Annals of Oncology Advance Access originally published online on July 15, 2008
Annals of Oncology 2008 19(11):1903-1909; doi:10.1093/annonc/mdn412
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lung cancer |
Noncytotoxic suramin as a chemosensitizer in patients with advanced non-small-cell lung cancer: a phase II study
1 Departments of Medicine, Pharmacology and College of Pharmacy, The Ohio State University, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, The National Cancer Institute, Bethesda, MD
2 Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, OH, USA
* Correspondence to: Dr M. A. Villalona-Calero, The Ohio State University, B406 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210-1240, USA. Tel: +1-614-293-7511; Fax: +1-614-293-4372; E-mail: miguel.villalona{at}osumc.edu
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Abstract |
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Background: The purpose of this study was to evaluate the potential of noncytotoxic doses of suramin to reverse chemotherapy resistance in advanced chemonaive and chemoresistant non-small-cell lung cancer patients.
Patients and methods: Patients received paclitaxel (Taxol) (200 mg/m2) and carboplatin (area under the concentration–time curve 6 mg/ml/min) every 3 weeks. The total suramin per cycle dose was calculated using a nomogram derived from the preceding phase I trial to obtain the desirable plasma concentration range of 10–50 µM.
Results: Thirty-nine response-assessable chemonaive patients (arm A) received 213 cycles. Thirty-eight cycles were administered to 15 patients with demonstrated resistance to paclitaxel and carboplatin (arm B). The pattern/frequency of toxic effects was similar to those expected for paclitaxel/carboplatin, and pharmacokinetic analyses (199 cycles) showed suramin plasma concentrations maintained between 10 and 50 µM in 94% of cycles. In arm A, response evaluation criteria in solid tumors (RECIST) response rate was 36% (95% confidence interval 22% to 54%; two complete, 12 partial); 15 patients (38%) had disease stabilization for 
4 months; median progression-free survival (intention to treat) was 6.4 months; median overall survival (OS) 10.4 months and 1-year survival rate 38%. In arm B, no RECIST responses occurred; four patients had disease stabilization for 4 months; median OS was 132 days and 1-year survival rate 7%. Plasma basic fibroblast growth factor levels were higher in chemopretreated/refractory patients compared with chemonaive patients (P = 0.05). Sequence analysis of the EGFR tyrosine kinase domain in a long-term disease-free survivor revealed an ATP-binding pocket mutation (T790M).
Conclusions: Noncytotoxic suramin did not increase paclitaxel/carboplatin's toxicity and the suramin dose was predicted from clinical parameters. No clinically significant reversal of primary resistance was documented, but a modulatory effect in chemotherapy-naive patients cannot be excluded. Controlled randomization is planned for further evaluation of this treatment strategy.
Key words: chemosensitization, drug resistance, FGF, lung cancer, suramin
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introduction |
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The polysulfonated naphthylurea suramin has been of interest as a candidate antitumor agent due to its activity against human tumor cell lines [1, 2]. Several mechanisms for suramin cytotoxicity have been proposed, including inhibition of reverse transcriptases and mitochondrial enzymes and inhibition of binding of growth factors to their receptors [3–12]. However, the suramin levels required for cytotoxicity have been associated with significant toxic effects [13–24].
In contrast to the high concentrations required for cytotoxicity, inhibition of some growth factors by suramin occurs at substantially lower concentrations. For example, basic fibroblast growth factor (bFGF), which has been implicated in neovascularization and tumor growth [11, 25], is inhibited at suramin concentrations below 50 µM [26]. Our group previously reported that high levels of acidic FGF and bFGF in solid metastatic tumors were associated with broad-spectrum resistance to anticancer drugs and documented reversal of chemoresistance in vitro and in vivo by low/noncytotoxic concentrations of suramin (10–20 µM) [27, 28]. Noncytotoxic suramin also reversed the chemotherapy-induced upregulation of survivin [29], a protein associated with chemoresistance [30].
Our previous observation of significant improvement of the antitumor effect of paclitaxel by noncytotoxic doses of suramin in tumor-bearing mice [28] motivated a phase I trial of suramin combined with paclitaxel/carboplatin in patients with advanced non-small-cell lung cancer (NSCLC) [31]. The primary end point was to determine safety and the suramin doses yielding plasma concentrations between 10 and 50 µM as higher concentrations have been associated with G1/S arrest and antagonism with doxorubicin [27, 32, 33]. Fifteen patients, including six previously treated with chemotherapy, received 85 cycles of carboplatin [calculated area under the concentration–time curve (AUC) of 6 mg/ml/min] and paclitaxel 175–200 mg/m2 in combination with suramin. The initial dose of suramin was 240 mg/m2, adjusted to yield the targeted concentrations in subsequent cycles on the basis of the real-time pharmacokinetic assessments. The combination was well tolerated and the pharmacokinetic data identified the equation that uses clinical parameters of individual patients to calculate the suramin dose (see ‘patients and methods’). Six of 10 patients with measurable disease experienced a partial response (PR) (RECIST criteria) and the median time to tumor progression for 12 assessable patients was 8.5 months [31].
This article reports the results of a phase II trial of the paclitaxel/carboplatin/suramin combination in two groups of advanced NSCLC patients: chemotherapy-naive and paclitaxel/carboplatin-resistant patients.
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eligibility
Patients with measurable and histologically confirmed stage IV NSCLC or with stage IIIB disease not amenable to curative-intent chemoradiation were eligible for this study. Patients were enrolled in one of two groups: arm A, chemotherapy naive and arm B, patients with disease progression while receiving paclitaxel (Taxol®, Bristol Myers Squibb)/carboplatin (Paraplatin®, Bristol Myers Squibb) or within 3 months of completion of this treatment. Prior irradiation was allowed provided the treated area was not the indicator lesion.
Eligibility criteria also included (i) age 18 years; (ii) Eastern Cooperative Oncology Group performance status of zero to two; (iii) life expectancy 3 months; (iv) no cytotoxic chemotherapy for 28 days; (v) adequate hematopoietic, hepatic and renal functions; (vi) no brain metastases/leptomeningeal disease, unless the lesions had been previously irradiated, not being treated with corticosteroids, and stable and asymptomatic; (vii) no myocardial infarction within the previous 6 months, congestive heart failure requiring therapy or unstable angina; (viii) no active infectious process or current treatment for human immunodeficiency virus; (ix) no uncontrolled diabetes mellitus; (x) no history of hypersensitivity to Cremophor EL; (xi) no grade 2 neuropathy; and (xii) absence of another invasive malignancy for >5 years. The treatment protocol and informed consent were approved by the Cancer Therapy Evaluation Program (CTEP) at the National Cancer Institute (NCI, Bethesda, MD) and the Institutional Review Board at The Ohio State University. Patients gave written informed consent before treatment.
dosage and drug administration
As recommended by the preceding phase I trial, the carboplatin dose was at an AUC of 6 mg/ml/min and the dose of paclitaxel was 200 mg/m2 [31]. The total dose of suramin was calculated on the basis of the following formula: dose in mg = FACTOR x (body surface area)2. The value of FACTOR for cycle 1 is 125 and for subsequent treatments is a function of the time elapsed since the initiation of the previous treatment. Suramin was administered in two divided doses: one preceding paclitaxel/carboplatin (two-thirds of dose) and the remaining 24 h later. Treatment was repeated at 3-week intervals.
Suramin was supplied by Division of Cancer Treatment and Diagnosis of NCI. Commercially available paclitaxel and carboplatin were obtained from the hospital pharmacy and prepared according to the manufacturer’s directions. All three drugs were administered by i.v. infusion, using an infusion pump. Suramin was administered over 30 min, paclitaxel over 3 h, and carboplatin over 1 h. Standard premedications included oral dexamethasone, diphenhydramine, famotidine, and ondasentron.
pretreatment assessment and follow-up studies
Histories, physical examinations, and routine laboratory studies were carried out before treatment and preceding each treatment cycle. Complete blood cell counts were also carried out weekly. Blood clotting times, urinalysis, pregnancy tests (when indicated), and electrocardiograms were carried out before initiating treatment. Toxic effects were graded according to the NCI Common Toxicity Criteria version 2.0 [34]. Tumors were measured after every two courses; treatment was continued in the absence of progressive disease or intolerable toxicity. The RECIST criteria [35] were utilized to define objective response.
blood sampling and analysis
To ascertain that the dosing calculation described above was able to achieve the desired plasma concentration of suramin (total of free and bound) between 10 and 50 µM, the pharmacokinetics of suramin were estimated during all treatments using the following limited sampling schedule. Blood samples (10 ml in green-top tubes) were obtained from a site contralateral to the drug infusion immediately before initiation of the suramin infusion and at 24 h postinfusion in the first 11 patients. The sampling was expanded in the remaining 47 patients at seven time points: within 1 h before the start of the first suramin infusion, at the end of the suramin infusion, at the end of paclitaxel infusion, at the end of carboplatin infusion, 6 h from the beginning of the first suramin infusion, within 1 h before the start of the second suramin infusion, and 2 h after the second infusion ended. Plasma concentrations were determined using high-performance liquid chromatography as previously described [36]. A two-compartment open pharmacokinetic model was fit to the plasma concentration–time data for individual patients to obtain the concentrations at 48 h of each cycle. Plasma levels of acid fibroblastic growth factor (aFGF)/bFGF were determined using ELISA kits (R&D systems, Minneapolis, MN) according to the manufacturer's instructions.
end points and statistical considerations
The primary end point was objective response rate. The predetermined sample size was different for the two groups of patients given the differences in the probability for antitumor responses. For the chemotherapy-naive patients, it was on the basis of an assumed 30% objective response rate for paclitaxel/carboplatin. Using a minimax two-stage phase II design of 28 and 11 response-assessable patients (total 39 patients), if eight or more patients responded in the first 28, the study was to continue to a total of 39 patients. An improvement in response rate from 30%–50%, with the addition of suramin, would be excluded with 90% power and an alpha of 0.1, if fewer than 8 of 28 or 16 of 39 responses were observed.
The sample size for the paclitaxel/carboplatin-resistant patients was on the basis of an uninteresting rate of response of 
10% and a response rate of 30% being clinically significant and suggestive of suramin reversal of resistance to paclitaxel/carboplatin. Using a minimax two-stage phase II design of 15 and 10 patients, if two or more patients responded in the first 15, the study was to continue to a total of 25 patients. A response rate of 30% would be excluded with 90% power and an alpha of 0.1, if fewer than 2 of 15 or 6 of 25 responses are observed.
Secondary descriptive end points for both groups of patients included median times to tumor progression, 1-year survival rates, and ability to calculate the suramin dose using clinical parameters of individual patients. bFGF plasma concentrations were evaluated for differences between patient groups and variation with time using analysis of variance and/or Student's t-test. The evaluation of relationships involving categorical variables used Spearman correlations. Analyses were carried out using the General Linear Model and TTEST procedures of SAS (Cary, NC).
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patient characteristics
Table 1 illustrates patient demographics. Fifty-eight patients were enrolled from September 2001 to February 2004: 43 on arm A and 15 on arm B. In arm A, one patient was not eligible due to a revised diagnosis to metastatic breast cancer, two patients were not assessable for treatment response due to the need for urgent radiation therapy shortly after the first dose of treatment, and one patient experienced sudden death within 2 weeks of the first administration of the combination. Thus, a total of 39 response-assessable patients in arm A received 213 cycles (range 2–10). Thirty-eight cycles were administered to the 15 patients on arm B.
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Previous treatment included prior irradiation in eight patients on arm A (to brain in four patients). In arm B, all patients had received previous paclitaxel/carboplatin treatments (median of 2, range 2–6 cycles) and had disease progression either while receiving treatments or within 3 months after treatments; nine patients had previous radiation and two had received additional chemotherapy following documented disease progression after paclitaxel/carboplatin.
toxicity
Toxic effects are depicted in Table 2. Grades 3 and 4 anemia occurred in 12% and 3% of patients, respectively, and 14% experienced grade 3 thrombocytopenia. Although grades 3/4 neutropenia were frequent (21% and 53% of patients, respectively), only one episode was associated with sepsis.
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Twenty-two percent of patients experienced grade 3 fatigue at some point during treatment and grade 3 neuropathy was observed in 7%. Toxic effects of lesser severity included nausea/vomiting and diarrhea. Two patients died on study for reasons other than disease progression: one due to myocardial infarction, while the other experienced sudden death of unknown etiology. One additional patient developed pulmonary thrombosis.
antitumor activity
Details pertaining to the antitumor effects of the combination are depicted in Table 3 and Figure 1. Fourteen of 39 assessable patients in arm A experienced major antitumor responses [two complete response (CR), 12 PR; response rate of 36%, 95% confidence interval of 22% to 54%] and 15 additional patients (38%) had prolonged disease stabilization (4 months). Response rate was 33% by intention to treat. Five patients showed progressive disease as best response. The distribution of responses according to histological NSCLC subtype was as follows: 5 of 17 adenocarcinomas; 5 of 12 squamous cell; 0 of 3 large-cell; and 4 of 7 not specified.
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Interestingly, a patient with stable disease (RECIST definition is < 30% reduction and < 20% increase in the sum of the longest diameters of all measured lesions and the appearance of no new lesions) by RECIST criteria, an African-American with previously resected squamous cell carcinoma and who had developed a second primary (well/moderately differentiated adenocarcinoma) metastatic to pleura and soft tissue, developed a positron emission tomography (PET) CR after two cycles of therapy. This response has been maintained for over 4 years after initial treatment. The median progression-free survival in the intention-to-treat group for the 42 NSCLC patients in arm A was 6.4 months; the median overall survival (OS) was 10.4 months; and the 1-year survival rate was 38%.
No responses were observed among 15 patients on arm B. However, disease stabilization was observed in seven patients including prolonged (4 months) disease stabilization in four patients and one patient had an unconfirmed (short-lasting) PR. The median OS was 132 days and the 1-year survival rate was 7%.
pharmacokinetics
The plasma concentrations of suramin are shown in Table 4. Residual concentrations were observed in the pretreatment samples from cycle 2 onward due to the long half-life. Concentrations were maintained above 10 µM in 96% of treatment cycles and below 50 µM in 97% and within the target range of 10–50 µM in 94% of treatment cycles.
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molecular correlates
Plasma concentrations of aFGF and bFGF were determined in six or more blood samples for day 1 (first cycle) of treatment and less frequently during the subsequent cycles. As a large fraction of the samples (
40%) showed nondetectable aFGF concentrations (below the detection limit of 63 pg/ml), measurement was discontinued after nine patients. Concentrations of bFGF were obtained from 71 patients (15 from the phase I trial and 56 from the phase II trial), including 21 who had been pretreated with chemotherapy among which 16 were chemotherapy refractory. Table 5 summarizes the plasma bFGF levels following the first cycle; significant intraday fluctuations were observed in individual patients (range up to >22-fold; median 4.3-fold; mean 5.3-fold; average standard deviation 95 ± 57% of the mean value). In comparison, the population mean values showed less fluctuation, with a range of 4.3–7.0 pg/ml for the chemotherapy-naive patients and 5.9–9.7 pg/ml in chemotherapy-pretreated/refractory patients. Figure 2 depicts the pretreatment bFGF levels according to RECIST response for both arms of the study. Although numbers are small, patients with CR or PR appear to have less spread in the bFGF concentration range. The data also showed a trend of increasing bFGF concentrations with the number of treatment cycles (P = 0.06, Spearman correlation).
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discussion |
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On the basis of the encouraging preclinical observation that noncytotoxic suramin potentiates the antitumor activity of chemotherapy in human xenograft tumors in mice [27, 28] and the encouraging safety profile of paclitaxel/carboplatin/suramin in a phase I trial [31], we launched the present phase II efficacy investigation. In consultation with NCI-CTEP, we tested preliminary efficacy of paclitaxel/carboplatin/suramin in two groups of advanced NSCLC patients, i.e. patients who had not been previously exposed to chemotherapy (arm A) and patients who had demonstrated primary resistance to paclitaxel/carboplatin (arm B).
The pharmacokinetic data demonstrated that the dosing nomogram derived from the phase I trial correctly predicted the targeted suramin concentration range of 10–50 µM in 94% of cycles. The safety profile was confirmed as well. However, the observed RECIST response rate in assessable patients, i.e. 14 of 39 or 36% in arm A and 0 of 15 in arm B, did not meet the respective prospectively set efficacy end points (16 of 39 and 2 of 15), thus excluding respective response rates of 50% and 30% in these two patient groups, with 90% power and an alpha of 0.1.
One might argue that a response rate of 50% in advanced, chemotherapy-naive NSCLC patients is unrealistic and that the observed median progression-free survival of 6.4 months by intention to treat is longer than expected in similar patients receiving paclitaxel/carboplatin without suramin or that the median OS of 10.4 months is at the upper end of the value that would be expected for paclitaxel/carboplatin. This argument is supported by the Waterfall plot (Figure 1) showing that only 5 of 39 assessable patients experienced tumor growth as their best response to therapy. In comparison, previous single-arm phase II trials using combinations of paclitaxel and carboplatin/cisplatin typically showed >20% of patients with progressive disease as best response [37, 38]. Similarly, a fraction of the patients (5 of 15 or 33%) with primary resistance to paclitaxel/carboplatin showed prolonged (4 months) disease stabilization or transient tumor shrinkage. Thus, it is possible that the primary end point (i.e. response rate) chosen in the design of the present study was not appropriate for ruling out the potential clinical benefit of disease stabilization by adding noncytotoxic suramin to chemotherapy.
The above is illustrative of the problems faced by traditional phase II clinical trials utilized in many instances for ‘go or no-go’ decisions in the development of novel anticancer therapies. This is especially compounded in trials that feature modulators of chemotherapy action. Further development could either be discouraged despite the presence of clinical benefit or a ‘positive’ phase II study would lead to a negative phase III trial [39]. A growing number of investigators favor large phase II trials that include a control group through randomization. Of note, the design for the recently published phase III study of bevacizumab in combination with paclitaxel/carboplatin in nonsquamous advanced NSCLC [40], which demonstrated an advantage in response rate (35 versus 15%), progression-free survival (6.2 versus 4.5 months) and median OS (12.3 versus 10.3 months) for the bevacizumab arm, was educated in the selection of proper end points and patient selection by a phase II randomized trial [41]. It is noted that in our study that patients with adenocarcinoma histology fared better in long-term survival parameters (median progression-free survival of 8.2 months; median OS time of 12.2 months and 1-year survival rate of 53%, n = 17) but showed a lower response rate (29%), compared with other histological types (progression-free survival of 5.2 months, OS of 7.0 months, 1-year survival rate of 27%, response rate of 41%, n = 22).
The role of bFGF expression in clinical prognosis is controversial. In pancreatic cancer, there is no relationship between the intratumoral level of bFGF and postoperative recurrence and survival, but an increased FGF receptor expression is associated with shorter survival [42]. A similar observation was made in NSCLC patients [43]. There are also reports indicating an opposite relationship in breast, ovarian, and pediatric high-grade gliomas [44–51]. Our finding of highly fluctuating plasma bFGF concentrations in individual patients suggests that the timing of bFGF measurements may confound data interpretation. The finding of higher plasma bFGF levels in chemopretreated/refractory patients compared with chemonaive patients suggests a relationship between chemotherapy exposure and bFGF.
It is of interest that the only patient progression free to date (5 years from enrollment) did not achieve a RECIST response, but a PET CR. He had pleural/chest wall pathologically proven recurrence of a resected lung adenocarcinoma (had also a previously resected squamous lung cancer). Sequence analysis of the tyrosine kinase (TK) domain of the gene encoding epidermal growth factor receptor (EGFR) in archived tissue material revealed an ATP-binding pocket mutation (T790M) in his adenocarcinoma and not in his previous squamous cell tumor (data not shown). While mutations in the TK domain of EGFR have been associated with antitumor activity in patients receiving EGFR-TK inhibitors [52, 53], the T790M mutation has been implied as mediating acquired resistance to these agents [54, 55]. In view of earlier reports that suramin binds to the ATP-binding pocket of EGFR and inhibits cell growth in the presence of normal or supranormal EGFR signaling [56–58], it is tempting to speculate that NSCLC patients treated with EGFR-TK inhibitors who subsequently develop resistance by acquiring the somatic T790M or related mutations might be successfully treated with a suramin-containing regimen.
In summary, noncytotoxic suramin can be combined with paclitaxel/carboplatin in NSCLC patients without an increase in toxicity, and suramin concentrations can be predicted on the basis of clinical parameters. A randomized trial including a chemotherapy-only control group is planned to effectively evaluate if adding noncytotoxic suramin to chemotherapy translates to clinical benefits in NSCLC patients.
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R37CA49816 (JLSA), R21CA91547 (JLSA), R01CA97067 (JLSA), and U01CA76576 (MG) from the National Cancer Institute, DHHS; NCI Merit Award to JLSA; Doris Duke Distinguished Clinical Scientist Award to CE.
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The authors thank Dr Ling Chen for her assistance with the bFGF results. Patients were treated at a General Clinical Research Center supported by M01-RR00034 from the National Institutes of Health, DHHS.
Received for publication February 19, 2008. Revision received May 28, 2008. Accepted for publication June 5, 2008.
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