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Annals of Oncology Advance Access originally published online on November 9, 2005
Annals of Oncology 2006 17(1):97-103; doi:10.1093/annonc/mdj055
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© 2005 European Society for Medical Oncology

Recombinant human angiostatin (rhAngiostatin) in combination with paclitaxel and carboplatin in patients with advanced non-small-cell lung cancer: a phase II study from Indiana University

A. Kurup1, C.-W. Lin3, D. J. Murry3, L. Dobrolecki2, D. Estes1, C. T. Yiannoutsos1, L. Mariano1, C. Sidor4, R. Hickey2 and N. Hanna1,*

1 Indiana University School of Medicine; 2 Indiana University, Indianapolis, IN; 3 University of Iowa, College of Pharmacy, Iowa City, IA; 4 EntreMed, Inc., Rockville, MD, USA

* Correspondence to: Dr N. H. Hanna, Indiana University, 535 Barnhill Drive, RT 473, Indianapolis, IN 46202, USA. Tel: +1-317-274-3515; Fax: +1-317-274-3646; E-mail: nhanna{at}iupui.edu


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 References
 
Background: Recombinant human angiostatin (rhAngiostatin) functions as a potent inhibitor of angiogenesis. This study combined rhAngiostatin with a standard chemotherapy regimen in patients with advanced non-small-cell lung cancer (NSCLC).

Patients and methods: Eligible patients had chemotherapy-naïve stage IIIB (with pleural effusion) or IV NSCLC, performance status (PS) 0 or 1, no history of bleeding, brain metastasis or requirements for anti-coagulation. Patients received carboplatin (AUC 5) intravenously and paclitaxel (175 mg/m2) intravenously day 1 + subcutaneous rhAngiostatin at either 15 mg or 60 mg twice daily. Cycles were repeated every 3 weeks, for up to six cycles. Patients without progression after completing at least four cycles were continued on maintenance rhAngiostatin until disease progression.

Results: Patient characteristics (n = 24) were: 16 males, median age 66 years (range 45–78), 54% PS 1, 83.3% stage IV and 62.5% adenocarcinoma. Grade 3/4 toxicities included: fatigue 47.8%, neutropenia 39.1%, dyspnea 39.1%, vascular 26.1% and infection 17.4%. The overall response rate was 39.1%, 39.1% stable disease and 21.7% progressive disease. Median time to progression was 144 days, and 1-year survival was 45.8%.

Conclusions: rhAngiostatin in combination with paclitaxel and carboplatin is feasible and results in a high disease control rate in patients with advanced NSCLC.

Key words: angiogenesis, carboplatin, lung cancer, paclitaxel, rhAngiostatin


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 References
 
Lung cancer is the leading cause of cancer mortality. The majority of patients with non-small-cell lung cancer (NSCLC) present with locally advanced or metastatic disease. In advanced NSCLC, platinum-based chemotherapy modestly improves survival compared with best supportive care [1Go–3Go]. Empiric treatment with many chemotherapy regimens results in response rates of 20–30%, with stable disease (SD) rates of approximately 30% [4Go, 5Go]. In metastatic disease, median time to progression (TTP) with these regimens is typically about 4 months, median survival time is 8–9 months and 1-year survival is 35–40%. Therefore, novel therapeutic approaches, such as angiogenesis inhibition, are being investigated to improve outcomes in advanced NSCLC.

Angiogenesis describes new blood vessel formation from pre-existing vascular networks or capillaries. As a normal physiologic process, it plays an important role in embryogenesis, pregnancy and tissue repair [6Go]. Angiogenesis also plays an important role in tumor growth and metastasis. In 1971, Folkman [7Go] hypothesized that cancer cells were dependent on angiogenesis to grow beyond 1 or 2 mm in size. His pioneering work showed that solid tumor cells which were implanted in vascular sites in animals grew rapidly, while cells implanted in avascular sites were unable to form masses larger than 1–2 mm. More recent laboratory studies have supported this conclusion [8Go–11Go]. New microvessels within tumors have a high turnover rate and the replication rate of the endothelial cells in tumors can be 100-fold greater than that of endothelial cells in vessels of normal tissue [12Go]. Therefore, impeding the angiogenic stimulus that promotes the high replication rate of tumor endothelial cells may lead to eventual involution of growing microvessels and cause tumor regression [7Go].

As a complex process, angiogenesis is under both positive and negative control. Evaluating the key components of initiation and control of angiogenesis has lead to novel strategies to inhibit it. Growth factors, such as vascular endothelial growth factor (VEGF), can be selectively targeted in multiple ways to block their stimulation by inhibition of endothelial cell proliferation [13Go]. Tumor growth inhibition of VEGF may be achieved via anti-VEGF monoclonal antibodies [14Go, 15Go], VEGF receptor small molecule kinase inhibitors [16Go, 17Go] or soluble VEGF receptors [18Go, 19Go].

Exogenous administration of agents that possess an endogenous negative regulatory influence on angiogenesis have also shown efficacy in animal models [20Go–22Go]. Angiostatin, a 38 kDa proteolytic fragment of plasminogen, is a naturally occurring potent inhibitor of angiogenesis, tumor growth and metastasis. Angiostatin was discovered during tumor dormancy studies explaining the process by which primary tumors inhibit growth of remote metastases [20Go]. Thus, recombinant human angiostatin (rhAngiostatin; EntreMed) was developed as a rational therapeutic agent for the treatment of cancer, such as NSCLC [23Go, 24Go]. In vitro, rhAngiostatin protein inhibited endothelial cell proliferation and migration in response to basic fibroblast growth factor (bFGF). In addition, in vitro, bFGF-induced angiogenesis was also inhibited by rhAngiostatin.

The activity of rhAngiostatin has been demonstrated in preclinical and clinical studies. Treatment of mice with this protein inhibited growth of tumors and their metastases [25Go, 26Go]. The combination of rhAngiostatin with chemotherapy or radiation therapy has been shown to enhance the antitumor effect [27Go, 28Go]. In phase I studies, intravenous and subcutaneous dosing with rhAngiostatin has been feasible [24Go, 29Go]. We report the results of a randomized, open-label, phase II study of two doses of subcutaneous rhAngiostatin protein administered in combination with paclitaxel and carboplatin to patients with advanced NSCLC. We also explored the use of surface enhance laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) to evaluate any protein expression pattern between disease response groups.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 References
 
eligibility
Eligible patients had histologically or cytologically confirmed NSCLC (including squamous cell carcinoma); stage IIIB with malignant pleural effusions or stage IV or recurrent disease (defined as previously resected lung cancer with recurrence of disease not amenable to curative treatment); no previous chemotherapy for NSCLC; bidimensionally measurable disease; aspartate aminotransferase and alanine aminotransferase ≤2.5x the upper limits of normal (ULN), total bilirubin ≤1.5 mg/dl, creatinine ≤1.5 mg/dl, absolute neutrophil count ≥1500/mm3, platelets ≥100 000/mm3, international normalized ratio ≤1.2, activated partial thromboplastin time ≤5 s of ULN; and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. All patients provided written informed consent.

Patients were excluded from study enrollment if they had central nervous system (CNS) metastases; grade ≥3 peripheral neuropathy; history of myocardial infarction or angina within the prior 6 months, or uncontrolled congestive heart failure; ≥30 ml hemoptysis within the prior 3 months; active infection; history of bleeding diathesis, hypercoagulable condition, or active bleeding disorder; or current treatment with heparin or warfarin.

study design
This was a randomized, open-label, phase II study designed to test the safety and efficacy of two dose levels of subcutaneous rhAngiostatin protein administered in combination with paclitaxel and carboplatin. The primary objectives were to assess safety and estimate tumor response rates. The secondary objectives were to estimate duration of response, TTP and survival at 1 year. The protocol was approved by the Indiana University institutional review board.

All patients received paclitaxel (175 mg/m2, 3-h infusion) followed by carboplatin (AUC of 5 mg/ml·min) administered by intravenous infusion on day 1, and repeated every 21 days, for up to six cycles of treatment. Patients were randomized to receive either 15 or 60 mg rhAngiostatin protein administered twice daily by subcutaneous injection continuously, beginning on day 2 of the first treatment cycle. Patients completing at least four cycles of treatment (chemotherapy and rhAngiostatin combination) and who continued to meet eligibility criteria were allowed to continue rhAngiostatin as a single agent until study termination. Patients were allowed to continue on study in the absence of progressive disease or treatment-related toxicity.

evaluation
Patients were evaluated at baseline and at every 21-day treatment period. After termination from the study, they were evaluated for survival at 4-week intervals up to 1 year after starting the study. Disease response was determined according to WHO criteria [30Go]. Tumor response was evaluated by radiographic assessment at baseline and repeated at the end of every other treatment cycle, for the duration of the combined chemotherapy and rhAngiostatin regimen. For those patients continuing on single-agent rhAngiostatin protein, tumor response was evaluated every 8 weeks.

pharmacokinetic studies
Blood samples (4 ml) for paclitaxel were collected in a serum separator or standard red top tube before the intravenous infusion and at 15, 30 and 45 min, and 1, 2, 3, 4, 6, 12 and 24 h after the end of the 3-h paclitaxel infusion. For carboplatin, blood samples were collected in tubes containing heparin before the carboplatin administration and at 30 min, and 1, 2, 3, 6, 12 and 24 h after infusion. Carboplatin plasma samples (200 µl) were transferred to two Centrifree centrifuge tubes (Amicon; Millipore) and spun at 1000 RCF. The ultrafiltrates were collected and stored. All of the samples were cryopreserved at –70°C until analysis. Analysis of carboplatin was performed by using a validated atomic absorption spectroscopy method. The assay was linear from 20 to 600 ng/ml of elemental platinum and control samples at 40 and 500 ng/ml were within 10% of the desired value. Paclitaxel was measured using a validated high-performance liquid chromatography with a mass spectrometer method. The assay was linear from 1 to 1000 ng/ml and control samples at 8, 75 and 500 ng/ml were within 10% of the measured value.

To determine the impact of rhAngiostatin co-administration, pharmacokinetic (PK) parameters for carboplatin and paclitaxel were determined by compartment-dependent methods on cycle 1 (no rhAngiostatin) and cycle 2 (with rhAngiostatin). ADAPT II software (Biomedical Simulation Resource, Los Angeles, CA, USA) was used for pharmacokinetic modeling, and parameters were estimated by standard maximum a priori (MAP) Bayesian estimation with prior parameter distributions determined from the literature.

statistical analysis
No previous rhAngiostatin and chemotherapy combination studies had been conducted on which to base sample size calculations for this trial. We assumed that the treatment would be worthy of further consideration if the true response rate were at least 20% (alternative hypothesis) versus a baseline rate of 5% (null hypothesis). This is a two-stage, non-comparative, parallel study design with two arms (rhAngiostatin at 15 and 60 mg). With a two-stage design, we planned to enroll 10 patients in the first stage and 19 at the second stage in each arm. After 10 patients were enrolled and received at least four cycles of combination therapy, an interim analysis was to be performed. If two or more of the 10 patients demonstrated a tumor response after four cycles of therapy, then 19 additional patients were to be enrolled in that treatment arm. With this design, if the treatment is effective, there would be at least an 80% chance (power) to conclude that the true response rate is higher than 20%, when carrying out the final analysis at the 5% alpha level. The study was closed prior to achieving the planned accrual because EntreMed, the sponsor for this trial, made a decision to discontinue the development of rhAngiostatin.

Descriptive statistics including median and range are given. A signed-rank non-parametric test was carried out to compare differences between PK parameters between cycles 1 and 2. Duration of time without progression was estimated by the Kaplan–Meier method. Confidence intervals (CIs) were produced by the method of Greenwood. All analyses were carried out by the SAS software (SAS Institute, Cary, NC, USA).

proteomics studies
Twenty-two patients consented to further serum studies, and an exploratory analysis of their sera via surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was conducted. Serum samples were obtained on day 1, prior to rhAngiostatin protein administration, and applied on weak cation exchange surface chip arrays. The arrays were prepared and analyzed by mass spectrometry in a standard fashion as per the Ciphergen Biosystems ProteinChip® system protocol.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 References
 
patient characteristics
From July 2002 to November 2003, 24 patients were enrolled onto the study. Patient characteristics are summarized in Table 1. The median age was 66.5 years (range 45–78), 46% of patients had an ECOG PS of 0, 83.3% had stage IV disease and 62.5% had adenocarcinoma.


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  		Table 1. Patient characteristics

 
Patients received a median of four cycles of chemotherapy (range one to six). Thirteen patients (54.2%) were randomized to receive 15 mg of rhAngiostatin (arm 1) and 11 patients (45.8%) received 60 mg rhAngiostatin (arm 2). Median duration of rhAngiostatin treatment was 125 days (range 1–573). There was 99.4% compliance with rhAngiostatin, with 6638 doses administered out of 6678 planned doses. One patient was discontinued off therapy after one dose of rhAngiostatin owing to patient's wishes.

toxicity
Table 2 summarizes toxicity data. Specific grade 3 or 4 toxicities included: neutropenia (39.1%), dyspnea (39.1%), infection (17.4%) and skin (4.3%). Grade 3/4 vascular events occurred in 26.1% of patients (three patients with atrial fibrillation, two with pulmonary embolus, one with transient ischemic attack and one with cerebrovascular attack). There were no treatment-related deaths.


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  		Table 2. Toxicity data (n = 23)

 
efficacy
Twenty-three of 24 patients enrolled in the study were evaluable for response (Table 3). One patient in arm 1 withdrew on day 2 of the study after receiving one cycle of chemotherapy and one dose of rhAngiostatin, owing to personal wishes. Of the 23 patients evaluated, there was a 39.1% partial response rate (PR), 39.1% SD and 21.7% progressive disease rate (PD). Duration of PR was up to 489 days. In arm 1 (n = 12 evaluable patients) there was a 25% PR, 50% SD and 25% PD. In arm 2 (n = 11) there was 54.5% PR, 36.4% SD and 9.1% PD. The overall median TTP was 144 days (95% CI 135–234) (Figure 1). There were four patients with partial responses that lasted >200 days (range 234–570), and one patient had SD for 252 days. Of these five patients, four (three PRs, one SD) received the 60 mg rhAngiostatin dose. The 1-year survival was 45.8% (exact 95% CI 25.6% to 67.2%). Five of the 24 patients enrolled are alive at last analysis (May 2005), and the range of survival was 106 to 626+ days.


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  		Table 3. Response data

 


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  		Figure 1. Overall time to progression.

 
pharmacokinetics
Ten patients completed carboplatin PK studies and 12 patients completed paclitaxel PK studies. Carboplatin clearance was not different from cycle 1 to cycle 2 (Figure 2). Paclitaxel Vmax and Km were not different from cycle 1 to cycle 2 (Figure 3).



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  		Figure 2. Box plots of carboplatin clearance (Cl) in cycle 1 and cycle 2. The dots represent the calculated carboplatin clearance for each individual patient. The blue line connects the two means.

 


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  		Figure 3. Compartment dependent model: box plots of Vm10 and Km10 of paclitaxel in cycle 1 and cycle 2. Black line: connection line of two means.

 
proteomics
Twenty-two baseline serum samples were obtained and analyzed via SELDI-TOF MS (Figures 4 and 5). Our data indicate that most of the protein peaks found in the SELDI-TOF spectra were present across the disease response groups (PR, SD, PD). Protein expression profiles and preliminary data analysis also show individual proteins that are expressed with different intensities between the response groups. In particular, protein peaks with an m/z value of 7600, 5800, 3800 and 3700 were expressed to substantially higher levels in individuals exhibiting a partial response to treatment than individuals exhibiting either SD or PD. A substantially larger pilot study involving additional patients would be required to identify and validate any clinically relevant response markers from the expression profiles seen for the three groups examined in our study.



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  		Figure 4. Protein expression profiles and disease response. PD, progressive disease; SD, stable disease; PR, partial response.

 


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  		Figure 5. Comparison of composite expression profiles by disease response groups. PD, progressive disease; SD, stable disease; PR, partial response.

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
References
 
This phase II study investigated the combination of rhAngiostatin protein with chemotherapy in the treatment of patients with stage IIIB or IV NSCLC. The response rate was at least comparable to or higher than previous responses to chemotherapy alone in advanced NSCLC. The overall disease control rate (PR + SD) was also higher than historical controls. The response rate was higher in the 60 mg dose rhAngiostatin arm, including some patients with durable response, but the patient numbers are too small to make strong conclusions regarding a dose response.

The overall activity of this regimen and survival data exceed that of historical controls of carboplatin/paclitaxel alone. Optimal utilization of these agents, including duration of treatment, is not defined. Other studies have shown that antiangiogenic agents may require long-term use to observe significant antitumor effect, and initially tumor progression might continue before tumor regression is evident [20Go, 31Go]. Patients in our current study were allowed to continue use of rhAngiostatin if they were able to complete at least four cycles of combined therapy with chemotherapy. It is not known whether in advanced disease, the antiangiogenic effects of rhAngiostatin can outbalance the tumor burden of advanced disease and the already established metastatic sites of disease. Angiogenesis inhibition might be more effective as chronic therapy in earlier disease stages. We have yet to understand the appropriate scheduling of chemotherapy and antiangiogenic agents in a rational biological approach to affect maximal antitumor activity. Perhaps we have not reached the optimal biological dose of this agent (as opposed to the maximally tolerated dose). There might be complex effects of carboplatin and paclitaxel on cancer cells that interfere with the antiangiogenic impact of rhAngiostatin on the same cells, or vice versa.

Recently the ECOG reported the positive results of a phase II/III study of bevacizumab [recombinant humanized monoclonal antibody against VEGF (Avastin)] in combination with carboplatin/paclitaxel as a first-line treatment in advanced NSCLC [32Go]. With the addition of bevacizumab, there was a statistically significant increase in response rate (27% versus 10%), progression-free survival (6.4 versus 4.5 months) and median survival (12.5 versus 10.2 months). This study and the positive study of bevacizumab in combination with chemotherapy in metastatic colorectal carcinoma [33Go] serve as ‘proofs of principle’ that inhibiting the angiogenesis pathway can clinically impact survival. Bevacizumab acts by inhibiting a proangiogenic protein, while rhAngiostatin acts as an antiangiogenic agent. The optimal strategy for angiogenesis inhibition in human tumors is not yet defined.

A previous phase I study of rhAngiostatin used alone in patients with various tumors observed grade 3 or 4 toxicities which included: CNS metastasis bleeding, deep venous thrombosis, dyspnea, hypertension and diarrhea [29Go]. No relevant changes in coagulation tests from baseline were noted during treatment. The vascular events noted in our study are of interest owing to concerns of detrimental effects with manipulation of the angiogenic cascade. In the phase II study of bevacizumab with carboplatin/paclitaxel in advanced NSCLC, six patients developed severe hemoptysis, including five resulting deaths [34Go]. Since four of these patients had squamous cell histology, the follow-up phase III trial (E4599) excluded patients with squamous cell carcinoma [32Go]. In that trial, the bevacizumab containing arm had more hemorrhage (4.1% versus 1.0%) and five treatment-related deaths due to hemoptysis. Although various vascular events may be a class effect for antiangiogenesis agents, this rhAngiostatin study did not have any severe hemorrhagic events.

Discovery of biomarkers that predict response to therapy will be important to tailor therapy to appropriate NSCLC patient groups. Proteomics-based approaches are the new, emerging technologies that attempt to understand the biology of cancer through protein expression analysis [35Go]. One of the more widely used approaches, SELDI-TOF, is capable of reliably detecting protein expression profiles that can distinguish between individuals with and without lung cancer. In addition, exploring differentially expressed proteins in appropriate patient groups may provide new strategies for predicting response to therapy and for identifying novel biomarkers. While a genome remains unchanged to a large extent, the proteins in any particular cell change dramatically as genes are turned on and off in response to the environment. Furthermore, while proteomics and genomics are complementary fields, proteomics extends functional analysis, since genomic information does not predict post-translational modifications that occur in most proteins. Our exploratory SELDI-TOF MS analysis of baseline serum samples of 22 patients demonstrated distinct protein profiles, which show specific proteins that are consistently expressed, but differ in their levels of expression, across disease response groups. Larger studies will be needed, with the ultimate goal of using individual and composite protein biomarkers to select patients appropriate for specific treatment regimens, to predict prognosis and to identify new targets for therapy.

Overall, rhAngiostatin in combination with carboplatin and paclitaxel was feasible. This combination results in a high disease control rate in patients with advanced NSCLC, compared with historical controls. While this study failed to meet its planned sample size, the results with this combination are similar to that seen with carboplatin/paclitaxel/bevacizumab in a phase III study (with a much larger sample size). The rate of vascular toxicity reported in this trial is of concern; however, the sample size is small and some of these events may have been due to the underlying malignancy. Further study of rhAngiostatin in NSCLC is warranted; however, further development of the drug is uncertain at this time.


   Acknowledgements
 
The authors also wish to thank Mark Schmidt for his excellent technical assistance. The proteomics work was supported in part by start-up funding for R.H. from the Indiana University Cancer Center.

Received for publication July 29, 2005. Revision received September 20, 2005. Accepted for publication September 26, 2005.


   References
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 results
 discussion
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Z. Shen, Z. F. Yang, Y. Gao, J. C. Li, H. X. Chen, C. C. Liu, R. T.P. Poon, S. T. Fan, J. M. Luk, K. H. Sze, et al.
The Kringle 1 Domain of Hepatocyte Growth Factor Has Antiangiogenic and Antitumor Cell Effects on Hepatocellular Carcinoma
Cancer Res., January 15, 2008; 68(2): 404 - 414.
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