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© 2002 American Society for Clinical Oncology Safety and Pharmacokinetic Effects of TNP-470, an Angiogenesis Inhibitor, Combined With Paclitaxel in Patients With Solid Tumors: Evidence for Activity in Non–Small-Cell Lung CancerByFrom the Departments of Thoracic/Head and Neck Medical Oncology, Pharmaceutical Sciences, Clinical Neuro-Oncology, Laboratory Medicine, and Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, and TAP Pharmaceutical Products, Inc, Lake Forest, IL. Address reprint requests to Roy S. Herbst, MD, PhD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 432, Houston, TX 77030; email: rherbst{at}mdanderson.org
PURPOSE: Preclinical studies suggested that the antiangiogenic agent TNP-470 was synergistic with cytotoxic therapy. TNP-470 was administered with paclitaxel to adults with solid tumors to define the safety and optimal dose of the combination regimen and to assess pharmacokinetic interactions. PATIENTS AND METHODS: Thirty-two patients were enrolled chronologically onto one of two treatment arms. Arm A involved a fixed TNP-470 dose with escalating doses of paclitaxel, and Arm B involved a fixed paclitaxel dose with escalating doses of TNP-470. Paclitaxel and TNP-470 pharmacokinetics were evaluated along with toxicity. RESULTS: The combination of TNP-470 administered at 60 mg/m2 three times per week and paclitaxel 225 mg/m2 administered over 3 hours every 3 weeks was defined as both the maximum-tolerated dose and the optimal dose. Myelosuppression was similar to that expected with paclitaxel alone. Mild to moderate neurocognitive impairment was observed; however, the majority of changes were subclinical and reversible as determined by prestudy and poststudy neuropsychiatric test results. A clinically insignificant decrease of paclitaxel clearance was observed for the combination. Median survival for all patients was 14.1 months. Partial responses were reported in eight (25%) of 32 patients and in six (38%) of 16 patients with NSCLC, 60% of whom had received prior chemotherapy. CONCLUSION: The combination of TNP-470 and paclitaxel, each at full single-agent dose, seems well tolerated, with minimal pharmacokinetic interaction between the two agents. Further studies of TNP-470 with chemotherapy regimens are warranted in NSCLC and other solid tumors.
THE TREATMENT of many advanced solid tumors is palliative, and despite improvements in cytotoxic chemotherapy, most patients will die of metastatic disease.1 One approach to further benefit these patients has been the identification of new and specific molecular targeted therapeutic agents.2 The microvascular endothelial cell has been shown to play a critical role in the growth, invasion, and metastasis of most tumors. The development of these cells into blood vessels, known as angiogenesis, is a critical process for human solid tumors3-6 and often is prognostic regarding the degree of metastatic spread.7-9 TNP-470, a synthetic analog of fumagillin, is an angiogenesis inhibitor that blocks the growth of new blood vessels by inhibiting methionine aminopeptidase, an enzyme critically important for endothelial cell proliferation.10,11 Studied extensively, both homograft and xenograft tumor growth slows significantly in animals treated with TNP-470 alone.12,13 While delay of tumor growth often led to improved survival time in animals, shrinkage of existing tumors was not observed.12,13 In animal studies, however, combinations of TNP-470 with paclitaxel, alone or with other agents, has led to tumor regression, prolonged disease response, slowed tumor growth, and improved survival time.12-18 In fact, combinations with cyclophosphamide in the mouse Lewis lung model produced long-term cures (> 2 years) in one published report.16 This phase I study evaluated the safety of combining TNP-470 with therapeutically effective doses of paclitaxel.15 Although the synergistic effects of tumor shrinkage and delayed regrowth are desirable, additive or synergistic toxic effects could limit the use of this combination. However, animal studies with TNP-470 and paclitaxel did not raise particular concerns of synergistic toxicity, and this was not a major concern in trial design. Additionally, it was of concern that pharmacokinetic interactions could alter the dosing or toxicity of either drug, as paclitaxel has been suggested to decrease epoxide hydrolase activity, and TNP-470 activity is dependent on this enzyme for its metabolism (Fig 1).19 Two TNP-470 metabolites (M-IV and M-II) have been shown to be active and to possess antiendothelial activity.10 An antiangiogenic agent could also, hypothetically, alter tumor distribution of chemotherapy, since increased tumor levels of cytotoxic drugs were found in animal studies in which antiangiogenic therapy actually produced an early increase in tissue blood flow and oxygen levels.15,16,20 In fact, this counterintuitive result could partially explain the synergy produced by TNP-470 and other antiangiogenic agents with chemotherapy. It is for this reason that a phase I design was implemented.
Paclitaxel doses of 135 mg/m2 to 225 mg/m2 were chosen because they were considered therapeutically active in most solid tumors.21-23 TNP-470, at doses of 20 mg/m2 to 60 mg/m2, demonstrates a dose-response toxic effect with a maximum-tolerated dose (MTD) of 60 mg/m2 given intravenously three times per week.24 The main reported toxic effect in these trials (at doses well above the MTD) was cerebellar and neuropsychologic neurotoxicity.25-27 To address this concern, all patients in our study had neuropsychologic evaluations before the study and after two cycles (6 weeks) of treatment. Finally, although TNP-470 does not directly inhibit the basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) receptors, it does inhibit bFGF-induced angiogenesis.28,29 It has been postulated that serum levels of bFGF and VEGF can serve as surrogate markers of angiogenesis, which clearly would be helpful in future studies. These values were observed during the course of this clinical study.
Patient Eligibility All patients had histologically confirmed, incurable, advanced solid tumors and had received no more than one prior chemotherapy regimen. They were required to have at least one measurable, unirradiated tumor site. Patients were required to give signed informed consent according to federal and institutional guidelines before entering the study. Table 1 lists patient characteristics in detail.
Patients were at least 18 years old, and all had an Eastern Cooperative Oncology Group performance status of  1, a life expectancy of more than 16 weeks, and no radiation therapy within 3 weeks of enrollment. Adequate hepatic, renal, and bone marrow function was required, with a WBC count of more than 3,000/µL, an absolute neutrophil count (ANC) of more than 1,500/µL, a platelet count of more than 100,000/µL, a hemoglobin value of more than 10 g/dL, serum creatinine values of less than 1.5 mg/dL, a total bilirubin level of less than two times the upper limit of normal, and ALT levels of less than 1.5 times the upper limit of normal.
Treatment Protocol
MTD Determination MTD was defined as the highest dose level at which fewer than two of three to six patients experience a dose-limiting toxicity (DLT). DLT was defined as a grade 3 or 4 nonhematologic toxicity or grade 4 hematologic toxicity (ANC < 500/mm3, platelet count < 20,000/mm3 for 7 days in duration or associated with bleeding).
Clinical Tests and Safety Evaluations The tumor type dictated which imaging modality was appropriate to determine the location, size, and type of lesions: chest radiography, computed tomography, magnetic resonance imaging, or bone scan. Imaging studies were repeated during treatment after every two cycles of therapy to assess disease response.
Tumors were measured in two dimensions, and the products of the measurements were recorded. Response was defined as a
Pharmacokinetic Analyses Blood samples (7 mL) for the determination of plasma concentrations of paclitaxel were drawn via venipuncture into heparinized tubes before dosing (0 hour) and at 1, 3, 5, 8, 12, 24, and 48 hours after the start of the 3-hour paclitaxel infusion. All plasma samples were transferred into appropriately labeled vials and stored frozen (-60°C to -80°C) until analysis. Concentrations of paclitaxel in plasma were analyzed at The University of Texas M.D. Anderson Cancer Center, Houston, TX, using a validated high-performance liquid chromatography method with ultraviolet detection with a lower limit of quantitation for the paclitaxel of 0.025 µg/mL. Pharmacokinetic parameters for paclitaxel were estimated using standard noncompartmental methods (WinNonlin Version 3.1).
Analyses of Serum Cytokine Levels
Epoxide hydrolase activity.
Statistical Methods
Demographics Thirty-two patients were enrolled onto the study between July 1998 and March 1999. Table 1 lists patient demographic details. The median age was 56.5 years (range, 34 to 75 years). Of this group, 22 patients (69%) had received prior chemotherapy. Tumor types included non–small-cell lung cancer (NSCLC) (16 patients, 50%), head and neck cancer (five patients, 16%), bladder cancer (four patients, 13%), kidney cancer (two patients, 7%), and cervix, uterus, breast, and sarcoma cancers (one each, 3%). The median performance status was Eastern Cooperative Oncology Group 1 (range, 0 to 1).
Safety and Tolerability
Nonhematologic adverse events (Table 4) were also generally mild to moderate in severity. Insomnia at the highest dose level of TNP-470 (60 mg/m2) occurred early in treatment and was managed with medication. Abnormal or blurred vision did occur slightly more frequently with higher doses of TNP-470 and with higher doses of the treatment combination, though this was mostly a grade 1 toxicity and no correction was needed. However, the changes in vision were transient, with no long-term effects observed. Neurologic events such as dizziness, ataxia, insomnia, tremor, and confusion have been identified as dose limiting in previous uncontrolled studies using TNP-470 as a single agent. In this study, neurologic events, including abnormal gait, peripheral neuropathy, dizziness, emotional liability, speech disorder, blurry or abnormal vision (transient difficulty in focusing, changes in vision, and changes in perception to light), and abnormal cognitive function, were generally mild to moderate in severity (grade 1) and were reversible when doses were reduced or the study treatment was stopped. No retinal hemorrhaging was seen.
Neuropsychologic assessment to monitor cognitive and motor function was performed before treatment and at the end of cycle 2. Of the patients enrolled onto the study, four patients were not seen for follow-up care or died before treatment could take place. The results of the neuropsychologic assessments are shown in Table 5. Attention, graphomotor speed, memory, language, visual-motor scanning speed, and quality of life did not change significantly during treatment. However, significant declines were observed in fine motor dexterity and frontal lobe executive function. The effects on motor dexterity were substantial, with mean scores falling to the moderately impaired range at follow-up. The contribution of TNP-470, if any, to this decline could not be determined in this study as motor dysfunction is a known side effect of paclitaxel treatment. Mean declines within the sample were heavily influenced by the performance of eight patients (30%) who experienced more severe deficits than observed in the overall study population. The most salient neurocognitive declines were seen in executive function, memory, and motor dexterity. There were no apparent risk factors for the development of neurocognitive decline that we could determine, and when present, these symptoms occurred within 1 to 2 weeks. Of these eight subjects, six underwent posttreatment assessments. Half of these patients recovered to their baseline level of performance, while three did not improve after treatment ended. The three patients whose performance did not return to their pretreatment baseline level of cognitive performance received high-dose TNP-470 as part of their treatment regimen (60 mg/m2). None of these patients received prior cranial irradiation. In general, this treatment regimen seemed only slightly more neurotoxic than current standard paclitaxel therapy alone (Meyers et al, manuscript in preparation).
Pharmacokinetic Study Results TNP-470 pharmacokinetics. Mean pharmacokinetic parameters were determined for TNP-470, M-IV, and M-II after a 60-mg/m2 intravenous dose of TNP-470 was administered alone or in combination with a 225-mg/m2 intravenous dose of paclitaxel (Table 6).
Overall, TNP-470 steady-state plasma concentrations were rapidly established, as indicated by fairly constant plasma concentrations during the 1-hour infusion. Although assessment of dose proportionality was hindered because of the limited number of patients at dose levels other than the MTD regimen, dose-normalized maximum concentration (Cmax) and area under the plasma concentration time curve (AUCt) in the presence or absence of paclitaxel suggested the pharmacokinetic effects of TNP-470 were independent of dose size. The combination of TNP-470 with paclitaxel resulted in an approximately 13% decrease in dose-normalized Cmax and a 25% decrease in dose-normalized AUCt values for TNP-470 compared with those values obtained after the administration of TNP-470 alone. Whereas increases in the dose-normalized Cmax and AUCt were observed for M-IV after the administration of paclitaxel, minor decreases in the dose-normalized Cmax and AUCt were noted for M-II. Since this was not a randomized study, and subjects received study medications alone or in combination sequentially, separation of treatment effects, period effects, or both during the analysis of data was not possible. In addition, previous clinical studies have demonstrated that the pharmacokinetics of TNP-470 are generally highly variable. Therefore, it is likely that changes observed in the pharmacokinetic effects of TNP-470 when it was administered with paclitaxel were not exclusively due to the treatment combination. Paclitaxel pharmacokinetics. Mean pharmacokinetic parameters were determined for paclitaxel after a 225-mg/m2 intravenous dose of paclitaxel was administered alone or in combination with a 60-mg/m2 intravenous dose of TNP-470 (Table 6). Following the combination of paclitaxel with TNP-470, the systemic clearance of paclitaxel decreased an average of 16%. As noted for TNP-470, the study design complicated the interpretation of the observed changes in the pharmacokinetic effects of paclitaxel, because treatment and period effects could not be separated. Because TNP-470 was administered after the completion of the paclitaxel infusion, the maximum impact of TNP-470 on paclitaxel pharmacokinetic results would have been expected to occur after the paclitaxel infusion. In an attempt to partially correct for these confounding factors, the ratio of AUC0-4 to AUC4-t was compared between treatments. A pairwise comparison of this ratio obtained after the administration of paclitaxel alone to the one obtained after the combination of paclitaxel with TNP-470 exhibited only a 4.6% difference.
Serum Cytokines
Epoxide hydrolase.
Treatment Outcomes
This phase I dose escalation study was primarily designed to assess the safety and pharmacokinetic profile of TNP-470 in combination with paclitaxel. The highest tolerated dose of each agent was achieved. The combination of a TNP-470 dose of 60 mg/m2 three times per week and a paclitaxel dose of 225 mg/m2 infusion every 3 weeks was well tolerated. The addition of TNP-470 to paclitaxel did not result in additive toxic effects with respect to hematologic toxicity, gastrointestinal symptoms, myalgia, arthralgia, and peripheral neuropathy when compared with literature reports for paclitaxel alone (Table 8). The incidence of infections was not different from what was expected with chemotherapy alone. TNP-470 exhibited linear pharmacokinetics within the dose ranges studied; the combination of drugs caused slight but clinically insignificant decrease of TNP-470 on paclitaxel clearance. Serum assays of VEGF and bFGF did not show any consistent change during treatment. While the efficacy of an antitumor regimen is difficult to discern from a heterogeneous group of patients in a phase I study, the large proportion of NSCLC patients allowed some analysis, especially since 60% of the patients received therapy in the second-line setting. The data suggest that the regimen has a favorable effect on patient survival when compared with published reports for paclitaxel alone, though clearly a larger study will be needed for definitive conclusions.
Given the specificity of angiogenesis inhibitors for tumor-related endothelial cells, it was assumed that these agents would be nontoxic in clinical trials. Interestingly, toxicity of these agents has been demonstrated in several clinical studies reported to date. For example, early combination clinical trials with the anti-VEGF monoclonal antibody in NSCLC were complicated by episodes of pulmonary hemorrhage,40 and the small-molecule receptor tyrosine kinase (VEGFR-2) inhibitor SU5416 produced more than the expected number of thrombotic events in early trials.41 The etiology of the neuropsychiatric toxicity was unknown, though it correlated closely with the TNP-470 infusion and resolved after cessation of TNP-470. The symptom complex was not clinically attributed to other causes and suggested frontal-subcortical cerebral dysfunction. TNP-470, a lipophilic molecule, was initially found to produce neurocognitive side effects at high doses.25,26 Logothetis et al26 conducted a trial in patients with progressive androgen-independent prostate cancer. The MTD was 70.88 mg/m2 with dose-limiting toxic effects characterized by a neuropsychiatric symptom complex (dysesthesia, gait disturbance, and agitation) that resolved when therapy ceased. Similar findings were seen in the other phase I studies with a weekly single-dose schedule of TNP-470 administered intravenously over 4 hours to patients with refractory solid tumors.27 In one study of 36 patients with solid tumors, the principal toxic effects included dizziness, lightheadedness, vertigo, ataxia, decreases in concentration and short-term memory, confusion, anxiety, and depression. The DLT at a dose of 235 mg/m2 was grade 3 cerebellar neurotoxicity, which started after patients had received treatment for 6 weeks.27 In prior studies, the heterogeneity of the patient population made the neuropsychiatric effects difficult to interpret. TNP-470 dose regimens above 60 mg/m2 were associated with the greatest neuropsychologic declines and were defined as intolerable; therefore, 60 mg/m2 was the maximum allowed TNP-470 dose in this study. The neuropsychologic evaluation in the current study consisted of a battery of tests completed before and after treatment. The findings (see Results) suggest that the neurotoxic side effects of this regimen, while clearly present, were no greater than those reported for other chemotherapy treatments and were substantially less than those reported for immunotherapy for cancer.42 For example, according to Scheibel et al (manuscript submitted), adverse effects of interferon-alfa 2a therapy on the cognitive and emotional functioning in a population of chronic myeloid leukemia patients occurred in 53% of patients. In an additional study, Schagen et al43 reported that 28% of women with breast cancer who were treated with standard adjuvant chemotherapy experienced persistent cognitive dysfunction 2 years after treatment. In a study currently underway at The University of Texas M.D. Anderson Cancer Center examining the cognitive and emotional function effects of tamoxifen in early-stage breast cancer patients, significant declines have been noted between pretreatment baseline and on-treatment follow-up evaluations. Specifically, on-treatment performance on the delayed recall portion of the memory assessment fell 2.16 SDs below the baseline level of function (C. Meyers, personal communication, March 2002). Analysis of the pharmacokinetic data demonstrated that there was minimal or no interaction between TNP-470 and paclitaxel. Paclitaxel clearance was reduced 16% when the combination was administered. This was not clinically significant. This is important, because in combinations of agents it is essential to make sure any increased therapeutic activity is not simply due to an increase in the systemic concentration of the drug. TNP-470 is believed to exert its antiangiogenic effect by inhibiting the intracellular enzyme methionine aminopeptide 2.11,44 In preclinical studies, treatment with single-agent TNP-470 primarily resulted in delay of tumor growth, though some studies showed disease regression. For example, Bergers et al45 demonstrated that the efficiency of different angiogenesis inhibitors could depend on the stage of carcinogenesis being targeted. In the Rip-Tag pancreatic model, TNP-470 was especially potent in established tumor models where significant regression of established tumors was seen. It is also possible that the dose and schedule of TNP-470 must be titrated to the proangiogenic activity of any given tumor. Furthermore, evidence suggests that a continuous infusion could be even more active than intermittent therapy, and this is now being tested in phase I trials alone and in combination with chemotherapy.46,47 There have been few documented clinical responses to TNP-470 alone. One complete response was seen in a phase I study24,25 in a 49-year-old woman with the diagnosis of recurrent squamous cell carcinoma of the cervix with pulmonary metastases. In phase II studies, three partial responses were documented in patients who received TNP-470 60 mg/m2, two in patients with breast cancer, and one in a patient with renal cell carcinoma. One of the patients with breast cancer continues to receive treatment on an extension protocol after more than 2 years. TNP-470 was one of the first agents examined in combination with chemotherapy and shown to have synergy. Teicher et al16,48 studied TNP-470 with multiple chemotherapeutic agents and with radiation therapy and demonstrated significant synergy. The results of these studies indicate that antiangiogenic agents can be very useful additions to cytotoxic treatment regimens for solid tumors. This is suggested by our early clinical results presented here. VEGF and bFGF have been studied as possible surrogate markers to measure antiangiogenic activity with variable and inconclusive results.48 Because both TNP-470 and paclitaxel presumably act directly on endothelial cells and not through an angiogenic receptor, it is perhaps not surprising that there is no correlation with treatment. The results of this phase I study demonstrate that TNP-470 is safe in a first- and second-line setting with chemotherapy. While length of survival was not a primary end point of the study, the fact that so many of the patients with advanced and often pretreated NSCLC lived long is intriguing and suggests the need for an efficacy study.48 Taken together, all the data suggest that TNP-470 should be studied further as the basis for new therapeutic combinations in lung cancer and other solid tumors.
Supported by a grant from TAP Pharmaceutical Products Inc, an American Society of Clinical Oncology Career Development Award, and an M.D. Anderson Cancer Center Physician Scientist Program Award to R.S.H.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
50% decrease that was maintained for at least 4 weeks. Progression was associated with a more than 25% increase or the appearance of a new lesion. Tumors shrinkage of less than 50% or growth of less than 25% represented stable disease. 
