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© 2002 American Society for Clinical Oncology Dose-Finding and Pharmacokinetic Study of Cisplatin, Gemcitabine, and SU5416 in Patients With Solid TumorsByFrom the Departments of Medical Oncology and Pulmonology, Vrije Universiteit Medical Center; Departments of Vascular Medicine and Internal Medicine, Academic Medical Center, University of Amsterdam; and New Drug Development Office Oncology, Amsterdam, the Netherlands; Department of Oncology, University of California Los Angeles Jonsson Cancer Center, Los Angeles; and Sugen Inc, South San Francisco, CA. Address reprint requests to Giuseppe Giaccone, MD, PhD, Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; email: G.Giaccone@ azvu.nl.
PURPOSE: To investigate the feasibility and pharmacokinetics of the combination cisplatin, gemcitabine, and SU5416. PATIENTS AND METHODS: Patients received cisplatin 80 mg/m2 on day 1, gemcitabine 1,250 mg/m2 on days 1 and 8, repeated every 3 weeks, and SU5416 (85 and 145 mg/m2) intravenously twice weekly. Pharmacokinetics of all three agents, side effects, and antitumor response were investigated in patients with solid tumors amenable to therapy with cisplatin/gemcitabine. RESULTS: In the first cohort of three patients entered at the 85 mg/m2 dose, no dose-limiting toxicities were observed. In the next cohort (145 mg/m2), three patients developed a thromboembolic event. After entry was restricted to patients with low thromboembolic risk, three additional patients enrolled at 145 mg/m2 developed a thromboembolic event. The dose was then reduced to 85 mg/m2 in all patients still on the study, and three additional patients were entered on this dose level. In 19 treated patients, eight patients developed nine thromboembolic events (three transient ischemic attacks, two cerebrovascular accidents, and four deep venous thromboses). The most common toxicities observed were those previously reported for SU5416 alone (headache and phlebitis) and for this chemotherapy regimen (nausea, thrombocytopenia, and leucopenia). No significant pharmacologic interaction among the three drugs was observed. Response rates were similar to those expected in the patient population selected for this study. Analysis of variables of the coagulation cascade and of vessel wall activation was performed in three patients and showed significant increases in thrombin generation and endothelial cell perturbation in a treatment cycle–dependent manner. CONCLUSION: The incidence of thromboembolic events, possibly related to the particular regimen tested in this study, discourages further investigation of this regimen.
ANGIOGENESIS, THE formation of new blood vessels, is essential for tumor growth and metastasis.1 One of the key components of the angiogenesis cascade is vascular endothelial growth factor (VEGF), which is produced by hypoxic or hypoglycemic tumor cells.2 The most important functions of VEGF, which was first discovered as a permeability factor, are endothelial cell (EC) proliferation, migration, and tube formation.3 Most tumors produce VEGF, and VEGF expression has often been shown to correlate with microvessel density in tumors and with prognosis, disease-free survival, and overall survival in patients.4-10 VEGF effects are mediated through several receptors located on ECs, and among them the Flk-1/KDR (VEGF receptor-2 [VEGFR-2]) receptor plays a critical role in angiogenesis. Disruption of cellular signaling through the VEGF/VEGFR pathway represents an attractive target for therapy. Several antiangiogenic therapy strategies have been developed.4,11 SU5416 (Z-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone) is a small, lipophilic, highly protein-bound synthetic molecule that inhibits Flk-1 autophosphorylation induced on interaction of VEGF with its receptor, by interfering with the tyrosine kinase domain.12 In preclinical studies, SU5416 was shown to be a potent inhibitor of VEGF-mediated Flk-1 receptor signaling.13-15 SU5416 is mainly metabolized via the cytochrome P450 (CYP) system. The maximum-tolerated dose for single-agent SU5416 in 69 patients with advanced malignancies enrolled onto a phase I study was determined16-18 to be 145 mg/m2. The dose-limiting toxicities (DLTs) consisted of projectile vomiting, nausea, and severe headache. Other adverse events included superficial and deep vein phlebitis, dry and raspy voice, and fatigue. No hematologic or organ toxicity was observed in this study. Chemotherapy is the mainstay of treatment for several solid tumors in advanced stages of disease. Because of the genetic instability of tumor cells, however, emergence of drug resistance is a common phenomenon.19 Another possible cause of resistance to chemotherapy may be the high interstitial pressure in tumors; this results in insufficient drug penetration.20 The combination of cisplatin and gemcitabine is a regimen often used for the treatment of several solid tumors, including non–small-cell lung cancer (NSCLC).21 These two agents exerted synergistic effects in preclinical studies.22,23 Angiogenesis inhibitors, such as SU5416, modify the tumor microenvironment, and because they affect genetically stable normal ECs, no drug resistance is expected. Furthermore, the side effects observed with SU5416 do not overlap with those of most chemotherapeutic drugs. Other theoretical advantages may be foreseen by the combination of chemotherapy with angiogenesis inhibitors. As a result of the angiogenesis-inhibiting therapy, tumors may be less capable of recovering from the damage caused by the cytotoxic agents. Furthermore, as a result of blocking the effects of VEGF, a decrease of the interstitial pressure in tumors may occur, leading to a greater penetration of the cytotoxic drugs. Maintenance therapy with an angiogenesis inhibitor after standard chemotherapy may result in a consolidation of the response obtained with the cytotoxic chemotherapy. We performed a phase I study of the combination of cisplatin and gemcitabine plus SU5416, with the primary objectives of investigating the feasibility and pharmacokinetics in patients for whom this combination chemotherapy is expected to be active.
Eligibility Criteria Entry onto this phase I trial was restricted to patients who met all of the following criteria: age older than 18 years, histologically proven solid tumors amenable to respond to cisplatin/gemcitabine chemotherapy (eg, NSCLC, esophagus cancers, head and neck cancers, and so on), an Eastern Cooperative Oncology Group performance status  2, and a life expectancy of longer than 12 weeks. Prior treatment with cisplatin/gemcitabine was not allowed, unless the patient responded to the previous treatment and the treatment-free interval was at least 6 months. One prior systemic chemotherapy regimen was allowed, provided that the treatment-free interval was longer than 4 weeks. Surgery within 4 weeks, treatment with erythropoietin, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor within 2 weeks before study entry, or treatment with any previous angiogenesis inhibiting agent was not allowed. Patients had to have an absolute neutrophil count (ANC) of more than 1,500/mm3, hemoglobin more than 5.5 mmol/L, platelet count more than 100,000/mm3, and serum creatinine less than 160 µmol/L or a creatinine clearance more than 50 mL/min. A significant liver function abnormality manifested by an increase in total bilirubin more than 35 µmol/L was not allowed. Patients who had a documented myocardial infarction during 12 months before study entry and those with severe or unstable angina pectoris were excluded. Patients with a history of atherosclerotic coronary artery disease requiring coronary artery bypass surgery had to be operated on at least 2 years before enrollment and were included only after consultation with a cardiologist. Patients with insulin-dependent diabetes mellitus or non–insulin-dependent diabetes mellitus with clinical evidence of severe peripheral vascular disease or diabetic ulcers were also excluded. The presence of other active malignancies, except basal cell carcinoma of the skin or in situ cervical carcinoma, was not allowed. Patients who had contraindications to systemic cisplatin or gemcitabine or with a known allergy to polyoxyl 35 castor oil (Cremophor, provided by Sugen, Redwood City, CA) were also excluded. Effective contraception was demanded, and written informed consent was obtained before study entry.
Design of the Study
Drug and Dosage Administration To prevent allergic reactions to the Cremophor, dexamethasone was administered orally 12 and 6 hours before the infusion. The dose of dexamethasone was 5 mg before the first two infusions, decreasing to 2 mg during the next two infusions and to 1 mg thereafter if no allergic reactions occurred. Furthermore, 2 mg of clemastine and 300 mg of cimetidine (or equivalent drugs/doses) were given intravenously half an hour before each infusion. Antiemetic treatment during cisplatin administration consisted of 8 mg of ondansetron (or equivalent) two to three times daily and, if necessary, continued in case of prolonged nausea in combination with dexamethasone 8 mg bid for a maximum of 2 days. The next cycle was given on day 22 if ANC was more than 1,500/mm3, WBC count was more than 3,000/mm3, platelet count was more than 100,000/mm3, and no clinically significant signs of toxicity remained. If these criteria were not met, treatment was delayed up to a maximum of 2 weeks. Gemcitabine dose modifications on day 8 were determined as follows: 1,250 mg/m2 if WBC count was more than 2,000/mm3 and platelet count was more than 100,000/mm3; and 1,000 mg/m2 if WBC count was between 1,000 and 2,000/mm3, platelet count was between 50,000 and 100,000/mm3, or both. No gemcitabine was given if WBC count was less than 1,000/mm3 or platelet count was less than 50,000/mm3. Furthermore, the dose of gemcitabine was reduced in all subsequent cycles to 1,000 mg/m2 in the following situations: ANC nadir less than 500/mm3, platelet nadir less than 50,000/mm3, or both for two consecutive counts 1 week apart; febrile neutropenia; or severe bleeding (National Cancer Institute of Canada grade 4). Dose modifications based on nonhematologic toxicity were as follows: in case of neuropathy grade 2 or higher, or in case of increases in serum creatinine level to more than 1.5 times the upper normal limit and/or creatinine clearance to less than 50 mL/min, cisplatin was discontinued, and in case of significant hypersensitivity reactions, SU5416 was discontinued.
Pharmacokinetics Samples for determination of SU5416 blood concentrations were drawn at the following time points. For cycle 1, days 4 and 8, they were drawn before infusion of SU5416, just before the end of the infusion, and 5, 15, 30, 60, 120, and 240 minutes after the infusion of SU5416. For cycle 2, day 1, they were drawn before infusion of gemcitabine, at the end of cisplatin infusion but before infusion of SU5416, just before the end of the SU5416 infusion, and 5, 15, 30, 60, 120, and 240 minutes after the infusion of SU5416 and 24 hours after gemcitabine infusion. Samples were collected into lithium heparin tubes, placed on ice, and centrifuged at 3,000 rpm at 4°C for 10 minutes. The upper layer was transferred with a glass pipette to a cryovial (1.5 mL) and stored at -70°C until further processing. Analysis of SU5416 and two oxidative metabolites (an alcohol and carboxylic acid) was performed at Specialty Laboratories (Santa Monica, CA) by using a method developed and validated by Specialty Laboratories which was based on an assay designed at Sugen Inc (South San Francisco, CA). In brief, 10 µL of 1 M hydrochloric acid was added to 200 µL of patient plasma. Then 50 µL of the internal standard SU5416-chloride (5.0 µg/mL) was added, and compounds of interest were extracted with 1.5 mL of acetonitrile, vortexed, mixed, and centrifuged. After centrifugation, the organic layer was decanted and evaporated under dry nitrogen at less than 40°C. The residues were reconstituted in solvent (dimethyl sulfoxide:CH3CN:mobile phase, 2:4:3, vol:vol:vol) and injected onto the column. Chromatography was reverse phase with a YMC (Wilmington, NC) ODS-AM 3-µm, 150 x 4.6-mm column (YMC catalog no. AM12S03-1546WT, AM-302-3). The mobile phase gradient consisted of 10 mmol/L of ammonium formate, pH 2.6, and acetonitrile over 30 minutes at a flow rate of 1.2 mL/min. The column was maintained at 40°C with ultraviolet/visible detection at wavelength 440 nm. Under these conditions, SU5416 retention time was 18 minutes, and internal standard retention time was 19 minutes. The assay was linear from 10 to 3,000 ng/mL, with coefficients of determination of 0.998 to 0.9999. Intra-assay coefficients of variation fell between 2.4% and 6.4% tested at low (100 ng/mL), medium (500 ng/mL), and high (2,000 ng/mL) plasma concentrations. The interassay coefficient of variation was between 3.2% and 4.5% over the same range of concentrations. Accuracy was 94% to 99%, and the lower limit of quantitation was 12 ng/mL. Recovery of SU5416 averaged 97% over the three concentrations, and recovery of the internal standard was 94%. Specificity of the methodology was determined by extracting blank human plasma (n = 20) and finding that no endogenous peaks coeluted at the retention times of interest. No interference was found with more than 30 therapeutic drugs and six endogenous compounds (alpha- and beta-carotene, vitamins A and K, and alpha- and beta-tocopherol) that were tested in the analysis. Trilevel quality control samples were developed to be included with each analytic run and were monitored with Westgard rules in compliance with Good Laboratory Practice. The assay was found to be linear, precise, accurate, and free of interferences caused by the biologic matrix or potentially coadministered therapeutic drugs, including the three drugs used as premedication before each dose of SU5416 and the chemotherapy agents cisplatin and gemcitabine. Calculation of pharmacokinetic variables was performed by applying a two-compartment population approach to the plasma concentration/time data (NonMem V Version 1.0; NonMem Project Group, University of California San Francisco, San Francisco, CA).
Toxicity and Response Evaluation During the combination therapy, complete physical examination, including vital signs and measurement of performance status, complete blood cell count, and serum chemistries, was obtained weekly. Every 3 weeks and after every serious adverse event, a teleconference with the investigators was held to discuss toxicity data. Twelve-lead ECG was performed before each cycle of chemotherapy. Tumor staging was assessed with computed tomography scans of all known tumor deposits. In case of multiple sites of metastasis, all measurable lesions were observed for the assessment of disease progression. Each dose of SU5416 was closely monitored for toxicity. Vital signs (temperature, respiratory rate, pulse rate, and blood pressure) were obtained before and at the end of infusion and at 15, 30, and 60 minutes after the end of infusion. At the end of each SU5416 infusion, patients were evaluated for toxicity, according to the National Cancer Institute of Canada toxicity criteria. Antitumoral activity was assessed according to the World Health Organization criteria every 6 weeks or more often in case of clinical suspicion of disease progression.26 Complete response was defined as the total disappearance of all measurable and assessable clinical evidence of cancer observed on two assessments separated by at least 4 weeks. Partial response (PR) was defined as at least a 50% reduction in the size of all measurable tumor areas as measured by the sum of the products of the greatest length and the maximal width of all measurable lesions. No lesions could have progressed, nor could new lesions have appeared. Tumor reduction must have been observed on two consecutive assessments separated by at least 4 weeks. A 25% to 50% reduction in the size of all measurable tumor areas without evidence of any new lesions and present on two assessments separated by at least 4 weeks was qualified as a minor response (MR). Progressive disease (PD) was defined as an increase of more than 25% in the size of all measurable tumor areas as measured by the sum of the products of the greatest length and maximal width, or the appearance of any new lesions. Stable disease was defined when a patient did not qualify for either a response or PD. Nonprogressing patients continued treatment either until unacceptable toxicity or tumor progression. Patients who were stable and responding to treatment received a maximum of six cycles of combination treatment. If they were still stable or responding after these six cycles, they were allowed to continue with SU5416 alone twice weekly for a maximum of 1 year after the start of the treatment. Patients not tolerating cisplatin/gemcitabine were allowed to receive SU5416 alone.
Blood Samples for Analysis of Variables of Coagulation and Vessel Wall Activation Blood samples were collected in sodium citrate (9 vol. blood per 1 vol. citrate; final concentration, 0.32%) and were centrifuged at 4,000 rpm at 4°C for 10 minutes. The separated plasma was then centrifuged a second time in an Eppendorf centrifuge at 14,000 rpm at 4°C for 3 minutes. After transfer to microtubes, these samples were stored at -80°C in 1-mL aliquots until further processing.
Assays For the measurement of von Willebrand antigen (vWF), we used an in-house ELISA according to methods reported previously.28 Soluble tissue factor and soluble E-selectin were determined with their respective ELISAs (American Diagnostics, Greenwich, CT; and R&D Systems, Abingdon, Oxon, UK, respectively).
From August 1999 to May 2000, 19 patients were entered onto this study: 13 at the Vrije Universiteit Medical Center in Amsterdam and six at the University of California Los Angeles Jonsson Cancer Center. Patient characteristics are listed in Table 1.
No DLT occurred in the first cohort of three patients at a dose level of 85 mg/m2, and the dose was therefore escalated to 145 mg/m2. On this dose level, one patient (no. 6) discontinued treatment at her own request because of a grade 3 headache after the first infusion of SU5416. Seven patients were treated at this dose level. In these seven patients, three patients developed a thromboembolic event (Table 1). Patient no. 5, who had metastatic prostate cancer, developed a transient ischemic attack (TIA) during the fourth cycle of therapy. He had no history of cardiovascular disease. During the first three cycles, this patient had gradually developed hypertension grade 2, and he was temporarily treated with antihypertensive medication. A magnetic resonance image (MRI) of the brain indicated bilateral high-intensity abnormalities centrally in the occipital, parietal, and frontal white matter. All abnormalities had disappeared on a second MRI scan 2 months after discontinuation of treatment. However, 3 months thereafter, this patient had a cerebrovascular accident (CVA) while receiving treatment with daily acetylsalicylic acid. Patient no.7, who had mesothelioma with a history of smoking, developed hemianopsia during the fourth cycle of therapy. This patient had no cardiac complaints despite the fact that he had experienced a myocardial infarction 7 years before study entry. An MRI of the brain indicated, besides asymptomatic brain metastases which did not explain the hemianopsia, a large area of ischemia in the right occipital lobe (CVA). Patient no. 8, who had pancreatic carcinoma, developed a deep venous thrombosis (DVT) of her right leg during the third cycle of therapy. Besides malignancy and smoking, no other risk factors were present in this patient. Because of a suspected increase in the incidence of thromboembolic events, a protocol amendment was written and approved by the Medical Ethical Committee that restricted entry to patients without a history of hypertension, thromboembolic or vascular events, or brain metastases. Six more patients were to be entered at the dose level of 145 mg/m2. In case of DLT, more patients would be treated at the lowest dose level of 85 mg/m2, the intermediate dose level of 110 mg/m2, or both. A detailed examination was performed by a cardiologist before study entry. Furthermore, 24-hour Holter ECG and continuous blood pressure monitoring were implemented (only at Vrije Universiteit Medical Center). The SU5416 dose on day 1 of every cycle was omitted, and only cisplatin and gemcitabine were administered on day 1 of every cycle, to reduce the risk of a potential interaction of the three drugs. In two of the next six patients receiving the dose level 145 mg/m2, vascular events occurred again. Despite the amendment, patient no. 16, who had a history of hypertension and a history of 40-pack-per-year smoking, was entered. This patient, who had NSCLC, developed right-sided hemiparesis in the first week of cycle 1, 3 days after the first infusion of SU5416. At admission, the platelet count was 23,000/mm3. An MRI of the brain on the same day and follow-up MRI indicated ischemic changes in the left parietal lobe as well as in the right frontoparietal region. No cerebral hemorrhage was found. Patient no. 13, who had an acinic cell carcinoma originating from the right parotid gland which in the past had been treated with several operations and radiotherapy, with the development of a local recurrence at the right carotid artery and metastatic disease, developed hypertension during the first cycle, which was treated with an angiotensin-converting enzyme inhibitor (captopril). One day after the initiation of this treatment, the patient developed a short lasting paralysis of her left leg and visual disturbances indicating a TIA of the right cerebral hemisphere. An MRI indicated locally diminished perfusion in the area supplied by the right middle and posterior carotid artery. Magnetic resonance angiography indicated a tortuous course of the right carotid artery, possibly caused by the previous operations and radiotherapy, but indicated no signs of stenosis or atherosclerotic plaques. Captopril was discontinued, because it was thought to be the main cause in this event; therefore, it seemed reasonable to continue treatment. At this point, it was decided to reduce the dose of SU5416 to 85 mg/m2 in all patients still receiving treatment and to enter three additional patients at this dose level. Because of severe phlebitis at the sites of the infusions of SU5416 and the difficulty obtaining peripheral intravenous access, a Port-a-Cath (PAC; SIMS Deltec, Inc, St Paul, MN) was placed before the second cycle in this patient. During the second cycle, she developed a DVT at the side of the PAC with multiple pulmonary emboli, which were documented by ultrasound and ventilation/perfusion scintigraphy. Patient no. 14, who had adenocarcinoma of unknown primary received one cycle on the dose level 145 mg/m2, and thereafter the dose was reduced to 85 mg/m2. During the second cycle, he developed a DVT of his left arm at the side of the PAC. This patient had no other risk factors for thromboembolic events, except active malignancy. Furthermore, patient no. 18, who had stage IV NSCLC, developed neurologic complaints consistent with multiple episodes of TIAs on the dose level 85 mg/m2 during the fourth cycle. A MRI of the brain indicated no abnormalities. Besides a history of smoking, this patient had no other risk factors. During the first cycle at dose level 85 mg/m2, patient no. 19, with stage IV NSCLC, developed left lower extremity DVT complicated by pulmonary embolism. Also, near the tip of a right upper chest external jugular PAC, terminating within the distal superior vena cava, a clot was noted on spiral computed tomography of the thorax. Both patient nos. 14 and 19 received anticoagulant therapy (oral warfarin continuously) and were allowed to continue with the combination treatment. Because five vascular events (two CVAs and three TIAs) and four venous thromboembolic events in eight of 19 patients occurred, this phase I study was terminated. Patient no. 17, who had stage IV NSCLC, developed two separate episodes of hemorrhage. The first hemorrhage was a gastrointestinal bleed during the first cycle at a platelet count of 42,000 mm3 and was related to a nonsteroidal antiinflammatory drug. In this patient the gemcitabine dose of the next cycles was reduced to 1,000 mg/m2. The second hemorrhage occurred during the third cycle during a platelet count of 20,000 mm3 and consisted of a liver bleed with hypotension. After this second serious adverse event, the patient was taken off the study. The other toxicities observed were those reported for SU5416 alone: headache, 98.5% (grade 3 or 4, 31.6%); and phlebitis, 36.8%. Those reported for the chemotherapy regimen alone were nausea, 100% (grade 3 or 4, 10.5%); vomiting, 84.2% (grade 3 or 4, 15.8%); anorexia, 42.1%; anemia, 52.6% (grade 3 or 4, 10.5%); leucopenia, 42.1% (grade 3 or 4, 31.6%); thrombocytopenia, 47.4% (grade 3 or 4, 36.8%); and alopecia, 42.1%. Because of treatment-induced phlebitis, difficulty obtaining peripheral venous access, or both, a PAC had to be placed in five patients. Fever (31.6%), infection (21.1%), neurotoxicity (21.1%), ototoxicity (31.6%), and nephrotoxicity (5.3%) were also observed. The combination of cisplatin/gemcitabine plus SU5416 apparently resulted in more asthenia (any grade, 100%; grade 3 or 4, 21.1%) than expected from the compounds given separately. Furthermore, diarrhea (68.4%; grade 3 or 4, 10.5%) was more often seen during this combination treatment. Only three of 19 patients completed all six cycles. Of these three patients, one requested termination, and the other two were prevented from further SU5416 continuation therapy because of the termination of the study. Furthermore, only one patient (no. 2) received 6 weeks of maintenance treatment with SU5416 alone, after completion of five cycles combination therapy. In this patient, therapy was discontinued because of tumor progression.
Pharmacokinetics
The pharmacokinetics of SU5416 seemed unaffected by the concomitant administration of cisplatin, gemcitabine, or both drugs (Table 3). The average time of infusion (75.6 ± 13 minutes) was longer than the average for single-agent studies, leading to slightly prolonged half-lives in this study. Induction of clearance was within the same range as for single-agent SU5416 treatment. AUC and Cmax results were also within the same ranges. Cmax and AUC for the major metabolite, a carboxylic acid, were similar to those seen in patients receiving SU5416 alone, and the amount of the alcohol metabolite was low and again similar to the levels seen in single-agent SU5416 studies (data not shown).
Tumor Response The best responses seen in these 19 patients were three PRs, three MRs, and seven stabilizations of disease (Table 1). Two patients were not assessable because of early withdrawal on the patient’s request and serious adverse events during cycle 1. Four patients had rapid PD. After accurate pathologic revision had indicated a lymphoma in patient no. 3, who had a PR after two cycles, this patient was taken off the study. A short-lasting PR of 6 weeks occurred in a patient with NSCLC, who had previously experienced a PR while receiving cisplatin/paclitaxel for 6 months. The other PR with an ongoing duration occurred in a patient with an adenocarcinoma of unknown primary. All three MRs occurred in patients with NSCLC. One of these patients had to discontinue treatment after four cycles because of a TIA, and after 5 months he developed PD. The other two patients who achieved an MR completed all six cycles of the combination treatment. However, one patient discontinued the maintenance therapy with SU5416 after a few infusions at her own request, and the other did not receive maintenance therapy because of closure of the study. Most stabilizations of disease were short lived; only in a patient with an adenocarcinoma of unknown primary and brain metastases, who received maintenance treatment with SU5416, did the stable disease last for 2 months.
Parameters of Activation of the Coagulation Cascade and of the Vessel Wall
The variable of EC activation, s-E-selectin, increased in all three patients during the first and second cycles of the combination therapy (Fig 3). The same pattern was also found for vWF and soluble tissue factor, indicating EC activation (data not shown). These variables decreased before the start of the second cycle, similar to the pattern noted for the coagulation markers.
This study was set up in preparation for a large randomized study in advanced NSCLC, in which chemotherapy with cisplatin/gemcitabine was going to be compared with the same chemotherapy plus SU5416. Unfortunately, an unexpectedly high incidence of thromboembolic events was observed in this study. Because this exceeds the incidence observed with this type of chemotherapy alone (0%) and SU5416 (2.2%) alone, this is probably the result of the combination.21,29-32 Besides a possible increase in asthenia and diarrhea as a result of the combination treatment, no significant increase of other toxicities was observed. The increase in thromboembolic events could not be explained by a direct pharmacokinetic interaction among the drugs. In particular, no differences in plasma levels of the three compounds were observed in the three patients who developed a vascular event in comparison with the five patients without a vascular event. The slightly lower accumulation of dFdCTP in WBCs has unclear clinical significance. A direct pharmacokinetic interaction among the drugs was not expected, because there are no common metabolic pathways. SU5416 is metabolized by CYP 3A4 and CYP 1A2; gemcitabine is inactivated by deamination in a reaction catalyzed by deoxycytidine deaminase and its active metabolite gemcitabine monophosphate by deoxycytidylate deaminase; cisplatin, mainly cleared by the kidneys, has limited enzyme-catalyzed metabolism. Antitumor activity was similar to that expected in the patient population selected for this study. Because the patient characteristics and degrees of prior treatment were so heterogeneous, no clear conclusion may be drawn on possible additive or synergistic effects between chemotherapy and SU5416. We observed significant increases in variables that reflect activation of the coagulation cascade and cellular activation during treatment in three patients. These changes occurred irrespective of the development of a thromboembolic event and in a treatment cycle–dependent manner. The role of VEGF in adult life is not completely clear, but there is enough evidence to support the role of VEGF in coagulation, because it also influences the hemostatic properties of ECs.33 For instance, VEGF increases the expression of tissue factor and thrombomodulin on ECs, it enhances vWF and factor VIII release from ECs, it induces nitric oxide synthetase expression and nitric oxide production in ECs, and it influences the expression levels of tissue-plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor, and the receptor of urokinase-type plasminogen activator.33-40 VEGF probably has both pro- and anticoagulant effects in coagulation, and its net effect on coagulation is not clear. We hypothesize that ECs become activated and shift toward a prothrombotic state when they are deprived of VEGF by the receptor-blocking effects of SU5416. Because cytostatic agents, especially cisplatin, can induce activation of platelets, monocytes, and ECs, a further shift toward a prothrombotic state will occur, resulting in the high rate of thromboembolic events seen after the administration of the combination regimen.41-44 Probably VEGF is not only a permeability, proliferation, and migration factor, but also a maintenance and protection factor for ECs during adult life. An analysis of coagulation and EC variables from patients treated with cisplatin/gemcitabine alone and from patients treated with SU5416 alone needs to be performed to support this hypothesis. However, there may be more explanations for the increased incidence in thromboembolic and vascular events. Thromboembolic and vascular events are multifactorial diseases. The development of a thromboembolic event depends on the balance between pro- and anticoagulant factors in relation to the properties of the local ECs.45,46 Cancer, inherited coagulation disorders, smoking, obesity, use of contraceptives, immobilization, and a postoperative period are well known risk factors for the development of venous thromboembolic events.47 Smoking, hypertension, hyperlipidemia, inherited metabolic disorders (hyperhomocystinemia), diabetes mellitus, obesity, family history, and sex (male) are well-known risk factors contributing to cardiovascular diseases.48 Furthermore, arteries in previously irradiated fields are prone to the development of atherosclerosis.49,50 Probably, this was an important contributing factor to the vascular complications in one of the patients (no. 13) in our study. Furthermore, the recall effect in previously irradiated fields has recently been observed when gemcitabine is administered systemically, and this might also help to explain some of the vascular events we observed.51-53 It is conceivable that this effect also includes activation of the ECs lining the artery in previously irradiated fields. Many case reports have been published describing myocardial infarctions or CVAs in relatively young patients after treatment with cisplatin.54-57 Moreover, thrombogenic effects from anticancer drug therapy in combination with corticosteroids in high dosages have also been described.58,59 The clinical and neuroradiologic features of one of the patients (no. 5) can be ascribed to reversible posterior leukoencephalopathy syndrome, which can be triggered by immunosuppressive and chemotherapeutic drugs, such as cisplatin.60 Part of a broad spectrum of neurologic complications of cisplatin are strokelike episodes, typically characterized by the acute onset of encephalopathy that resolves spontaneously.61 In the literature, no increased risk of thromboembolic events of gemcitabine alone or in combination with cisplatin has been so far reported.21,29-31 An incidence of only 0% to 5% thrombotic complications of PACs has been reported.62-65 Therefore, it is remarkable that in our study two of five patients with a PAC developed a symptomatic DVT of the arm, which in one was complicated by pulmonary embolism. In one (patient no. 19), an asymptomatic clot was noted at the tip of the PAC, and because this patient also had a DVT of the left leg, it is unclear if the pulmonary embolus originated from the PAC or the DVT in his leg. SU5416 belongs to a novel class of agents, the tyrosine kinase inhibitors. Although SU5416 has been shown to be a specific inhibitor of VEGFR-2, the tyrosine kinases are an ever-expanding family, and it is conceivable that inhibition of as yet unknown receptors may be implicated in the development of the vascular events we observed in this study. In ongoing studies of other combinations, with fluorouracil, fluorouracil/irinotecan, paclitaxel, and carboplatin/paclitaxel, so far no increased incidence in thromboembolic events has been reported.66 The higher incidence of vascular events may therefore be particularly related to the regimen tested in our phase I study. We did not attempt to reduce the dose of the chemotherapeutic drugs, because this may affect the activity of the combination. There might be a potential role for prophylactic use of anticoagulant therapy. However, this is not a trivial problem. Recently unexpected serious adverse events have been also reported in a study in which carboplatin/paclitaxel was combined with a recombinant humanized monoclonal antibody to VEGF (rhuMAb VEGF). Sudden and life-threatening hemoptysis was seen in six (four fatal) of 67 patients with NSCLC stage IIIb/IV treated with this combination.67 The explanation for these bleeding complications is unclear. Another unexpected toxicity observed during treatment with the rhuMAb VEGF alone was severe hypertension in two patients.68 These findings, together with our study, suggest an interaction of chemotherapy and biologic agents targeting the VEGF/VEGFR pathway with the coagulation cascade, ECs, or both. Therefore, we decided not to further pursue the continuation of this trial with prophylactic anticoagulants and not to expose more patients to potentially serious side effects. We think that it is advisable to perform and await the analysis of the coagulation studies and to perform in vitro studies to elucidate the exact cause of the thromboembolic events before attempting further steps in patients. In conclusion, the combination of the VEGFR-2 inhibitor SU5416 with cisplatin/gemcitabine seems not to be safe in patients with advanced solid tumors. The unexpected high rate of serious adverse events observed in this study and other studies suggests caution in the investigation of novel biologic agents and chemotherapy and requires adequate testing before starting large trials.
Supported in part by Sugen Inc. We thank J. Kauw, U. Zwiers, and K. van der Born for their contribution to the pharmacokinetics.
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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
) and with () SU5416 (145 mg/m2; n = 5).
