients had received one prior line of chemotherapy, the incidences of grades 3 and 4 neutropenia were 25% and 7.5%, respectively.23 Comparison with the literature thus suggests that the addition of vesnarinone to gemcitabine does not modify the myelosuppressive toxicity profile but instead recapitulates the hematologic toxicities observed with gemcitabine administered as a single agent (used in a 4-week schedule) in previously treated patients. The mean dose-intensity of gemcitabine for all cycles was 593 mg/m2/wk (79%), ranging from 500 mg/m2 (67%) to 719 mg/m2 (96%). At the recommended phase II dose of 90 mg of vesnarinone, the gemcitabine dose-intensity was 505 mg/m2/wk (67%) in heavily pretreated patients, whereas the gemcitabine dose-intensity was 660 mg/m2/wk (88%) in minimally pretreated patients at the 120-mg vesnarinone dose. The dose-intensity observed with this regimen approaches that reported in other studies of gemcitabine administered in a 4-week schedule in combination with cytotoxic agents.24,25 In earlier phase I/II studies of gemcitabine and cisplatin in advanced non–small-cell lung cancer, the dose-intensity of gemcitabine ranged from 710 to 715 mg/m2/wk (95%); however, these studies consisted of only chemotherapy-naïve patients.26,27 In two single-agent phase II studies of gemcitabine for patients with advanced metastatic breast cancer who had received prior therapy, the dose-intensity ranged from 577 mg/m2/wk (77%) to 725 mg/m2/wk (97%).22,23 The greater tolerability of gemcitabine in patients with minimal prior therapy has been well documented in the literature, and our findings are consistent with this.26-28 Increasing doses of vesnarinone had minimal impact on gemcitabine dose-intensity in our study, whereas prior treatment status was a strong determinant of gemcitabine tolerability. In the present study, there was no evidence of pharmacologic interaction between vesnarinone and gemcitabine. Mean vesnarinone Cmin did not differ significantly between weeks when gemcitabine was present or absent. Similarly, gemcitabine and dFdU plasma EOI concentrations did not vary significantly between week 1 and subsequent weeks. Although the plasma EOI concentrations of gemcitabine obtained in this study are similar to those of some reports in the literature, it is difficult to make any direct comparisons because of the variability in plasma levels of agents that undergo intracellular metabolism.29 Vesnarinone Cmin values displayed significant interpatient variability and were dose-proportional only between 60 and 120 mg/d, in contrast with data from healthy volunteers, where single and repeated (once-daily) administration of vesnarinone at doses ranging from 7.5 to 240 mg resulted in dose-proportional parameters of exposure.19 The inability to detect a definitive linear relationship between vesnarinone Cmin values and dose may have been due to several mechanisms, including the limited numbers of patients at doses greater than 120 mg/d, saturation of absorption, induction of metabolism, and increased elimination. In this trial, concomitant use of drugs metabolized by CYP3A and CYP2E1 enzymes was limited, thus reducing the likelihood that alterations in hepatic metabolism contributed to the pharmacokinetic findings. Vesnarinone is a unique antiproliferative agent that seems to exert antitumor effects through the processes of differentiation and apoptosis. Such agents may potentiate the effects of cytotoxic chemotherapy, and the results of this study demonstrate that the combination of vesnarinone with gemcitabine is tolerable in patients with minimal and extensive prior therapy. Moreover, two partial responses were observed in patients with chemotherapy-refractory malignancies. Thus the current study lends support to the feasibility of combining vesnarinone with gemcitabine and raises the possibility that there may be greater antitumor activity than observed with gemcitabine alone. These results suggest that it may be worthwhile to pursue further disease-directed evaluations of the combination of vesnarinone and gemcitabine, perhaps as second- or third-line therapy in patients with metastatic breast or non–small-cell lung cancer. The diverse spectrum of cellular targets of vesnarinone suggest a complex but intriguing potential for synergistic interaction with traditional cytotoxic agents or with other novel, selective and targeted therapies, and the agent should continue to be investigated and incorporated into such novel regimens.
Some patients were treated at the Frederic C. Barter Clinical Research Unit of the Audie Murphy Veterans Administration Hospital, San Antonio, TX, supported in part by grant no. MO1 RR01346 from the National Institutes of Health, Bethesda, MD. Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.
1. Asanoi H, Sasayama S, Kiuchi K, et al: Acute hemodynamic effects of a new inotropic agent (OPC-8212) in patients with congestive heart failure. J Am Coll Cardio 9: 865-871, 1987[Abstract] 2. Kawamata H, Nakashiro K, Uchida D, et al: Induction of TSC-22 by treatment with a new anti-cancer drug, vesnarinone, in human salivary gland cancer cell. Br J Cancer 77: 71-78, 1998[Medline] 3. Otsuka America Pharmaceutical, Inc: Clinical Investigator’s Brochure. Palo Alto, CA, Otsuka America Pharmaceutical, Inc, 1993
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Cohn JN, Goldstein SO, Greenberg BH, et al: A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. N Engl J Med 339: 1810-1816, 1998 6. Sato M, Harada K, Yoshida H: Induction of differentiation and apoptosis, and Ley antigen expression by treatment with vesnarinone in a human salivary cancer cell line. Acta Histochem Cytochem 27: 591-599, 1994 7. Yokozaki H, Ito R, Ono S, et al: Effect of 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinolinone (vesnarinone) on the growth of gastric cancer cell lines. Cancer Lett 140: 121-128, 1999[Medline] 8. Sato M, Harada K, Bando T, et al: Characteristics of antitumor activity of vesnarinone against a human adenoid squamous carcinoma-forming cell line grown in athymic nude mice. Cancer Lett 91: 1-9, 1995[Medline] 9. Nakai S, Kawai K, Aihara K, et al: Vesnarinone as anti-tumor agent with differentiation or apoptosis inducing activity in human cancer xenografts in nude mice. Proc Am Assoc Cancer Res 35: A2407, 1994 (abstr) 10. Sato M, Kawamata H, Harada K, et al: Induction of cyclin-dependent kinase inhibitor, p21WAF1, by treatment with 3,4-dihydro-6-[4-(3,4)-dimethoxymenzoyl-1-peperazinyl]-2(1H)-quinolone (vesnarinone) in a human salivary cancer cell line with mutant p53 gene. Cancer Lett 112: 181-189, 1997[Medline]
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INTRODUCTION
