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Pemetrexed Plus Gemcitabine As First-Line Chemotherapy for Patients With Peritoneal Mesothelioma: Final Report of a Phase II Trial

George R. Simon, Claire F. Verschraegen, Pasi A. Jänne, Corey J. Langer, Afshin Dowlati, Shirish M. Gadgeel, Karen Kelly, Gregory P. Kalemkerian, Anne M. Traynor, Guangbin Peng, John Gill, Coleman K. Obasaju, Hedy L. Kindler

From the H. Lee Moffitt Cancer Center, Tampa, FL; University of New Mexico, Albuquerque, NM; Dana-Farber Cancer Institute, Boston, MA; Fox Chase Cancer Center, Philadelphia, PA; Case Western Reserve University, Cleveland, OH; Wayne State University, Detroit, MI; University of Kansas Cancer Center, Kansas City, KS; University of Michigan Health System, Ann Arbor, MI; University of Wisconsin Paul P. Carbone Comprehensive Cancer Center, Madison, WI; Eli Lilly & Co, Indianapolis, IN; and the University of Chicago, Chicago, IL

Corresponding author: George R. Simon, MD, Thoracic Oncology Program and Experimental Therapeutics Program, H. Lee Moffitt Cancer Center and Research Institute, MRC-4W, 12902 Magnolia Drive, Tampa, FL 33612-9497; e-mail: george.simon{at}moffitt.org

	ABSTRACT

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Purpose Pemetrexed in combination with cisplatin is approved for the treatment of pleural mesothelioma and is active in malignant peritoneal mesothelioma (MPeM). Pemetrexed and gemcitabine are synergistic in preclinical models, but the activity of this combination in MPeM is unknown. This clinical study assessed safety and efficacy of pemetrexed plus gemcitabine in chemotherapy-naïve patients with MPeM.

Patients and Methods Treatment consisted of gemcitabine 1,250 mg/m² on days 1 and 8, and pemetrexed 500 mg/m² on day 8, administered immediately before gemcitabine. Treatment was repeated every 21 days for six cycles or until disease progression. All patients received folic acid, vitamin B₁₂, and dexamethasone supplementation. End points included tumor response, toxicity, time to disease progression (TTPD), and overall survival (OS). Disease control rate (DCR) was also calculated.

Results Twenty patients were enrolled between December 2002 and May 2004. The confirmed response rate was 15% (95% CI, 3.2% to 37.9%), with three patients experiencing a partial response. The DCR was 50% (95% CI, 27.2% to 72.8%). The most common grade 3 to 4 nonhematologic toxicities included fatigue (20%), constipation (10%), vomiting (10%), and dehydration (10%). Hematologic toxicities included grade 3 to 4 neutropenia (60%) and febrile neutropenia (10%). One patient death was attributed to treatment. Median TTPD and OS times were 10.4 months and 26.8 months, respectively.

Conclusion The combination of pemetrexed plus gemcitabine was active in patients with MPeM with a notably high incidence of neutropenia. Median TTPD and OS seem promising. This regimen may provide an alternative to standard therapies, especially for patients who cannot tolerate a platinum-based regimen.

	INTRODUCTION

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Malignant peritoneal mesothelioma (MPeM) is an extremely rare cancer arising from the mesothelial cells of the peritoneum. MPeM accounts for approximately 10% of all mesotheliomas, with the vast majority of the remaining cases arising from the pleura.^1,2 It is estimated that approximately 250 new cases of MPeM are diagnosed in the United States annually.³ Both peritoneal and pleural mesotheliomas are strongly linked with environmental exposure to asbestos.^4,5

Historically, MPeM has been viewed by clinical oncologists as a terminal condition with limited treatment options. Currently, there are no established standard treatments for this disease.^6,7 A number of therapeutic modalities, including surgical debulking of macroscopic disease, systemic chemotherapy, and radiation therapy have been investigated without substantial improvement in outcomes for MPeM patients.^8-14 More recently, combination strategies involving the use of cytoreductive surgery and intraoperative and/or perioperative intraperitoneal chemotherapy with and without abdominal radiation therapy have suggested improvements in patient survival.^15-18 On occasion, long-term survival has been observed. However, cytoreductive surgery is not always possible for patients with extensive intraperitoneal disease and these multimodal therapeutic strategies are associated with significant morbidity. In addition, the low incidence of this disease makes pilot phase II efforts difficult and precludes randomized trials that might conclusively define the benefit of systemic chemotherapy and other treatment options. Thus, there remains a critical need for novel investigative strategies that will demonstrate benefit in the limited number of patients available with MPeM.

A number of chemotherapeutic agents have shown promise as single agents or in combination with other drugs in the treatment of mesothelioma, including MPeM.⁶ Pemetrexed, a multitargeted antifolate, was the first agent approved for the treatment of advanced pleural mesothelioma. In a pivotal phase III trial, the combination of pemetrexed plus cisplatin provided patients with significantly improved survival when compared with cisplatin alone.¹⁹ Additionally, pemetrexed alone or in combination with cisplatin has been reported to be active and safe in patients with MPeM.⁶

Gemcitabine, a pyrimidine nucleoside antimetabolite, is also known to be active in patients with MPeM both as a single agent^20-22 and in combination with cisplatin.^23-25 The combination of pemetrexed plus gemcitabine has synergistic antitumor activity in vitro,²⁶ and has demonstrated clinical activity in patients with a variety of tumors.^27-29 In a phase I trial, the combination of pemetrexed plus gemcitabine produced a partial response in a patient with mesothelioma.³⁰ However, the activity of the pemetrexed-plus-gemcitabine combination in patients with MPeM has not been formally determined. Given the sound preclinical rationale and the need for improved treatment strategies for MPeM, we conducted this open-label, multicenter, phase II trial to determine the safety and efficacy of the novel nonplatinum combination of pemetrexed plus gemcitabine as first-line therapy for patients with MPeM. This trial was designed to enroll all patients with malignant mesothelioma, including pleural mesothelioma. Results for the patients with pleural mesothelioma will be reported separately.³¹

	PATIENTS AND METHODS

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Patient Eligibility
Patients with histologically confirmed MPeM not amenable to curative treatment with surgery were enrolled. Patients were required to have measurable disease as defined by modified Southwest Oncology Group (SWOG) criteria.³² Additional inclusion criteria were age of at least 18 years, life expectancy of at least 12 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, and adequate renal, hepatic, and bone marrow function.

Exclusion criteria included prior systemic chemotherapy, prior radiation therapy to the target lesion (unless the lesion was clearly progressing and the last radiation treatment was 4 weeks before enrollment), and known or suspected brain metastases. Pregnant women were not eligible, and an approved birth control method was required for all men or women of reproductive potential. Patients with serious concomitant disorders incompatible with the study were excluded at the discretion of the investigator.

All patients provided written informed consent before initiation of therapy. Institutional review boards at each participating institution approved the trial protocol before patient enrollment. This study was performed in compliance with the principles of good clinical practice, the Helsinki Declaration, and federal and institutional guidelines.

Study Design
All patients entering the study received pemetrexed 500 mg/m² administered by intravenous injection over approximately 10 minutes on day 8 and gemcitabine 1,250 mg/m² administered by intravenous injection over approximately 30 minutes on day 1 and immediately after pemetrexed on day 8. Treatment was repeated every 21 days for six cycles or until progressive disease (PD). Additional cycles of therapy were administered at the discretion of the investigator. Folic acid (350 to 600 µg or equivalent) supplementation was administered orally beginning 1 to 2 weeks before the first dose of pemetrexed and continued daily until the patient discontinued study therapy. Vitamin B₁₂ (1,000 µg) was administered by intramuscular injection 1 to 2 weeks before the first dose of study therapy and repeated every 9 weeks until the patient discontinued therapy. To reduce the risk of severe skin rash, dexamethasone was administered orally for 3 days of each cycle, beginning 1 day before pemetrexed dosing.

Dose Reductions
Day 1 of each cycle was administered if the absolute neutrophil count (ANC) was greater than 1,000/mm³, the platelet count greater than 100,000/mm³, and all nonhematologic toxicities resolved to grade 2 or lower. Dose adjustments were based on the nadir hematologic values for the preceding cycle. Gemcitabine doses were reduced by 25% if the platelet nadir was 50,000/mm³ or less, or the ANC nadir 500/mm³ or less. If the nadir of both platelets and ANC were below these values, gemcitabine doses were reduced by 50%. Treatment could be delayed for up to 21 days from the end of a cycle to allow a patient sufficient time to recover from study therapy-related toxicity. Treatment on day 8 was withheld to allow time for recovery to a platelet count greater than 50,000/mm³ and an ANC greater than 1,000/mm³. If the platelet count nadir was 25,000/mm³ or lower or the ANC nadir was 500/mm³ or lower, subsequent doses of pemetrexed and gemcitabine were reduced by 50%. Additional dose reduction criteria on day 8 were specified for grade 3 or 4 nonhematologic toxicities. Patients requiring dose reductions were not eligible for dose escalations for the remainder of the study. Patients exceeding a 21-day delay were taken off study. Patients could also be removed from the study at the discretion of the investigator as a result of other toxicities.

Study Assessments
Patients underwent a physical examination and performance status assessment before day 1 of each cycle. Visual, palpable, and radiologic assessments of tumor measurement occurred at baseline and on day 1 before the third cycle of therapy and after every other cycle thereafter. Chemistry assessments occurred at baseline and on day 8 of the first cycle, then on days 1 and 8 of each subsequent cycle. Hematology assessments occurred at baseline and on days 8 and 15 of the first cycle, and then on days 1, 8, and 15 of each subsequent cycle.

Study End Points
One end point of this study was determination of the objective tumor response rate. Tumor measurements were evaluated according to SWOG criteria.³² Complete response (CR) was defined as complete disappearance of all measurable and assessable disease, with no new lesions and no disease-related symptoms. Partial response (PR) was defined as one of the following: at least 50% decrease under baseline in the sum of products of perpendicular diameters of disease for patients with bidimensionally measurable disease; at least 30% decrease under baseline in the sum of the greatest diameters of lesions for patients with unidimensionally measurable disease, with nonmeasurable lesions being at least stable, and with no new lesions. Any CR or PR required confirmation at least 4 weeks after the first scan. Typically, follow-up scans were repeated after two additional cycles were delivered or after 6 weeks. Patients were routinely scanned after every other cycle, while receiving treatment. PD was defined for patients with bidimensionally measurable disease as at least a 50% increase or an increase of 10 cm² (whichever is smaller) in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease). For patients with unidimensional disease, PD was defined as at least a 25% increase in the sum of the longest dimension of measurable lesions over the smallest sum observed (over baseline if no decrease). In the presence of both lesion types, PD was defined as progression of either lesion type, or at least stable disease for the other, worsening of assessable disease, or death from disease. Stable disease (SD) was defined as all other evaluations not qualifying for CR, PR, or PD.

Additional end points in the study included disease control rate (DCR), overall survival (OS), time to disease progression (TTPD), and duration of response. DCR was defined as the percentage of patients with CR, PR, and SD. OS time was defined as the time from the date of enrollment to the date of death resulting from any cause. TTPD was defined as the time from the date of enrollment to the first date of documented progression.

Statistical Considerations
OS and TTPD were analyzed using the Kaplan-Meier product-limit method.³³ OS was censored for patients still alive at the date of last visit. For patients without documented PD, TTPD was censored at the date of death from reasons other than PD or at date of last visit. In addition, other antitumor therapies were not considered for TTPD censoring. The 95% CIs for tumor response rate were calculated on the basis of an exact binomial probability. Patient characteristics and toxicities were summarized in descriptive statistics. Toxicities were defined according to the National Cancer Institute Common Toxicity Criteria, version 2.0.³⁴ All calculations were performed using SAS version 8.2 software (SAS Institute, Cary, NC).

	RESULTS

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Patient Characteristics
Between December 19, 2002, and May 12, 2004, 20 patients were enrolled at 10 participating clinical sites in the United States. Table 1 summarizes patient characteristics. The majority of enrolled patients were male (75%) and white (90%), and only one patient had received prior radiotherapy. Before enrollment, 15 patients had at least one surgical procedure related to their disease and four patients underwent surgery with curative intent. For one patient, ECOG performance status was not recorded. The median patient follow-up after completing treatment for this trial was 15.9 months (range, 0.9 to 33.2 months).

Table 2 summarizes treatment administration results. Enrolled patients received a median of six treatment cycles (range, one to 10 cycles), with 12 patients (60%) completing at least six cycles and 15 patients (75%) completing at least four cycles. The median delivered dose intensity was greater for pemetrexed (91.6%) than for gemcitabine (81.4%).

Efficacy: TTDP and OS
Additional efficacy end points of this study were TTPD and OS. Median TTPD was 10.4 months (95% CI, 5.3% to not reached; 40% censored). The estimated percentage of patients without PD at 1 year was 55.8% (95% CI, 30.9% to 80.8%) and 31.9% (95% CI, 7.0% to 56.8%) at 2 years. Median OS for all patients was 26.8 months (95% CI, 11.7% to not reached; 50% censored). The estimated 1-year survival rate (Fig 1) was 67.5% (95% CI, 46.0% to 89.0%) and the 2-year survival rate was 50.0% (95% CI, 26.6% to 73.4%).

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Overall survival (OS) for the study population. NR, not reached.

	DISCUSSION

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Pemetrexed has been shown to be active in a variety of cancers, including mesothelioma.³⁰ In a definitive phase III trial, Vogelzang et al¹⁹ reported that pemetrexed administered in combination with cisplatin produced a statistically significant improvement in median survival time compared with cisplatin alone in patients with malignant pleural mesothelioma. Subsequent reports have also shown pemetrexed to be active as a single agent^6,36 or in combination with cisplatin^6,37 in patients with MPeM. Response rates for the combination of pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) in these reports ranged from 26% to 36%, which was higher than the 15% (three PRs in 20 patients treated) response rate observed in the current trial using pemetrexed (500 mg/m² on day 8) plus gemcitabine (1,250 mg/m² on days 1 and 8). Considering that five patients in the current trial were not assessable for tumor response, the actual response rate was 20% (three PRs in 15 assessable patients). In addition, the actual disease control rate (CR + PR + SD) among assessable patients was 67%, which is comparable to the rate of 71.2% observed by Jänne et al,⁶ and the rate of 77% reported by Karthaus et al³⁷ in studies using pemetrexed plus cisplatin.

In the same preliminary report by Karthaus et al,³⁷ the median survival time was 13.7 months and the median TTPD was 11.5 months for a small cohort of 22 MPeM patients treated with pemetrexed plus cisplatin. In the largest phase II trial to date, Jänne et al⁶ reported median survival times for previously treated MPeM patients who received either pemetrexed plus cisplatin or pemetrexed alone were 13.1 and 8.7 months, respectively. For MPeM patients in the current trial, all of whom were chemotherapy naïve, the median survival time was estimated to be 26.8 months and the median TTPD was 10.4 months. Despite the high censoring rate, these efficacy results seem promising relative to the earlier reports using pemetrexed ± cisplatin in patients with MPeM.

Like pemetrexed, gemcitabine is a cytotoxic agent that inhibits DNA synthesis. In the clinical setting, myelosuppression is the most significant toxicity associated with the administration of either pemetrexed or gemcitabine. For pemetrexed, prophylactic supplementation with vitamin B₁₂ and folic acid can abrogate hematologic toxicity.³⁸ In the current study, the toxicity profile (Table 3) for the pemetrexed/gemcitabine combination showed relatively high levels of grade 3 to 4 neutropenia (60%) and febrile neutropenia (10%). Slightly lower rates of neutropenia and febrile neutropenia were observed in the pleural patient cohorts that were part of the current trial.³¹ The high level of neutropenia reported here for MPeM patients is also similar to some, but not all, of the clinical trial results reported for the same 21-day pemetrexed/gemcitabine regimen evaluated in patients with a variety of tumor types, including non–small-cell lung, pancreatic, and breast cancers.^27-29 By comparison, the earlier studies using pemetrexed plus cisplatin in patients with both pleural and peritoneal mesothelioma reported levels of neutropenia under 5%.^6,37 Thus, it seems that the combination of pemetrexed and cisplatin has a more favorable hematologic toxicity profile than does the combination of pemetrexed plus gemcitabine at the doses administered in this trial.

The response rate and the DCR observed in the current trial suggest that the pemetrexed/gemcitabine combination regimen is active in patients with MPeM. In addition, the OS estimate in our study was greater than those reported previously for the combination of pemetrexed/cisplatin.^6,37 However, the encouraging efficacy results of this trial must be tempered by several considerations. Although enrollment of 20 peritoneal patients in this trial is impressive given the low incidence of this disease, from a statistical standpoint the limited number of assessable patients created considerable variance associated with the estimates of OS and TTPD. In addition, the hematologic toxicity associated with this regimen was problematic, resulting in 25% (n = 5) of enrolled patients discontinuing the trial, and one patient death. On the basis of the relative gemcitabine dose intensity of 81.4% and the notable level of neutropenia observed in this trial, the authors would recommend reducing the dose of gemcitabine in future clinical trials.

In summary, this study provides new and important information about the use of pemetrexed/gemcitabine combination in MPeM, adding to a limited number of clinical trial reports and patient case summaries describing the use of systemic chemotherapy agents in the treatment of this rare disease. Recent advances in the use of cytoreductive surgery in concert with intraperitoneal chemotherapy have shown improved median survival times approaching 5 years for selected patients with MPeM.⁷ However, although selected patients with this disease may benefit from this treatment strategy, many patients are not viable candidates for surgical resection. Therefore, the development of alternative chemotherapeutic options will be necessary to improve outcomes for patients with MPeM.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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.

Employment or Leadership Position: Guangbin Peng, Eli Lilly & Co (C); John Gill, Eli Lilly & Co (C); Coleman K. Obasaju, Eli Lilly & Co (C) Consultant or Advisory Role: George R. Simon, Eli Lilly & Co (C); Pasi A. Jänne, Eli Lilly & Co (C); Corey J. Langer, Eli Lilly & Co (C); Karen Kelly, Eli Lilly & Co Thoracic Oncology Advisory Board (C); Gregory P. Kalemkerian, ImClone Systems Inc (C), Merck (C) Stock Ownership: John Gill, Eli Lilly & Co; Coleman K. Obasaju, Eli Lilly & Co Honoraria: George R. Simon, Eli Lilly & Co; Afshin Dowlati, Eli Lilly & Co, Genentech Inc; Shirish M. Gadgeel, Eli Lilly & Co; Karen Kelly, Eli Lilly & Co Speakers Bureau; Gregory P. Kalemkerian, Eli Lilly & Co, Genentech Inc Research Funding: George R. Simon, Eli Lilly & Co; Pasi A. Jänne, Eli Lilly & Co; Corey J. Langer, Eli Lilly & Co; Afshin Dowlati, Celgene, GlaxoSmithKline, Eli Lilly & Co; Shirish M. Gadgeel, Eli Lilly & Co; Gregory P. Kalemkerian, Abbot Pharmaceuticals, Eli Lilly & Co, Millennium; Anne M. Traynor, Pfizer Inc, Eli Lilly & Co, Novartis; Hedy L. Kindler, Eli Lilly & Co Expert Testimony: None Other Remuneration: None

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Claire F. Verschraegen, Pasi A. Jänne, Hedy L. Kindler

Provision of study materials or patients: George R. Simon, Claire F. Verschraegen, Pasi A. Jänne, Corey J. Langer, Afshin Dowlati, Shirish M. Gadgeel, Karen Kelly, Gregory P. Kalemkerian, Anne M. Traynor, Hedy L. Kindler

Collection and assembly of data: George R. Simon, Claire F. Verschraegen, Pasi A. Jänne, Corey J. Langer, Afshin Dowlati, Gregory P. Kalemkerian

Data analysis and interpretation: Claire F. Verschraegen, Afshin Dowlati, Guangbin Peng, John Gill, Coleman K. Obasaju

Manuscript writing: George R. Simon, Claire F. Verschraegen, Pasi A. Jänne, Corey J. Langer, Afshin Dowlati, Gregory P. Kalemkerian, Guangbin Peng, John Gill, Coleman K. Obasaju

Final approval of manuscript: George R. Simon, Claire F. Verschraegen, Pasi A. Jänne, Corey J. Langer, Afshin Dowlati, Shirish M. Gadgeel, Karen Kelly, Gregory P. Kalemkerian, Anne M. Traynor, Guangbin Peng, John Gill, Coleman K. Obasaju, Hedy L. Kindler

	ACKNOWLEDGMENTS

 
We thank Jian Yu and Sharon Zou for their support.

	NOTES

 
Supported by a grant from Eli Lilly & Co, Indianapolis, IN.

Presented at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

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

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Submitted November 13, 2007; accepted January 9, 2008.

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