Dr. Carr, Mr. Knight, and Dr. Humerickhouse are all employees of and stockholders in Abbott Laboratories.
A phase 1 trial of 2 dose schedules of ABT-510, an antiangiogenic, thrombospondin-1-mimetic peptide, in patients with advanced cancer†
Article first published online: 17 OCT 2008
Copyright © 2008 American Cancer Society
Volume 113, Issue 12, pages 3420–3429, 15 December 2008
How to Cite
Gordon, M. S., Mendelson, D., Carr, R., Knight, R. A., Humerickhouse, R. A., Iannone, M. and Stopeck, A. T. (2008), A phase 1 trial of 2 dose schedules of ABT-510, an antiangiogenic, thrombospondin-1-mimetic peptide, in patients with advanced cancer. Cancer, 113: 3420–3429. doi: 10.1002/cncr.23953
Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, Illinois, May 31-June 3, 2003.
- Issue published online: 4 DEC 2008
- Article first published online: 17 OCT 2008
- Manuscript Accepted: 14 JUL 2008
- Manuscript Revised: 21 JUN 2008
- Manuscript Received: 30 APR 2008
- Abbott Laboratories, Abbott Park, Illinois
- angiogenesis inhibitors;
- phase 1;
- clinical trial;
- thrombospondin-1 inhibitor
ABT-510 is a substituted nonapeptide that mimics the antiangiogenic activity of the endogenous protein thrombospondin-1 (TSP-1). The current study was designed to establish the safety of ABT-510 in the treatment of patients with advanced malignancies on a once-daily (QD) and twice-daily dosing schedule.
Patients were randomly assigned to 1 of 6 dosing regimens: 20 mg, 50mg, or 100 mg QD or 10 mg, 25 mg, or 50 mg twice daily. ABT-510 was administered by subcutaneous bolus injection in cycles of 28 days. Tumor response and disease progression were monitored at 8-week intervals by computed tomography scan or magnetic resonance imaging.
Thirty-six patients were randomly assigned in equal numbers to the 6 study regimens, with an additional 13 patients randomized to the 10-mg-twice-daily and 50-mg-twice-daily ABT-510 regimens. The expected pharmacokinetic target was achieved at all dose levels tested. The majority of adverse events were grade 1 or 2 (according to National Cancer Institute Common Toxicity Criteria [version 2]) and were not found to be dose related. The most frequently reported adverse events that were possibly related to ABT-510 included injection site reactions, asthenia, headache, and nausea. Grade 3 events considered to possibly be related included nausea, dyspnea, bone pain, constipation, vomiting, asthenia, and chills and tremors. One partial response was observed in a patient with carcinosarcoma who received 20 mg QD. The 6-month progression-free survival rate was 6%. Approximately 42% of patients (21 of 50 patients) had stable disease for ≥3 months.
ABT-510 can be administered at doses of 20 mg/day to 100 mg/day without significant toxicity. In the current study, minimal antitumor activity was observed, which was similar to observations in other single-agent antiangiogenic trials. Cancer 2008. © 2008 American Cancer Society.
There is abundant evidence that primary tumor growth and metastatic progression require new blood vessel formation (angiogenesis).1 Tumors secrete multiple inducer proteins, including basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), that activate microvascular endothelial cells, causing them to proliferate, migrate, and organize into capillary structures.2 Activated endothelial cells also enhance malignant progression by producing cytokines that inhibit programmed cell death (apoptosis).3 The treatment of rodent tumors with specific inhibitors of angiogenesis such as angiostatin, endostatin, and vascular endothelial growth factor inhibitors cause significant tumor growth delay.4, 5 Antiangiogenic therapy targets genetically stable endothelial cells; therefore, the resistance typically observed after cytotoxic chemotherapy is not anticipated.6 Moreover, angiogenesis inhibitors should not have the intrinsic toxicity of cytotoxic chemotherapy. These properties of angiogenesis inhibitors are consistent with the goal of using such agents synergistically with conventional cytotoxic or hormonal therapies and using these agents for a prolonged term to suppress tumor growth and metastasis.
To our knowledge, thrombospondin-1 (TSP-1) was the first natural angiogenesis inhibitor to be discovered. TSP-1 is a large, multifunctional protein that is transcriptionally activated by the tumor suppressor gene product p537 in fibroblasts and by other tumor suppressors in other cell types. Recent evidence indicates that the activity of TSP-1 depends on its interaction with the receptor CD36 or closely associated proteins on the surface of endothelial cells.8 TSP-1 rapidly inhibits endothelial cell migration and enhances the rate of endothelial cell apoptosis by p38 mitogen-activated protein kinase and activating caspase-3-like activity.9 Normal tissue expression of TSP-1 limits neovascularization.10, 11 TSP-1 is transcriptionally activated by the tumor suppressor gene product p53, and therefore is down-regulated in p53-defective tumors.12 In rodent tumor models, the ectopic overexpression of TSP-1 inhibits the malignant phenotype, as does the direct administration of TSP-1 into the circulation. However, to our knowledge, the direct clinical use of TSP-1 has not been feasible because of its large size and multiple functions.13–16
The antiangiogenic activity of TSP-1 has been localized to the properdin (type-1) repeats within the 50,000-molecular weight N-terminal stalk region of the protein.17 Small synthetic peptides from within this region have only weak antiangiogenic activity, but a single D-amino acid replacement, (D-iosleucine) of a particular properdin-region heptapeptide was reported to enhance activity by 1000-fold.18 ABT-510 is a parenterally available nonapeptide analog of this substituted heptapeptide and mimics its antiangiogenic properties. It is soluble and stable in water and is supplied for clinical use as an acetate salt in 5% dextrose solution.
Preclinical studies have indicated that ABT-510 exhibits the features of an antiangiogenic cancer therapeutic. In vitro, ABT-510 inhibits the chemotactic VEGF-stimulated migration of human microvascular endothelial cells.19 In vivo, ABT-510 administered subcutaneously at a dose of 10 mg/kg/day blocks the normal vascularization of mouse cornea in response to the surgical placement of VEGF or bFGF pellets.19 In addition, ABT-510 reportedly has antitumor activity in several murine and human xenograft models.19
In a single-dose phase 1 study in healthy volunteers, ABT-510 was found to be well tolerated at doses up to 130 mg (Abbott Laboratories IND 63,154). Adverse events were generally mild in nature and of uncertain clinical relevance. A maximum tolerated dose was not identified. In a dose-escalating phase 1 study in patients with advanced cancer, doses of 100 mg to 260 mg per day administered as subcutaneous bolus injections were evaluated. A dose of 260 mg per day was determined to be the maximum clinically practical dose because of the large injection volume required (2 injections of 1.3 mL per day).
In preclinical models, doses of ABT-510 as low as 0.3 mg/kg/day demonstrated significant antitumor activity. Pharmacokinetic and pharmacodynamic modeling of preclinical efficacy identified a minimum pharmacokinetic target of plasma concentrations exceeding 100 ng/mL for ≥3 hours.20 Human pharmacokinetic modeling suggests ABT-510 doses as low as 20 mg/kg/day would achieve these exposures in humans.
The purpose of the current study was to establish the safety profile and pharmacokinetics of ABT-510 when administered at doses designed to target the minimum plasma concentrations required for antitumor activity.
MATERIALS AND METHODS
This phase 1, randomized, open-label, dose-ranging study of ABT-510 was conducted at 2 sites of the Arizona Cancer Center. The primary objective of the study was to establish the safety profile of 3 doses of ABT-510 in patients with advanced malignancies when administered as once-daily (QD) or twice-daily subcutaneous bolus injections. The secondary endpoints were to correlate pharmacokinetics with pharmacodynamic markers and to evaluate antitumor activity in treated patients. Patients were recruited between January 3, 2002 and April 14, 2004. The institutional review board of the University of Arizona reviewed and approved the study, and all patients provided written informed consent before study enrollment.
Patients were required to be aged ≥18 years and have a measurable, histologically or pathologically documented advanced solid tumor that was refractory to standard therapy and for which there was no effective life-prolonging therapy. Patients were also required to have an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2 and a predicted life expectancy ≥3 months. Patients were not to have received antitumor radiotherapy, chemotherapy, immunotherapy, or investigational drugs within 4 weeks or antitumor hormonal therapy within 1 week of ABT-510 administration. Patients were to be clinically stable and capable of receiving subcutaneous injections. Patients with clinically significant disease unrelated to the primary malignancy and those with primary brain tumors or previously treated central nervous system metastases were excluded from participation. Pregnant or lactating women were also excluded. Strictly defined clinical laboratory parameters were not included as part of the eligibility criteria. Additional eligibility decisions used the clinical judgment of the investigator based on the patient's medical history, physical examination, and laboratory profile.
Patients were randomly assigned to 1 of 6 treatment regimens: 20 mg, 50 mg, or 100 mg QD or 10 mg, 25 mg, or 50 mg twice daily. At least 6 patients who met the enrollment criteria were enrolled into each dose cohort. ABT-510 was originally supplied in 5% dextrose in single-use vials at 100 mg/mL (1.1 mL/vial). Later supplies were produced at 40 mg/mL (0.75 mL/vial). ABT-510 was self-administered as a subcutaneous bolus injection. Patients were dosed for 28 consecutive days, after which they were allowed to continue into an extension period at their current dose and regimen, provided their safety assessments were acceptable. At the time of completion of the enrollment of 36 patients, additional patients were scheduled for randomization in equal numbers to the 10-mg-twice-daily and 50-mg-twice-daily ABT-510 regimens to further evaluate the safety of these 2 doses, which were chosen to be evaluated in phase 2 studies based on their pharmacokinetic profiles and preliminary efficacy data.
Patients were screened over a 14-day period; tumor assessments were made within 4 weeks of the initiation of the study. Patients visited the study site for assessment weekly during the first 28 days, then at Weeks 6 and 8, and monthly thereafter. Tumor response and disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) were monitored using either computed tomography or magnetic resonance imaging every 8 weeks. Blood samples for serial pharmacokinetic evaluations were collected on Days 1 and 22. Plasma concentrations of ABT-510 were measured using a liquid chromatography with a mass spectrometric detection (liquid chromatography followed by mass spectroscopy/mass spectroscopy in tandem [LC/MS/MS]) assay method developed by Abbott Laboratories. Serial blood samples for the pharmacodynamic analysis of circulating endothelial cells (CECs) were obtained before dosing on Days 1 and 22, at Week 8, every 8 weeks thereafter, and at the time of the final visit. The number and percentage of patients reporting treatment-related adverse events were tabulated using the fifth edition of Coding Symbols for Thesaurus of Adverse ReactionTerms (COSTART), with a breakdown by dosage and dosing frequency (QD or twice daily).
Patients were withdrawn from the study if any of the following events occurred: disease progression; the patient requested withdrawal; >1 dose reduction or interruption in administration of the study drug was required; radiotherapy, surgery, or therapy with alternate antineoplastic agents was initiated; the patient became pregnant; or the investigator believed that it was in the best interest of the patient to discontinue treatment with the study drug. Procedures outlined for the final visit were to be completed within 72 hours of the last dose of study drug.
Quantification of CECs
Blood was collected by standard peripheral venipuncture into a Vacutainer (BD Biosciences, Franklin Lakes, NJ) containing acid citrate dextrose (ACD) and assayed for CECs within 24 hours of collection by flow cytometry. A total of 100 μL of ACD anticoagulated blood was incubated with 10 μL of anti-CD31-PE (BD PharMingen), 10 μL of anti-CD45-FITC (BD PharMingen, San Diego, Calif), and 10 μL of a 4-μg/μL solution of LDS-751 (Molecular BioProducts, Inc, San Diego, Calif). Tubes were incubated for 30 minutes at room temperature and then 100 μL of a 5X solution of BD FACS lysing solution (BD Biosciences, San Jose, Calif) was added to lyse erythrocytes and fixate cells. Tubes were analyzed within 4 hours on a BD FACScan (BD Biosciences, San Jose, Calf). CECs were defined as a population of nucleated cells (positive LDS-751 staining) that were negative for the hematopoietic marker CD45 and positive for the endothelial cell marker CD31 (PECAM). The number of CECs/μL of whole blood was determined by the following equation: (white blood cell count/μL) × (%CEC/100).
Pharmacokinetic and Statistical Analysis
Concentration-time profiles throughout the dosing interval were determined for each subject by fitting a compartmental pharmacokinetic model to the observed data. Noncompartmental methods were then used to determine values for the pharmacokinetic parameters of ABT-510, including peak plasma concentration (Cmax), time to Cmax (Tmax), terminal elimination phase rate constant (β), half-life (t1/2), area under the plasma concentration-time curve (AUC), and apparent plasma clearance (CL/F). Analysis of covariance (ANCOVA) was performed on Day 1 pharmacokinetic variables to address questions of dose proportionality and linear kinetics. ANCOVA was performed on Day 22 pharmacokinetic variables, with the total daily dose and dosing frequency as factors. The variables included dose-normalized Cmax, Tmax, dose-normalized predose concentration (Ctrough), dose-normalized AUC, and β. Ctrough was assessed on Day 22. A 2-way analysis of variance (ANOVA) of the changes from the first dose to the Day-22 dose was performed for the dose-normalized AUC and β, with the total daily dosage and dosing frequency as factors.
A total of 50 patients were enrolled in the current study. The number of patients enrolled in the respective dosing groups were: 13 patients at 10 mg twice daily, 6 patients at 20 mg QD, 7 patients at 25 mg twice daily, 6 patients at 50 mg QD, 12 patients at 50 mg twice daily, and 6 patients at 100 mg QD. The demographic characteristics are summarized in Table 1. The dose levels, number of patients, and number of cycles are summarized in Table 2. The median length of treatment was 2 cycles (range, 0.2-16 cycles).
|10 mg BID||20 mg QD||25 mg BID||50 mg QD||50 mg BID||100 mg QD||Total|
|No. of patients entered||13||6||7||6||12||6||50|
|No. of patients evaluable||10||6||6||6||9||5||42|
|Male||8 (62%)||4 (67%)||5 (71%)||5 (83%)||6 (50%)||4 (67%)||32 (64%)|
|Female||5 (38%)||2 (33%)||2 (29%)||1 (17%)||6 (50%)||2 (33%)||18 (36%)|
|18-64||8 (62%)||4 (67%)||2 (29%)||3 (50%)||7 (58%)||2 (33%)||26 (52%)|
|≥65||5 (38%)||2 (33%)||5 (71%)||3 (50%)||5 (42%)||4 (67%)||24 (48%)|
|ECOG performance status|
|0||6 (46%)||5 (83%)||2 (29%)||4 (67%)||5 (42%)||3 (50%)||25 (50%)|
|1||6 (46%)||1 (17%)||5 (71%)||2 (33%)||6 (50%)||3 (50%)||23 (46%)|
|2||1 (8%)||0||0||0||1 (8%)||0||2 (4%)|
|Colorectal||2 (15%)||4 (67%)||4 (57%)||3 (50%)||3 (25%)||4 (67%)||20 (40%)|
|Sarcoma||3 (23%)||2 (33%)||1 (14%)||1 (17%)||2 (17%)||0||9 (18%)|
|Renal||1 (8%)||0||1 (14%)||0||4 (33%)||1 (17%)||7 (14%)|
|Breast||2 (15%)||0||1 (14%)||0||2 (17%)||1 (17%)||6 (12%)|
|Melanoma||3 (23%)||0||0||3 (50%)||2 (17%)||1 (17%)||9 (18%)|
|Chemotherapy||13 (100%)||6 (100%)||6 (86%)||6 (100%)||7 (58%)||4 (67%)||42 (84%)|
|Radiotherapy||4 (31%)||4 (67%)||3 (43%)||3 (50%)||5 (42%)||2 (33%)||21 (42%)|
|Surgery||13 (100%)||6 (100%)||7 (100%)||6 (100%)||12 (100%)||6 (100%)||50 (100%)|
|Immunotherapy||5 (38%)||0||2 (29%)||3 (50%)||7 (58%)||1 (17%)||18 (36%)|
|Hormonal therapy||1 (8%)||0||1 (14%)||1 (17%)||3 (25%)||0||6 (12%)|
|Dose Level||Total No. of Patients||Median No. of Cycles (Range)||SAEs|
|10 mg BID||12||2.64 (1.0–11.11)||0|
|20 mg QD||6||4.87 (1.04–16.57)||0|
|25 mg BID||7||2.0 (1.0–8.04)||0|
|50 mg QD||6||2.57 (1.93–8.07)||0|
|50 mg BID||13||1.82 (0.25–4.25)||0|
|100 mg QD||6||2.05 (0.21–3.39)||0|
Safety was evaluated using the National Cancer Institute Common Toxicity Criteria (version 2). Of the 50 patients enrolled, 47 completed at least 1 treatment cycle without evidence of dose-limiting toxicities (DLTs). Three patients discontinued the study prematurely secondary to adverse events unrelated to ABT-510. Of the 50 patients enrolled in the study, all 50 (100%) experienced at least 1 treatment-related adverse event. A total of 441 nonserious adverse events were reported. The majority of events (90%) were mild to moderate (grade 1-2) in severity. Approximately 76% of these events were determined to be not related (61%) or most likely not related (15%) to ABT-510 therapy. The most frequent ABT-510-related adverse events included mild injection site reactions, asthenia, headache, and nausea (Table 3). Injection site reactions were typically mild and characterized by a 1-cm to 2-cm erythematous lesion associated with mild pruritis that lasted approximately 1 hour after injection.
|COSTART Term||20 mg QD N = 6||50 mg QD N = 6||100 mg QD N = 6||10 mg BID N = 13||25 mg BID N = 7||50 mg BID N = 12||Total No. of Patients (%)|
|Abdominal pain||0||0||0||0||0||1||1 (2%)|
|Injection site reaction||2||3||2||7||4||5||23 (46%)|
|Bone pain||0||0||1||0||0||0||1 (2%)|
|Cough increased||0||1||0||0||0||1||2 (4%)|
A total of 32 serious adverse events were reported in 14 patients. Three of the events—dehydration, vomiting, and a gastrointestinal bleed—were experienced by patients undergoing screening evaluation before exposure to the study drug and therefore were not considered to be related to the study drug. Of the remaining 29 events, none was considered by the investigators to be possibly or most likely related to the administration of ABT-510 and were all believed to be related to the patient's underlying malignancy. No deaths were reported during the current study.
Five patients in this study experienced a total of 7 grade 3 or grade 4 adverse events that were considered possibly or most likely related to ABT-510. These events included bone pain (1), constipation (1), nausea and vomiting (1), chills (1), aggravation of existing anemia (1), aggravation of existing asthenia (1), and dyspnea (1). None of these adverse events were considered to be serious.
A total of 12 grade 3 or grade 4 laboratory abnormalities were identified in 8 patients in the study; 1 abnormality was reported as an adverse event. Three patients experienced lymphopenia during treatment with ABT-510; however, 1 of the patients entered the study with grade 3 lymphopenia that did not significantly change during the course of therapy. Other laboratory findings found to occur in >1 patient were hyperglycemia in 2 patients and hypokalemia in 2 patients.
|Pharmacokinetic Parameters||Dose Regimen|
|20 mg QD||50 mg QD||100 mg QD||10 mg BID*||25 mg BID*||50 mg BID*|
|Day 1, Mean ± SD|
|(N = 6)||(N = 6)||(N = 6)||(N = 13)||(N = 7)||(N = 12)|
|Tmax, h||0.4 ± 0.1||0.8 ± 0.6||0.8 ± 0.3||0.6 ± 0.2||0.6 ± 0.2||0.7 ± 0.3|
|Cmax, ng/mL||619 ± 367||1095 ± 615||2118 ± 714||266 ± 102||725 ± 221||1207 ± 370|
|AUC∞, h•ng/mL||1381 ± 570||3110 ± 2104||6521 ± 2177||636 ± 144||1790 ± 600||3416 ± 1508|
|t½, h†||1.1 ± 0.5||1.2 ± 0.3||1.4 ± 0.1||1.1 ± 0.4||1.1 ± 0.3||1.2 ± 0.3|
|CL/F, L/h||17.4 ± 9.0||21.2 ± 10.0||17.4 ± 7.5||16.4 ± 3.3||15.3 ± 4.7||17.2 ± 6.9|
|Vz/F, L||31.7 ± 19.5||39.7 ± 26.2||35.9 ± 17.8||29.5 ± 15.5||25.5 ± 8.8||31.2 ± 13.9|
|Day 22, Mean ± SD|
|(N = 6)||(N = 6)||(N = 6)||(N = 13)||(N = 7)||(N = 12)|
|Tmax, h||0.4 ± 0.1||0.8 ± 0.6||0.8 ± 0.3||0.5 ± 0.2||0.6 ± 0.2||0.7 ± 0.3|
|Cmax, ng/mL||619 ± 367||1106 ± 631||2113 ± 711||266 ± 100||737 ± 217||1275 ± 559|
|AUCτ, h•ng/mL‡||1378 ± 569||3093 ± 2108||6527 ± 2178||616 ± 149||1635 ± 683||3203 ± 1632|
|t½, h†||1.1 ± 0.5||1.2 ± 0.3||1.4 ± 0.1||1.0 ± 0.6||0.8 ± 0.5||0.9 ± 0.5|
|CL/F, L/h||17.4 ± 9.1||21.2 ± 9.8||17.3 ± 7.5||13.8 ± 4.5||16.2 ± 6.6||16.7 ± 8.5|
|Vz/F, L||31.6 ± 19.5||39.6 ± 25.8||35.8 ± 17.7||21.0 ± 6.2||19.8 ± 7.1||22.9 ± 11.0|
|Time over 100 ng/mL, h/day||3.6 ± .0||5.6 ± 2.2||7.7 ± 0.5||4.7 ± 1.6||9.4 ± 2.5||10.9 ± 3.2|
When administered as a subcutaneous bolus injection, ABT-510 was rapidly absorbed, with a Tmax of approximately 0.5 hours. Thereafter, ABT-510 concentrations decreased, with a t1/2 of approximately 1 hour. All dose regimens produced ABT-510 concentrations of ≥100 ng/mL for >3 hours/day.
Across regimens, there were no statistically significant trends with dose noted in the ABT-510 dose-normalized AUC, Tmax, or β (P ≥ .07). The dose-normalized ABT-510 Cmax on Day 1 decreased somewhat with increasing dose (approximately 20% from 10 mg to 100 mg; P ≥ .03). However, there was no statistically significant difference in the dose-normalized ABT-510 Cmax noted between the 10-mg and 100-mg dose groups (P = .12). There was no statistically significant trend with dose noted in the Tmax, or dose-normalized ABT-510 Cmax on Day 22 (P ≥ .11). The ABT-510 dose-normalized Cmax and dose-normalized AUC decreased with increasing weight (approximately 50% from 50 kg to 100 kg; P ≤ .01). Females had larger β values than males (P = .01); however, ABT-510 t1/2 values averaged between 1 hour to 1.5 hours for both sexes. ABT-510 pharmacokinetics were similar on Day 1 and Day 22. Variability in the ABT-510 pharmacokinetics between individuals was relatively low. Across dose groups, coefficients of variation in the ABT-510 Cmax and AUC averaged approximately 40%. After multiple subcutaneous bolus doses in patients with cancer, ABT-510 clearance (CL/F) averaged 22 L/hour (mean ± standard deviation; N = 12) and the apparent volume of distribution (Vz/F) averaged 33 L.
Individual patient exposure to ABT-510 is shown in Figure 2. Tumor assessment data for the 50 patients who received ABT-510 indicated that 28 patients (56%) had stable disease at the 8-week tumor evaluation, 10 patients (20%) had stable disease at the 16-week tumor evaluation, and 6 patients (12%) had stable disease at the 24-week evaluation. Although there were few patients at each dose level, there was no suggestion of a dose response.
Three of 9 patients (33%) with soft tissue sarcoma were free of disease progression for ≥24 weeks while on the study. One patient with a carcinosarcoma of the parotid gland and metastases in the lung who received 20 mg of ABT-510 QD had a confirmed partial response beginning at the 8-week tumor evaluation; the response was equivalent to an overall decrease in tumor volume of >60% at the 56-week assessment. This patient remained on study for 65 weeks until disease progression.
CECs were quantified in patients at baseline, at Week 3, at Week 8, and at the time of disease progression. Of the 165 specimens drawn for CEC analysis, only 114 were considered interpretable (69%), with the remaining specimens considered to be uninterpretable secondary to poor specimen viability (25%) or protocol deviations (6%). For comparison of CEC trends over time, patients were divided into 2 groups: those patients with rapid disease progression as defined as remaining on study ≤8 weeks (n = 29 patients) versus patients who remained on study for >12 weeks (n = 14 patients). There was no statistical difference noted with regard to the median number of CECs/μL at baseline for patients with rapid disease progression versus those who were on study for >12 weeks (27 CECs/μL vs 18 CEC/μL). However, at the later time points of 3 weeks and 8 weeks, there was a suggestion of increasing CECs in those patients whose disease progressed rapidly versus those who remained on study for >12 weeks (Fig. 3). The difference in CEC levels did not reach statistical significance (P = 0.2); however, the number of blood samples from the patients who remained on study >12 weeks was small.
The results of the current phase 1 study demonstrated that ABT-510 can be administered at doses ranging from 20 mg/day to 100 mg/day without significant toxicity. The pharmacokinetic target threshold of ABT-510 (ie, ABT-510 at ≥100 ng/mL for a minimum of 3 hours per day) was achieved for all the dose regimens evaluated in this study. No DLT was observed at the doses and schedules studied.
In animal toxicology studies, ABT-510 is reported to have a favorable profile.20 The only significant toxicity noted was renal tubular epithelial damage, which was observed in rats in whom ABT-510 was administered by bolus injection at a dose of 75 mg/kg/day for 1 week. No toxicities were observed in rats or monkeys at Cmax and plasma exposures (AUCs) >10-fold higher than those observed at the highest clinical dose tested.
ABT-510 has been administered to >300 patients with cancer at doses ranging from 20 mg to 260 mg per day for up to 17 months.21–25 Overall, the safety profile has been favorable. The majority of adverse events related or possibly related to ABT-510 have been reported as grade 1 or 2 toxicities (mild or moderate). Those toxicities considered possibly or most likely related to ABT-510 were injection site reaction (100%), asthenia (52%), nausea (34%), and headache (35%). To our knowledge, no correlation between dose and adverse events has been identified to date, and a maximally tolerated dose has not been determined. No laboratory abnormalities related to ABT-510 have been reported in ongoing advanced cancer studies. To our knowledge, there also has been no evidence of drug-related renal toxicity, myelosuppression, or hypertension, toxicities that are commonly associated with other antiangiogenic agents, observed to date. Dose escalation was stopped at 260 mg per day, the maximum clinically practical dose.
ABT-510 pharmacokinetics were found to be dose proportional and independent of time across the range tested. After subcutaneous dosing, ABT-510 was rapidly absorbed, with the Cmax most frequently observed 0.5 hours after dosing. ABT-510 was eliminated with a t1/2 of approximately 1 hour. The minimal accumulation of plasma concentrations after QD and twice-daily dosing was consistent with the t1/2 and stable pharmacokinetics over time. In the current study, ABT-510 pharmacokinetics were similar to those previously observed in healthy subjects and in prior studies of patients with advanced cancer.21 All ABT-510 dose regimens administered in the current study achieved the potential pharmacokinetic endpoint of maintaining plasma concentrations >100 ng/mL for at least 3 hours per day,20 ranging from 3.6 hours per day for the 20-mg-QD dose to 10.9 hours per day for the 50-mg-twice-daily dose schedule.
Although to our knowledge ABT-510 drug-drug interaction studies have not been conducted in human patients to date, the effects of ABT-510 on cytochrome P450 (CYP) activity have been evaluated in vitro. At concentrations of 30 μM (approximately 30 μg/mL), ABT-510 did not alter cytochrome P450-dependent monooxygenase activities in pooled human liver microsomes, including CYP3A, 2D6, 2A6, 2C9, 2C19, 2E1, and 1A2.19 Metabolism-based interactions are not anticipated between ABT-510 and drugs whose clearance is mediated predominately via metabolism by these cytochromes.
Preliminary data on tumor assessment for the 50 patients who received ABT-510 indicate that 28 patients (56%) had stable disease at the 8-week tumor evaluation, 10 patients (20%) had stable disease at the 16-week tumor evaluation, and 6 patients (12%) had stable disease at the 24-week evaluation. Minimal single-agent activity was observed that may be secondary to the cytostatic nature of antiangiogenic agents, the redundancy of antiangiogenic pathways in heavily pretreated patients and those with refractory disease, or the inactivity of the drug at the doses or schedules tested. This level of antitumor activity is similar to the results obtained with other antiangiogenic agents in monotherapy phase 1/2 clinical trials, including bevacizumab.26–28 Although the data are limited, stabilization in the number of CECs also appeared to be correlated with prolonged disease stabilization in the patients in the current study and suggests that our results with ABT-510 treatment may be secondary to antiangiogenic rather than other antitumor effects. Other groups have documented that decreases in CEC levels are correlated with responses to antiangiogenic therapies while increasing levels are predictive of progressive disease.29–31 To our knowledge the best method or subgroup of CECs for monitoring antiangiogenic effects is still controversial.32, 33 Recent publications have suggested that analysis of the apoptotic fraction of CECs or measurement of CEC precursors (CEP) may be superior biomarkers for antiangiogenesis monitoring rather than quantification of the total number of CECs.34, 35 CEC levels also can decrease in response to effective antitumor therapies that do not target angiogenesis and thus alternative mechanisms for disease stabilization observed with ABT-510 therapy are possible.
In summary, the thrombospondin-mimetic peptide ABT-510 is a potent, pleiotropic inhibitor of angiogenesis. The pharmacokinetic profile of ABT-510 makes it appropriate for once-daily or twice-daily subcutaneous injection, and ABT-510 has an acceptable safety profile when administered using daily subcutaneous bolus injection in patients with cancer. The toxicities associated with other antiangiogenic agents, including hypertension and proteinuria, have not been observed to date with the use of ABT-510.24 Future phase 2 studies in both solid tumors and hematologic malignancies therefore are justified. The safety and metabolic profile of ABT-510 make it an attractive agent for use in combination with cytotoxic chemotherapy. It is in this role, combined with chemotherapy for use as first-line or second-line treatment of solid tumors, that we will best determine its ultimate efficacy as an antiangiogenic agent.
- 9Signals leading to apoptosis-dependent inhibition of neovascularization by thrombospondin-1. Nat Med. 2000; 61: 41–48., , , et al.
- 19Abbott Laboratories. Information for Clinical Investigators: ABT-510. Global Pharmaceutical Research and Development of Abbott Laboratories. 4th ed. Abbott Park, IL: Abbott Laboratories; 2002.
- 20Pharmacokinetic/pharmacodynamic (PK/PD) relationships for the angiogenesis inhibitor ABT-510 in preclinical efficacy models. Eur J Cancer. 2002; 38( suppl 7): 250., , , et al.
- 23Dose-finding and pharmacokinetic study of ABT-510 with gemcitabine and cisplatin in patients with advanced cancer. Ann Oncol. 2006; 8: 1320–1327., , , et al.
- 25A randomized phase 2 study of the thrombospondin-mimetic peptide ABT-510 in patients with advanced soft tissue sarcoma (STS) [abstract]. Proc Am Soc Clin Oncol. 2005; 23: 9013a., , , et al.