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Phase II Study of Pemetrexed for Second-Line Treatment of Transitional Cell Cancer of the Urothelium

Christopher J. Sweeney, Bruce J. Roth, Fairooz F. Kabbinavar, David J. Vaughn, Michael Arning, Rafael E. Curiel, Coleman K. Obasaju, Yanping Wang, Steven J. Nicol, Donald S. Kaufman

From the From Hoosier Oncology Group, Indianapolis, IN; Vanderbilt University Medical Center, Nashville, TN; University of California Los Angeles Medical Center, Los Angeles, CA; University of Pennsylvania, Philadelphia, PA; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN; and the Massachusetts General Hospital, Boston, MA

Address reprint requests to Donald S. Kaufman, MD, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114; e-mail: dskaufman{at}partners.org

	ABSTRACT

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PURPOSE: To assess the antitumor activity and toxicity of pemetrexed as second-line chemotherapy in patients with locally advanced or metastatic transitional cell carcinoma (TCC) of the urothelium.

PATIENTS AND METHODS: Eligible patients had a performance status of 0 or 1, adequate organ function, previous treatment with one prior chemotherapy regimen for locally advanced or metastatic TCC of the urothelium or relapsed within 1 year of adjuvant or neoadjuvant treatment. Patients received pemetrexed 500 mg/m² intravenously on day 1 every 21 days, with vitamin B₁₂, folic acid, and dexamethasone prophylaxis.

RESULTS: Forty-seven patients were enrolled and included in the intent-to-treat efficacy analysis. Responses: 3 (6.4%) complete responses and 10 (21.3%) partial responses produced an overall response rate of 27.7%. Ten patients (21.3%) had stable disease and 22 patients (46.8%) progressed. The median time to progressive disease was 2.9 months (95% CI, 1.7 months to 4.6 months) and median overall survival was 9.6 months (95% CI, 5.1 months to 14.6 months). Median duration of response was 5.0 months (95% CI, 3.9 months to 13.8 months). Of the 47 patients assessable for safety, grade 3 or 4 hematologic events were thrombocytopenia (8.5%; 0.0%), neutropenia (4.3%; 4.3%) and anemia (2.1%; 2.1%), respectively. Nonlaboratory toxicities included grade 4 stomatitis/pharyngitis, sepsis syndrome (one patient each), and grade 3 fatigue (three patients) and diarrhea (two patients).

CONCLUSION: Single-agent pemetrexed is safe and active as second-line treatment of patients with advanced TCC of the urothelium. Additional evaluation in the first- or second-line setting in TCC of the urothelium is warranted.

	INTRODUCTION

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The incidence of transitional cell cancer (TCC) of the bladder, ureter, and other urinary organs in the United States is estimated to be 65,720 cases with 13,930 fatalities in 2005.¹ Chemotherapy is the primary treatment modality for metastatic TCC of the urothelium. Survival in this patient population is influenced by performance status and the presence of visceral metastasis.² Unfortunately, patients with progressive disease after initial chemotherapy have limited treatment options, and no therapy is known to prolong survival.

Pemetrexed (Alimta; Eli Lilly and Company, Indianapolis, IN) is a novel, multitargeted antifolate that is active in multiple tumor types.^3,4 Its primary mechanism of action is inhibition of thymidylate synthetase, resulting in decreased availability of the thymidine necessary for pyrimidine synthesis. Pemetrexed also inhibits dihydrofolate reductase and glycinamide ribonucleotide formyl transferase (a folate-dependent enzyme involved in purine synthesis). Folate and vitamin B₁₂ nutritional status affects the toxicity of pemetrexed, including rates of neutropenic fever. Treatment with pemetrexed without vitamin supplementation results in a significantly higher incidence of toxicity.^3,5,6 Supplementation with low-dose folic acid (350 µg to 1,000 µg orally, daily) and vitamin B₁₂ (1,000 µg intramuscularly, every 9 weeks) is important for ameliorating pemetrexed toxicities.

An earlier phase II study conducted without vitamin supplementation established single-agent pemetrexed as an active first-line agent in metastatic TCC, with an overall response rate of 33%.⁷ Thus, pemetrexed has activity in the first-line setting comparable with many of the commonly used single agents in bladder cancer. Currently, there are no approved chemotherapy agents for patients with TCC of the urothelium that has recurred. This single-cohort phase II study assessed pemetrexed for safety and efficacy as second-line chemotherapy for metastatic disease or first-line chemotherapy of metastatic disease that has recurred within 12 months of adjuvant therapy.

	PATIENTS AND METHODS

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Patients with histologically or cytologically confirmed stage IV TCC of the urothelium, as determined by the American Joint Committee on Cancer Staging Criteria for Bladder Cancer Staging Group, were assessed for eligibility. Mixed histologies were allowed as long as the predominant histologic type was TCC. All patients received one prior chemotherapy regimen. Patients were eligible if their disease had progressed at any time after therapy for advanced or metastatic disease or within 12 months of neoadjuvant or adjuvant setting. Patients were required to have a performance status of 0 or 1 per WHO criteria, assessable disease by Southwestern Oncology Group criteria, and adequate bone marrow and hepatic function as well as a calculated creatinine clearance per the Cockroft and Gault estimate of greater than 45 mL per minute. Patients with an inability to interrupt nonsteroidal anti-inflammatory drugs were excluded, as were patients with uncontrolled pleural effusions or ascites, symptomatic brain metastases, clinically detectable secondary primary malignancy, or significant weight loss (10% or more body weight in the preceding 6 weeks). The protocol was approved by the ethical review board of participating institutions and all patients signed a written informed consent before treatment.

Treatment Plan
Eligible patients received pemetrexed 500 mg/m² as a 10-minute intravenous infusion on day 1 of each 21-day cycle. Cycles were repeated until disease progression, unacceptable toxicity, or until the patient or the investigator requested therapy discontinuation. Vitamin supplementation and dexamethasone were coadministered according to the US Food and Drug Administration-approved label. A maximum of two dose reductions were allowed based on nadir counts or clinically significant nonhematologic toxicities, and dose delays up to 42 days from day 1 of the most current cycle were allowed for recovery from adverse events. Granulocyte colony-stimulating factor support was only allowed to treat grade 4 neutropenia lasting more than 3 days, neutropenic fever, or documented infections in neutropenic patients.

Toxicity was based on National Cancer Institute Common Toxicity Criteria, version 2.0. Before each cycle, a limited physical examination was performed. Tumor measurements were assessed radiologically after every two cycles using modified Southwestern Oncology Group criteria.⁸ Measurable disease according to this criteria were bidimensionally measurable lesions with clearly defined margins by medical photograph including a metric ruler or plain x-ray, with at least one diameter 0.5 cm or greater (bone lesions not included); or computed tomography, magnetic resonance imaging, or other imaging scan, with both diameters greater than the distance between cuts of the imaging study; or palpation (eg, supraclavicular lymph node), with both diameters 2 cm or greater. A complete response (CR) was recorded if there was complete disappearance of all lesions. A partial response (PR) was recorded if a patient had at least one measurable lesion, and had greater than or equal to a 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable disease. In both cases there was to be no progression of assessable disease and no new lesions. Stable disease was documented if the lesions did not qualify as CR, PR, or progression. Responses were recorded only if they were confirmed to have lasted more than 3 weeks. Patients were treated until progression, which was defined to be a 50% increase or an increase of 10 cm² (whichever was smaller) in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease), clear worsening of any assessable disease, reappearance of any lesion which had disappeared, appearance of any new lesion/site, or failure to return for evaluation because of death or deteriorating condition (unless clearly unrelated to this cancer).

Statistical Analysis
Response rate was the primary end point of the study. A two-stage design included an overall sample size of 43 patients. It was anticipated that a tumor response rate of 7% or less would not be considered worthy of additional testing, however, a tumor response rate of 25% would be worthy of further consideration. The sample size provided an overall significance level of .022 and power of 86% to differentiate this from the 7% response rate.

An exact 95% CI for the tumor response rate was calculated based on the binomial distribution. Other efficacy variables including duration of response, time to progressive disease, time to treatment failure, and overall survival time were analyzed using the Kaplan-Meier method.⁹ The duration of response was defined as the time from first objective status assessment of response to the first date of documented progression, or death from any cause and was censored at the date of the last post-therapy follow-up visit for responders who were still alive and who had not progressed. Time to treatment failure was defined as the time from study entry to the first observation of early discontinuation of treatment, disease progression, or death from any cause. Time to treatment failure was censored at the date of the last post-therapy follow-up visit for patients who did not experience any treatment failure. Time to documented disease progression was defined as the time from study entry to the first date of documented disease progression. Time to documented disease progression was censored at the date of death for patients who had not had documented disease progression. For patients who were still alive at the time of analysis and who had not had documented disease progression, time to documented disease progression was censored at the date of the last follow-up visit. Survival was defined as the time from study entry to time of death from any cause and was censored at the time of last post-therapy follow-up visit for patients who were still alive.

Additional planned analyses of efficacy end points were performed for the subgroup of patients who had platinum-refractory disease (that is, patients whose disease progressed while on or within 1 month after receiving platinum therapy). Other subgroup analyses were performed posthoc to describe the outcome of patients with visceral disease (lung, liver, or bone metastases) or with nodal metastases. Also, the outcome was described for patients who received prior chemotherapy only in the adjuvant or neoadjuvant setting versus those who received treatment in the metastatic setting. Patients who received both adjuvant/neoadjuvant and metastatic treatment were considered to be in the metastatic group.

	RESULTS

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Patient Characteristics
Between October 2001 and July 2004, 47 patients (38 men, nine women) with TCC of the urothelium were accrued at 16 centers in the United States. All 47 patients enrolled in the study were assessable for safety analysis. Of these 47 patients, 45 were assessable for efficacy analysis per protocol. Two patients failed to meet assessability criteria for efficacy analysis due to lack of postbaseline tumor assessments because of either clinical deterioration during cycle one, or a decline in performance status during cycle two with response status unknown. These patients were counted as early progressors and as such all of the 47 treated patients are included in the intent-to-treat analysis. At the time of analysis, 78.7% (37 of 47) of the patients had died. Demographics for all 47 treated patients are detailed in Table 1.

View larger version (11K): [in this window] [in a new window]   Fig 1. (A) Kaplan-Meier (K-M) estimates of overall survival; intent-to-treat patients. (B) Kaplan-Meier estimates of median time to progression (TtPD); intent-to-treat patients. (Dashed lines are upper bound and lower bound of 95% CI of Kaplan-Meier estimates.)

Outcomes were also assessed based on whether prior therapy was given for adjuvant treatment or for metastatic disease. Of the 18 patients who received therapy in the adjuvant or neoadjuvant setting, five patients (27.8%; three CR and two PR) responded, and the median survival of this group was 10.0 months (95% CI, 8.3 months to 18.4 months). Of the 29 patients treated in the metastatic setting, eight patients responded (27.6%; all PR) and the median survival of this group was 9.2 months (95% CI, 3.8 months to 14.6 months).

Of the 27 patients with lymph node metastases, and/or pelvic disease alone, nine patients (33.3%; three CR, six PR) responded and the median survival of this group was 9.6 months (95% CI, 5.0 months to 15.4 months). Of the 20 patients with visceral metastases (lung, liver, or bone), four patients (20%; all PR) responded and the median survival for the group was 9.3 months (95% CI, 3.8 months to 18.4 months). Only patients with lung, liver, or bone metastases were included in the visceral disease group in order to follow the convention of Bajorin et al.² Four patients with adrenal metastases were therefore considered to have nodal disease and not included in this analysis.

Treatment Administration and Toxicity
The 47 enrolled patients received a total of 243 cycles of treatment. The median number of cycles administered was three (range, 1 cycle to 27 cycles). In this study, 2% (five of 243) of cycles had doses that were reduced: two due to thrombocytopenia and one each due to febrile neutropenia, neutropenia, or fatigue; 5.3% (13 of 243) cycles were delayed: three doses because of clinical findings, including anorexia, cellulitis, and dyspnea; the reasons for two dose delays were unspecified; and eight doses were delayed due to scheduling conflicts. No study drug discontinuations or dose omissions occurred due to adverse events. The mean dose intensity of pemetrexed was 96.5% (160.9 mg/m² of 166.7 mg/m²) of the planned weekly dose.

All treated patients (N = 47) were assessable for toxicity. Laboratory, including hematologic, and nonlaboratory toxicities are summarized in Tables 3 and 4. Grade 4 hematologic toxicity was observed in two of 47 patients: one patient had neutropenia and one patient had anemia, leukopenia, and neutropenia. Grade 3 hematologic toxicity was reported in eight of 47 enrolled patients. The most frequently reported grade 3 hematologic toxicities were thrombocytopenia (four patients) and neutropenia (two patients). There was one instance of grade 3 (hypophosphatemia) and no instances of grade 4 nonhematologic laboratory toxicities. Grade 4 nonlaboratory toxicity was observed in two of 47 patients: stomatitis/pharyngitis,¹ and sepsis-syndrome.¹ Grade 3 nonlaboratory toxicity was reported in eight of 47 enrolled patients. The most commonly reported grade 3 nonlaboratory toxicities were fatigue³ and diarrhea.² Grade 1 creatinine and grade 1 urinary frequency/urgency were seen in one patient (2.1%) each. Grade 1 alopecia was observed in three patients (6.4%).

	DISCUSSION

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This phase II study demonstrates the ability of pemetrexed to induce a 27.7% response rate with a manageable toxicity profile as an outpatient treatment for second-line metastatic TCC. In addition, similar results were obtained in both patients who received treatment for metastatic disease, as well as those relapsing after adjuvant treatment. Moreover, this therapy was associated with a disease control rate (CR + PR + SD) of 48.9% after two cycles of chemotherapy, median overall survival of 9.6 months and 1-year survival of 41.8%, with a median follow-up of 9.2 months.

Methotrexate has classically been used in the first-line treatment of TCC. Another antifolate evaluated in the second-line setting is piritrexim, which induced an 18% response rate (RR; 10 patients) in one study and 7% in another (11 patients). One prior phase II study of single agent pemetrexed in TCC has been performed in the first-line setting.⁷ This study included patients with advanced disease, but was conducted without vitamin supplementation. The starting dose was 600 mg/m² once every 21 days, but after six patients the dose was reduced to 500 mg/m². Thirty-one patients were entered, with 26 patients assessable for efficacy. The response rate was 33.3%; 15% of patients experienced a neutropenic fever and 11% had grade 3 or 4 diarrhea. There were two toxic deaths, both associated with neutropenia. Most of the toxicity observed could be explained by the lack of vitamin supplementation.

Previous studies have established the activity of antifolates in the pretreatment of TCC of the urothelium. One possible reason for this activity is inhibition of de novo purine synthesis via glycinamide ribonucleotide transformylase (GARFT). Specifically, tumors involving methylthioadenosine phosphorylase (MTAP) deletion are potentially more sensitive to pemetrexed.¹²

One trial of pemetrexed (administered after gemcitabine on day 8 of a 21 day cycle) in combination with gemcitabine to treat first-line TCC has been reported.¹³ In this trial of 62 patients, the preliminary response rate was 26.5% and the median survival was 10.1 months. These results appear to be inferior to platinum combination regimens in first-line treatment. A trial of this combination is currently being conducted by the Eastern Cooperative Oncology Group (trial E4802). At the time of this writing, data from the latter trial was not available, but when reported, the results will help to understand the role of this nonplatinum doublet regimen in the front-line treatment of TCC.

Previous trials assessing the efficacy of chemotherapy in second-line treatment of TCC of the urothelium have demonstrated variable success. The results from 15 single agent trials in the second-line setting showed response rates ranging from 0% to 29%.^10,11,14-26 The variability in response rates in these studies is likely due to variability in drug activity and also the confounding factor of differing patient populations between studies. In view of this, a description of the patient characteristics becomes critical to evaluate clinical trials in this disease setting. Response to second-line therapy appears to be predicted by chemosensitivity to first-line therapy,¹⁸ performance status,²⁷ presence of visceral metastases,²⁸ prior therapy: adjuvant versus metastatic,²⁸ or a combination of performance status and presence of visceral metastasis.²⁸ The results of combination chemotherapy in the second-line setting also have substantial variability with response rates from 13% to 47%.^27-34

The clinical applicability of pemetrexed is supported by its outpatient administration with a tolerable toxicity profile in previously treated patients. No cycle-based grade 3 to 4 nonhematologic toxicities occurred at a frequency greater than 1.2%. No patient had severe alopecia or neuropathy, though one patient received 27 cycles of chemotherapy. The low toxicity observed is comparable with that observed by Hanna et al,⁴ which used vitamin-supplemented, single-agent pemetrexed in the second-line treatment of advanced non–small-cell lung cancer. All patients in this trial were required to have a creatinine clearance greater than or equal to 45 mL per minute. Patients with lower values are at risk for greater treatment related toxicity and should not receive pemetrexed. Nonetheless, significant myelosuppresion was not a characteristic finding during treatment, and no clinically significant renal deterioration was noted.

Pemetrexed has demonstrated a favorable therapeutic index when used as single agent as second-line treatment for advanced TCC of the urothelium. To determine whether this benefit can be further extended, evaluations in earlier stages of TCC will need to be performed via rationally designed clinical trials. These may include trials exploring pemetrexed in combination with either cytotoxic agents or targeted therapies. Given the safety profile seen in this study, multiagent combinations incorporating pemetrexed may be possible.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Christopher J. Sweeney Eli Lilly and Company (A) Eli Lilly and Company (A) David J. Vaughn Eli Lilly and Company (A) Michael Arning Eli Lilly and Company (N/R) Eli Lilly and Company (A) Rafael E. Curiel Eli Lilly and Company (N/R) Eli Lilly and Company (A) Coleman K. Obasaju Eli Lilly and Company (N/R) Eli Lilly and Company (A) Yanping Wang Eli Lilly and Company (N/R) Eli Lilly and Company (A) Steven J. Nicol Eli Lilly and Company (N/R) Eli Lilly and Company (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Christopher J. Sweeney, Michael Arning, Steven J. Nicol, Donald S. Kaufman Administrative support: Rafael E. Curiel Provision of study materials or patients: Christopher J. Sweeney, Bruce J. Roth, Fairooz F. Kabbinavar, David J. Vaughn, Donald S. Kaufman Collection and assembly of data: Christopher J. Sweeney, Bruce J. Roth, Fairooz F. Kabbinavar, Donald S. Kaufman Data analysis and interpretation: Christopher J. Sweeney, Michael Arning, Rafael E. Curiel, Coleman K. Obasaju, Yanping Wang, Steven J. Nicol, Donald S. Kaufman Manuscript writing: Christopher J. Sweeney, Michael Arning, Rafael E. Curiel, Coleman K. Obasaju, Yanping Wang, Steven J. Nicol Final approval of manuscript: Christopher J. Sweeney, Bruce J. Roth, Fairooz F. Kabbinavar, David J. Vaughn, Michael Arning, Rafael E. Curiel, Coleman K. Obasaju, Yanping Wang, Steven J. Nicol, Donald S. Kaufman

 

	ACKNOWLEDGMENTS

 
We thank Rafat Ansari, Robert Belt, Gurkamel Chatta, Mayer Fishman, John Hainsworth, Celestia Higano, Yoo-Joung Ko, Israel Wiznitzer, Ray Page, Joel Picus, Sandy Srinivas, George Chen, and Loretta Taylor for assistance with the conduct of this study and this manuscript.

	NOTES

 
Supported by a grant from Eli Lilly Oncology, Indianapolis, IN.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology in Chicago, IL, May 31-June 3, 2003, and the 21st Annual Chemotherapy Foundation Symposium New York, NY, November 12-15, 2003.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted August 4, 2005; accepted May 12, 2006.

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