Annals of Oncology Advance Access originally published online on May 25, 2006
Annals of Oncology 2006 17(8):1320-1327; doi:10.1093/annonc/mdl102
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© 2006 European Society for Medical Oncology
A phase I study assessing the safety and pharmacokinetics of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 with gemcitabine and cisplatin in patients with solid tumors
Departments of 1 Medical Oncology, 3 Pharmacy and 4 Pulmonology, University of Groningen and University Medical Center Groningen, Groningen; 2 Department of Medical Oncology, Erasmus MC, Rotterdam, the Netherlands; 5 Abbott Laboratories, Chicago, IL, USA
* Correspondence to: Dr J. A. Gietema, Department of Medical Oncology, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, the Netherlands. Tel: +31-50-3611847; Fax: +31-50-3614862; E-mail: j.a.gietema{at}int.umcg.nl
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Abstract |
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Background: The aim of the study was to determine the safety profile, pharmacokinetics and potential drug interactions of the angiogenesis inhibitor ABT-510 combined with gemcitabine–cisplatin chemotherapy in patients with solid tumors.
Patients and methods: Patients with advanced solid tumors received gemcitabine 1250 mg/m2 intravenously (i.v.) on days 1 and 8 and cisplatin 80 mg/m2 on day 1 of a 3-week cycle in combination with ABT-510. ABT-510 was administered subcutaneously twice daily at doses of 50 mg or 100 mg. Plasma samples for pharmacokinetics were obtained on days 1 (gemcitabine, cisplatin as single agents), 15 (ABT-510 as single agent) and 22 (gemcitabine, cisplatin and ABT-510 as combination).
Results: Thirteen patients received ABT-510 as either 50 mg b.i.d. (seven patients) or 100 mg b.i.d. (six patients) in combination with gemcitabine–cisplatin. The most common reported adverse events reflected the known toxicity profile induced by gemcitabine–cisplatin without ABT-510. One episode of hemoptysis occurred in a patient with non-small-cell lung cancer (NSCLC) after 13 days of treatment. No clinically significant pharmacokinetic interactions between ABT-510, gemcitabine and platinum were observed. Three partial responses were observed in 12 evaluable patients (one head and neck cancer, one melanoma and one NSCLC).
Conclusions: Combining ABT-510 at doses of 50 mg and 100 mg with gemcitabine–cisplatin is feasible. Pharmacokinetic interactions were not observed and adding ABT-510 does not appear to increase toxicity.
Key words: ABT-510, angiogenesis inhibitor, cisplatin, gemcitabine, phase I
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introduction |
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Endothelial cells are an attractive target for anti-cancer therapy because of increasing evidence that the tumor vasculature is important for sustaining tumor growth and metastasis [1
]. Inhibition of angiogenesis as anti-cancer therapy has been pursued for several years. The naturally occurring angiogenesis inhibitor thrombospondin-1 (TSP-1) is of particular interest, as it blocks multiple pro-angiogenenic factors [2, 3], while it promotes endothelial cell apoptosis [4]. Normal tissue expression of TSP-1 inhibits neo-vascularization. Decreased expression of TSP-1, resulting from mutation or altered expression of tumor suppressors and oncogenes, is associated with increased angiogenesis. A downregulation of TSP-1 transcription in areas of tumorigenesis has been observed in many solid tumors [5].
ABT-510, a TSP-1-mimetic peptide, is a parenterally available analog of the anti-angiogenic properdin-repeat-region heptapeptide in which isoleucine has been replaced by a D-amino acid [6]. This substitution increases the in vitro anti-angiogenic activity of ABT-510 by 1000-fold [3]. ABT-510 competes with TSP-1 for binding to endothelial cells. Subcutaneous (s.c.) administration of ABT-510 in murine models of different tumor types is effective in slowing tumor growth at doses as low as 3 mg/kg/day (data on file at Abbott Laboratories).
In two phase I studies conducted in cancer patients, ABT-510 administered as daily s.c. single agent injections showed no major toxicity [7, 8]. The most common reported adverse events were fatigue, headache, insomnia, anorexia, nausea, rash and injection site reactions. No maximum tolerated dose (MTD) was identified. The pharmacokinetic target of ABT-510 plasma concentrations of 100 ng/ml for more than 3 h/day as determined from the murine efficacy models was achieved at a dose of 10 mg twice daily. By increasing the frequency of injections from a once to twice-daily (b.i.d.) regimen, a longer time above threshold was achieved in comparison to doubling the dose. In the two phase I studies, ABT-510 administered as a s.c. bolus injections induced long-term stable disease in several patients and a partial response in a patient with sarcoma [7, 8].
Advanced solid malignancies are commonly treated with cytotoxic drugs. However, drug resistance often leads to treatment failure. While monotherapy with angiogenesis inhibitors has shown a limited response rate [9–11] the combination of angiogenesis inhibitors with cytotoxic therapy remains an attractive strategy due to a potential increase in antitumor activity through synergy between the two treatment modalities [12]. For example, bevacizumab, an anti-VEGF antibody, showed modest antitumor activity in patients with advanced renal cell cancer. However, in a phase III trial in metastatic colorectal cancer patients, the addition of bevacizumab to treatment with 5-fluorouracil, leucovorin and irinotecan resulted in increased response rates and survival [12, 13].
This combination approach was investigated in the current phase I study in which ABT-510 treatment was combined with gemcitabine and cisplatin. The combination of gemcitabine and cisplatin is often used in the treatment of solid tumors, including non-small-cell lung cancer (NSCLC) and bladder cancer [14, 15]. It is known from preclinical metabolism studies that ABT-510 is metabolized by hydrolase enzymes to form a weakly active M-1 metabolite [7]. Gemcitabine is primarily metabolized to its inactive form 2-difluoro-2-deoxyuridine (dFdU) by cytidine deaminase and is eliminated in urine. Cisplatin, a heavy metal complex, is largely eliminated in the urine. Based on the disposition pathways, we anticipated no drug interaction when ABT-510 is combined with gemcitabine and cisplatin therapy. The objectives of this study were to determine the safety profile and pharmacokinetics of ABT-510 and to exclude clinically relevant drug interactions with gemcitabine and cisplatin.
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patients and methods |
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eligibility criteria
Patients with a histologically confirmed diagnosis of an advanced solid malignancy for whom no standard therapy options were available or for whom the combination of gemcitabine and cisplatin chemotherapy was considered an appropriate treatment were eligible. Additional eligibility criteria included: age
18 years; Eastern Cooperative Oncology Group (ECOG) performance status <3; an estimated life expectancy of 3 months; no radiotherapy, chemotherapy or hormonal therapy within 4 weeks before start of the study with the exception of small field radiation therapy; and the ability to receive s.c. injections of ABT-510. Specific exclusion criteria included: a known positive human immunodeficiency virus status; clinical signs of brain tumor or known central nervous system metastases; and evidence of uncontrolled clinically significant disease unrelated to the primary malignancy. The study was approved by the local ethics boards of the two participating university medical centers. All patients gave written informed consent.
drug administration
On days 1 and 8 of each repeating 21-day cycle, gemcitabine (Gemzar®, Eli Lilly, Indianapolis, IN) 1250 mg/m2 was administered i.v. in 250 ml 0.9% NaCl solution over 30 min. Cisplatin (Platinol®, Faulding, Warwickshire, UK) 80 mg/m2 dissolved in 1 l 0.9% NaCl solution was administered i.v. over 3 h after completion of the gemcitabine infusion on day 1.
ABT-510 (Abbott Laboratories, Chicago, IL) was supplied in vials containing 1.1 ml ABT-510 (100 mg/ml) or 0.75 ml ABT-510 (80 mg/ml) dissolved in 5% dextrose. The vials were stored at 2–8°C and brought to room temperature 1 h prior to dosing. ABT-510 was administered s.c. twice daily every day from day 2 of cycle 1 and continued until the patient went off study. Patients self-administered ABT-510, preferably at the same time each day, with an interval of approximately 12 h in between doses. The starting dose of ABT-510 was 50 mg twice daily, based on safety and pharmacokinetic data obtained in a phase I study of single-agent ABT-510 [7].
study design
The ABT-510 dose levels studied were 50 and 100 mg b.i.d., with six to 12 patients enrolled at each dose level. A cycle was defined as 21 days (3 weeks). Every patient who completed one full cycle was considered evaluable for toxicity. ABT-510 dose escalation to 100 mg b.i.d. was based on the safety assessments of all patients in the first cohort using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. There was no dose escalation within a cohort. Before the dose could be escalated, at least three patients having received one full cycle were evaluated at a given dose level. An additional three patients at the same dose were treated if one of the first three patients exhibited a dose-limiting toxicity (DLT). If two patients exhibited a DLT, the same dose level was considered to be the MTD. DLT was defined as any grade 3 or 4 adverse event (except inadequately treated nausea or vomiting or adverse event deemed treatable by the investigators) or any unexpected grade 2 or higher adverse event possibly or probably related to treatment requiring dose modification or treatment delay and occurring in the first treatment cycle. A maximum of six chemotherapy cycles were to be administered. In case of a tumor response or stable disease after six chemotherapy cycles patients could continue treatment with single agent ABT-510. Patients were discontinued from the study in cases of progression of disease (PD), unacceptable toxicity or refusal of treatment.
treatment modifications
In case of inadequate bone marrow function on day 8 of a cycle, the gemcitabine dose was to be reduced to 1000 mg/m2. Gemcitabine was to be withheld if the WBC was <1.0 x 109/l or platelets were <50 x 109/l. If at two consecutive counts in 1 week, the neutrophil count was <0.5 x 109/l, platelet count was <50 x 109/l, or in the event of febrile neutropenia, the gemcitabine dose was to be reduced to 1000 mg/m2 in all subsequent cycles. On day 22, the gemcitabine administration was to be delayed up to 2 weeks if the neutrophil count was <1.5 x 109/l or platelet count was <100 x 109/l. Cisplatin administration was to be discontinued when serum creatinine reached >1.5 times the upper limit of normal or if CRCL declined to <50 ml/min. No ABT-510 dose reduction was to be performed. If gemcitabine and cisplatin were discontinued due to toxicity, patients were allowed to continue treatment with ABT-510 provided there were no signs of disease progression.
pretreatment and follow-up studies
Prior to therapy, a complete medical history was taken and a physical examination, an electrocardiogram and a chest X-ray were performed. Patients were monitored with weekly complete blood counts. Biochemistry measurements, coagulation analysis and urinalysis were performed at baseline and each scheduled evaluation. Toxicity was assessed after each cycle. Tumor measurements were performed after every two cycles using the World Health Organization (WHO) criteria for response [16].
blood sampling and assay for pharmacokinetics
All blood samples for pharmacokinetic (PK) analysis were collected from an indwelling i.v. canula into EDTA-containing tubes. The samples for PK analysis of ABT-510 were drawn prior to ABT-510 dosing and at 5, 15 and 30 min, and at 1, 2, 4 and 8 h following the morning dose on days 15 and 22. Samples for gemcitabine PK were collected prior to the gemcitabine infusion and at 15 and 30 min after the start of the gemcitabine infusion, and at 15, 30 and 45 min and 1, 2, 4 and 6 h following completion of the infusion on days 1 and 22. Samples for cisplatin PK were collected prior to the cisplatin infusion and at 1, 2 and 3 h after the start of the cisplatin infusion, and 30 min and 1, 2, 3 and 5 h following completion of the infusion on days 1 and 22. After collection of blood samples for ABT-510 and gemcitabine, the samples were immediately placed on ice and centrifuged at 2000 x g at 4°C for 10 min, after which plasma was stored at –20°C until analysis. Plasma samples for cisplatin were separated by centrifugation at 3000 x g for 10 min, after which 500-µl aliquots of the plasma supernatant were added to 1.0 ml of ice-cold (–20°C) ethanol, and the remaining plasma was stored frozen until analysis. The ethanol treated samples were mixed and stored at –20°C for at least 5 h, after which they were centrifuged at 23 000 x g for 5 min. These samples were stored at –70°C until analysis.
Plasma concentrations of ABT-510 and its major metabolite M-1 were determined using a validated liquid chromatography with tandem mass spectrometric (LC-MS/MS) method described previously [7]. The lower limit of quantitation (LLOQ) in plasma for ABT-510 and major metabolite M-1 was 0.5 ng/ml and 3 ng/ml, respectively.
Plasma concentrations of gemcitabine and its metabolite dFdU were determined using a Merck–Hitachi autosampler L7200 with a Merck–Hitachi pump L7110 and a Merck–Hitachi diode array detector L7450 (VWR, Amsterdam, the Netherlands). Sample preparation included combining 1 ml of isopropanol, 50 µl of the internal standard and 200 µl of plasma in a glass centrifuge tube. After mixing 2.5 ml ethyl acetate was added and mixed. The sample was centrifuged at 2500 x g for 10 min. The supernatant was evaporated to dryness. The residue was reconstituted in 100 µl of cyclohexane and then transferred into a limited volume insert of an autosampler vial and injected into the HPLC system. An Alltech Econosphere NH2 5 µm 250 x 4.6 mm column performed the chromatographic separations. The components were detected at different wavelengths; with the detector set at 265 nm, dFdU was eluted at a retention time of 7.2 min. At 280 nm, the internal standard was eluted at a retention time of 11.7 min. The LLOQ in plasma was 0.125 µg/ml for gemcitabine and dFdU.
For measurement of unbound platinum, aliquots of 1000 µl of the ethanolic supernatant was evaporated to dryness under nitrogen at approximately 80°C, and the residue was reconstituted in 200 µl water containing 0.2% (v/v) Triton X-100 and 0.06% (w/v) cesium chloride (diluent). A volume of 20 µl, in duplicate, was eventually injected into the graphite furnace of the atomic absorption spectrophotometer (AAS, Perkin Elmer Model 4110 ZL spectrometer with Zeeman-background) [17]. The LLOQ of this assay was 0.0300 µg/ml platinum in plasma. The LLOQ for determination of total platinum concentrations in plasma was 0.200 µg/ml.
urine sampling and assay for pharmacokinetics
Urine for PK analysis was collected from 0 to 12 and 12 to 24 h after dosing of ABT-510 on days 15 and 22. Two samples were collected immediately prior to dosing on day 1 for the baseline drug assay. For measurement of urine concentrations of ABT-510 and metabolite M-1, urine was processed according to previously described methods [7]. The lower limits of quantification in urine for ABT-510 and metabolite M-1 were 6 ng/ml and 99 ng/ml, respectively [7]. The assay for the determination of total platinum in urine was similar to that in plasma; the LLOQ was 0.01 µg/ml.
circulating endothelial cells collection and analysis
Blood samples were collected by venipuncture in EDTA containing vacutainer tubes at baseline (day 1), every two cycles thereafter and at the final visit. Samples were immediately sent to Esoterix (a laboratory contracted by ChromaVision Laboratories; San Juan Capistrano, CA) for slide preparation, within 24 h, followed by circulating endothelial cells (CEC) measurement. The red blood cells (RBCs) were lysed, the resulting white blood cell population was placed on slides at a density of 1 x 106 cells/slide. Slides were stained using an endothelial specific monoclonal antibody and a secondary antibody for visualization by indirect immunocytochemistry. CECs were counted by cytomorphologic review following ACIS analysis. Samples were acceptable for CEC analysis if the viability of the cells was more than 80%.
pharmacokinetic analysis
Non-compartmental methods were used to determine values of plasma PK parameters of ABT-510, M-1, gemcitabine and its metabolite dFdU, and total and unbound platinum (from cisplatin) using WinNonlin-ProTM, version 4.1 (Pharsight Corporation, Cary, NC). The area under the plasma concentration–time curve from time 0 to the time of the last measurable concentration (Clast, AUC0–last) was determined using the linear trapezoidal rule. To facilitate determination of AUC over the 12-h ABT-510 dosing interval (AUC0–
), 12-h concentrations were estimated by linear regression of the logarithms of the plasma concentration versus time data from the terminal log-linear phase of the profile, based on visual inspection.
For gemcitabine and unbound platinum, the parameters estimated were: Cmax, Tmax, ß, t1/2, clearance (CL) and volume of distribution (Vz). The AUC from time zero to infinite time (AUC0–
) was calculated by adding AUC0–last and AUCext, where AUCext was calculated by dividing Clast by ß. The unbound platinum fraction was calculated by dividing the AUC0–8h for unbound platinum by the AUC0–8h for total platinum. The fraction of the dose excreted in urine for total platinum, ABT-510 and M-1 was calculated as the amount recovered in the urine over the dosing interval divided by the dose. The amount of M-1 recovered in urine was converted to equivalent ABT-510 amount by multiplying the M-1 amount by a ratio of the molecular weights of ABT-510 over M-1 (994/501).
statistical analysis
The sample size was based on clinical justification and patient numbers historically used for testing new anti-neoplastic compounds. In models for the analysis of safety data, dose was treated as a factor with discrete levels or as a continuous variable. For the PK analysis, descriptive statistics of parameters were determined. An analysis of variance (ANOVA) was performed on the parameters of drugs when administered as single agents and with combination therapy by including patient and day as classification variables. Two sided P values <0.05 were considered significant.
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results |
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A total of 13 patients were enrolled into two dosing cohorts in the study from December 2002 to July 2003. Patient characteristics are listed in Table 1. Seven patients received 50 mg ABT-510 b.i.d. and six patients received 100 mg ABT-510 b.i.d. Forty-four cycles of ABT-510 combined with gemcitabine and cisplatin were administered. The median number of combined cycles was three (range 1–6 cycles). Gemcitabine reduction was performed in three cycles in three patients due to grade 3 thrombocytopenia or grade 4 leucocytopenia. Gemcitabine and cisplatin were prematurely discontinued in five patients due to prolonged myelosuppression in three patients, a liver abscess in one patient with gallbladder cancer, and pain of bone metastasis in one patient. After discontinuation of gemcitabine and cisplatin in these patients, ABT-510 was continued at the same dose level for one to three cycles (13 cycles total).
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toxicity
The incidence of grade 3 or 4 toxicities reported during combined treatment are listed in Table 2. The frequency of grade 3 and 4 adverse events is considered normal for the administration of the gemcitabine–cisplatin combination. None of these adverse events were considered to be possibly or probably related to ABT-510 except for an episode of hemoptysis in a 72-year-old male patient with NSCLC occurring on day 13 of 50 mg ABT-510 b.i.d. of treatment. He had received no prior chemotherapy and was known to have a history of tumor-related hemoptysis without using anticoagulant medication. The administration of ABT-510 was discontinued and a causal relationship with ABT-510 could not be ruled out. The patient died 2 months after the event due to disease progression. As the patient did not complete the first cycle of chemotherapy, an additional patient was enrolled in the first cohort. No DLT was observed and the ABT-510 dose was escalated to 100 mg b.i.d. Local skin reactions at the injection site, with elevated redness, sometimes painful, but no inflammation or hemorrhage, were mild and common-side effects were possibly or probably related to ABT-510. Both dose levels of ABT-510 appeared feasible and exhibited acceptable tolerance profiles.
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pharmacokinetics
Plasma sampling for PK analysis of ABT-510 and cisplatin was available from 11 patients and for gemcitabine from 13 patients. The PK parameters of ABT-510 (parent and M-1) as single agent for the 50 and 100 mg b.i.d. groups were similar to those reported earlier in a similar cohort of patients [6
] (Table 4, Figure 1). Both doses achieved the PK target of plasma ABT-510 concentrations over 100 ng/ml for more than 3 h/day. The PK parameters of ABT-510 (parent and M-1) when administered as a single agent (day 15) and in combination with gemcitabine–cisplatin (day 22) were similar (Table 4, Figure 1). There were no statistical significant differences in Cmax and AUC for ABT-510 and M-1 between days 15 and 22. On days 15 and 22, the majority of the ABT-510 was recovered in the urine as M-1. Little parent drug (<1% of the dose on average) was recovered in the urine. The percent of the dose recovered in the urine was similar on days 15 and 22.
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Gemcitabine, dFdU, unbound and total platinum pharmacokinetics were similar with or without ABT-510 co-administration (Table 3, Figures 2 and 3). There were no statistically significant differences in the pharmacokinetic parameters, with and without ABT-510 co-administration (Table 3). The unbound platinum fraction on days 1 and 22 were also similar 21.7% versus 20.3%, respectively, as was total platinum excreted in the urine. Therefore, no pharmacokinetic interaction was observed between ABT-510 and gemcitabine, dFdU and platinum.
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CEC analysis
The individual CEC/106 WBC over time is presented in Figure 4. One patient that had long-term stable disease, defined as progression free survival of more than six cycles, had a decrease in CEC numbers at the last measurement compared with measurements in the previous cycles. Another patient with long-term stable disease had low CEC numbers at baseline and had an increase in the numbers at cycle 2. But the numbers returned to baseline by cycle 4. Both these patients received ABT-510 at the dose of 100 mg b.i.d. Two patients (one in the 50 mg b.i.d. and one in the 100 mg b.i.d. group) had low CEC number at baseline, but they increased just before their disease was determined to be progressive. Overall, from the available data there is no clear trend in changes in CEC numbers following ABT-510 treatment.
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tumor response
Three patients (one head and neck cancer patient, one melanoma patient and one NSCLC patient) experienced a PR after two cycles of treatment. The durations of these PRs were four cycles, four cycles and two cycles (the NSCLC patient discontinued the study drug due to adverse event). Stable disease lasting more than two cycles was observed in eight patients; three of these patients (one with NSCLC, one with head and neck cancer, and one with melanoma) had SD lasting more than four cycles.
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discussion |
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The present phase I study shows that the combination of a new angiogenesis inhibitor ABT-510 with gemcitabine and cisplatin is feasible. ABT-510, a TSP-1 mimetic administered subcutaneously twice daily, in combination with gemcitabine and cisplatin had a similar toxicity profile as the chemotherapy alone and seemed to be well tolerated. The toxicity of the combination of ABT-510 with gemcitabine and cisplatin consisted mainly of myelosuppression, nausea and vomiting. One patient with NSCLC experienced hemoptysis, which was considered to be possibly related to the combination of ABT-510 with chemotherapy, although it may be related to NSCLC disease process. No thromboembolic complications were observed. The scheduled dosages of gemcitabine and cisplatin were comparable to those commonly used in regimens without an angiogenesis inhibitor [14
, 15]. The dosages of ABT-510 were comparable to those used in a previous phase I single-agent study [7]. No new toxicity of ABT-510 was observed and there were no clinically significant pharmacokinetic interactions during the combination treatment. In this phase I clinical combination trial, antitumor activity was observed with three PRs.
Several studies have assessed the effectiveness of angiogenesis inhibitors in combination with a variety of chemotherapy regimens. In one phase I study, the experimental angiogenesis inhibitor SU-5416, a VEGFR-2 tyrosine kinase inhibitor, was combined with gemcitabine 1250 mg/m2 and cisplatin 80 mg/m2 [18]. This combination caused a higher than reported incidence of thromboembolic events for SU-5416 as a single agent (2.2%), ranging from deep venous thrombosis to cerebrovascular accident in eight out of 19 patients (42%) and the study was prematurely terminated [19]. The increase in thromboembolic events could not be explained by a direct pharmacokinetic interaction among the drugs. A proposed mechanism behind these events is possibly related to a treatment, cycle-dependent increase of thrombin [18]. In another combination study in which SU5416 was combined with paclitaxel, three of the 12 patients (25%) experienced a thromboembolic event [20]. It was speculated that the combination of SU-5416 with cytostatics activates both coagulation and endothelial cells, producing a net effect of shifting the coagulation cascade towards a prothrombotic state.
In several other studies, the VEGF pathway was targeted by bevacizumab, a monoclonal antibody to VEGF. In a randomized phase II study, previously untreated metastatic colorectal cancer patients received 500 mg/m2 5-fluorouracil and 500 mg/m2 leucovorin weekly for 6 weeks followed by 2 weeks of rest or treatment with 5 or 10 mg/kg bevacizumab [21]. In a recently reported phase III trial in metastatic colorectal cancer, the addition of bevacizumab (5 mg/kg every 2 weeks) to weekly 5-fluorouracil (500 mg/m2), leucovorin (20 mg/m2) and irinotecan (IFL) (125 mg/m2) resulted in a significant increase in survival from 15.6 months to 20.3 months [12]. There was no difference in the incidence of venous and arterial thrombotic events reported in both arms (19.4% for IFL plus bevacizumab versus 16.2% for IFL; P = 0.26). The frequency of grade 3 or 4 bleeding complications was similar in both arms. However, the incidence of hypertension was higher in the IFL plus bevacizumab arm (22.4% versus 8.3%; P <0.01) [12]. Overall, this is the first combination study in which the targeted VEGF pathway combined with a chemotherapy combination results in a survival benefit. Although minor mucosal bleeding (e.g. epistaxis), hypertension and proteinuria are adverse events that have been observed in other clinical trials of bevacizumab, of concern is a recently reported trial in patients with NSCLC in which carboplatin and paclitaxel were combined with bevacizumab (7.5–15 mg/kg). In this trial, bleeding complications, including life-threatening pulmonary hemorrhages, were more frequent in the bevacizumab arm [22]. Especially patients with squamous type carcinoma of the lung were more at risk for these complications resulting in excluding those patients in current lung cancer studies [23]. So, while SU-5416 and bevacizumab both interact with the VEGF pathway to inhibit angiogenesis, combining either of these with chemotherapy regimens may increase the vascular toxicity profile.
The TSP-1 mimetic ABT-510 is an endogenous angiogenesis inhibitor that, when combined with a chemotherapeutic schedule, does not appear to increase vascular and thromboembolic toxicity. Of interest is the question of whether endogenous angiogenesis inhibitors such as TSP-1 and angiostatin added to chemotherapy result in less frequent adverse vascular and thromboembolic events when compared with combinations in which the VEGF pathway is inhibited. There are preliminary data from a small phase II study in patients with NSCLC in which angiostatin was added to carboplatin and paclitaxel [24]. This combination was active in NSCLC patients and was well tolerated; only three of the 24 patients enrolled developed thromboembolic complications. More combination studies with endogenous angiogenesis inhibitors are needed to investigate their antitumor potential and define the toxicity profile.
In the present study, pharmacokinetics of ABT-510, gemcitabine and cisplatin as single agents were similar to those reported in previous studies. The lack of pharmacokinetic interaction observed in this study is consistent with the different disposition pathways involved in the elimination of ABT-510, gemcitabine and cisplatin.
Three of 12 assessable patients with various tumor types experienced PRs. Based on previous phase I data, several phase II trials have already been initiated in NSCLC, lymphoma, sarcoma and renal cell cancer patients with single-agent ABT-510 regimens or ABT-510 in combination with a cytostatic regimen. Any antitumor activity of combination treatment with ABT-510 needs to be explored in randomized phase II and III studies.
In conclusion, a regimen of SC twice daily doses of 50 or 100 mg ABT-510 in combination with 1250 mg/m2 gemcitabine on days 1 and 8 and 80 mg/m2 cisplatin on day 1 can be given i.v. in a 3-week cycle with acceptable toxicity. No significant pharmacokinetic interactions were observed. Further phase II and III studies are warranted to evaluate the safety and efficacy of this combination in the treatment of advanced solid tumors.
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Acknowledgements |
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Presented in part at the Annual meeting of the American Society of Clinical Oncology, New Orleans, USA, 2004.
Received for publication October 19, 2005. Revision received March 23, 2006. Accepted for publication March 30, 2006.
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