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PubMed2005

Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non-small cell lung cancer: a multicenter, randomized, phase II trial.

PURPOSE: To determine efficacy and toxicity of two pemetrexed-based regimens in chemonaive patients with locally advanced or metastatic non-small cell lung cancer. EXPERIMENTAL DESIGN: Patients were randomly assigned to receive pemetrexed 500 mg/m(2) plus oxaliplatin 120 mg/m(2) (PemOx) or pemetrexed plus carboplatin AUC6 (PemCb). All drugs were given on day 1 of a 21-day cycle for up to six cycles. Folic acid and vitamin B(12) were given to all patients to minimize pemetrexed-related toxicities. RESULTS: Forty-one patients received PemOx and 39 received PemCb. Objective tumor response rates were 26.8% for PemOx patients (95% confidence interval, 14.2-42.9) and 31.6% for PemCb patients (95% confidence interval, 17.5-48.7). Median time to progression was 5.5 and 5.7 months, respectively, for PemOx and PemCb. Median overall survival times were 10.5 months for both treatment groups (range, <1 to >20 months). The 1-year survival rate was 49.9% for PemOx patients and 43.9% for PemCb patients. Common toxicity criteria grade 3 or 4 hematologic toxicities among PemOx patients were grade 3 or 4 neutropenia (7.3%), grade 3 thrombocytopenia (2.4%), and grade 3 anemia (2.4%). PemCb patients experienced grade 3 or 4 neutropenia (25.6%), grade 3 or 4 thrombocytopenia (17.9%), and grade 3 anemia (7.7%). Grade 3 vomiting occurred in three PemOx patients and grade 3 fatigue occurred in three PemCb patients. One grade 3 neurosensory toxicity occurred in the PemOx group. Three patients (PemOx 1 and PemCb 2) experienced febrile neutropenia. CONCLUSIONS: Efficacy measures for both regimens seem similar to the most effective chemotherapies for advanced non-small cell lung cancer (platinum combinations) with less hematologic and nonhematologic toxicity. Comparing either of these two regimens to platinum-based therapies in a large randomized trial is warranted.

Adult↗
PubMed2006

Single-arm, open label study of pemetrexed plus cisplatin in chemotherapy naïve patients with malignant pleural mesothelioma: outcomes of an expanded access program.

BACKGROUND: An expanded access program (EAP) provided patient access to pemetrexed prior to its commercial availability. The current report consists of US patients in the EAP who had chemotherapy naïve pleural mesothelioma. METHODS: Eligible patients had a histologic or cytologic diagnosis of malignant mesothelioma that was not amenable to curative treatment with surgery. Study treatment consisted of pemetrexed 500mg/m(2) in combination with cisplatin 75mg/m(2) once every 21 days. Vitamin B12, folic acid, and dexamethasone were administered as prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmacovigilance database for all patients enrolled in the EAP. RESULTS: Of 1056 patients receiving at least one dose of pemetrexed in the EAP, 728 had chemotherapy naïve pleural mesothelioma. Median age of this group was 70 years (range 23-89 years) and 84% were male. Among 615 patients, overall response rate was 20.5%, including 12 complete responses (2.0%) and 114 partial responses (18.5%). An additional 290 patients (47.2%) had stable disease. Median survival for all 728 patients was 10.8 months (95% CI=9.8, 12.3; 60.3% censorship) and 1 year survival was 45.4%. The most commonly reported SAEs in the overall EAP irrespective of causality were dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%). CONCLUSIONS: In this large cohort, 67.7% of patients treated with first-line chemotherapy experienced a response or stable disease. Survival time and toxicity from this EAP were promising for this difficult-to-treat disease.

Adult↗
PubMed2005

Clinical application of a semimechanistic-physiologic population PK/PD model for neutropenia following pemetrexed therapy.

PURPOSE: The objective of these analyses was to examine the effect of variations in the explanatory factors of neutropenic response, identified by semimechanistic-physiologic population pharmacokinetic/pharmacodynamic (PK/PD) modeling, on clinically important features of the absolute neutrophil count (ANC)-time profile (e.g, the nadir of the ANC [NANC], its timing [T (Nadir)], and the timecourse of recovery [T (Rec)]). METHODS: Correlation analyses were used to evaluate the relationship of NANC, T (Nadir), and T (Rec) as a function of overall systemic exposure (AUC) and each of the covariates contained in the population PK/PD model. Simulations using the final PK/PD model were used to generate complete ANC-time profiles. Frequency counts of NANCs from the simulated profiles were used to quantitatively explore differences in the incidence and severity of neutropenia associated with a variety of scenarios (500 mg/m2 versus 600 mg/m2, normal vitamin deficiency markers versus elevated vitamin deficiency markers, and body surface area-based versus renal function-based dosing) and to evaluate the effect of individual explanatory factors with respect to neutropenic response. RESULTS: Information obtained from correlation analysis and simulations was helpful in quantitatively exploring the impact of dose, exposure, and/or patient characteristics on neutropenic response. The information gained from these simulations provided supportive evidence for the decision to routinely include vitamin supplementation during pemetrexed treatment as a means of managing the risk of severe neutropenia secondary to pemetrexed administration. These techniques also provided information regarding the specific T (Nadir) and T( Rec) for inclusion in product labeling and suggested that a 14-day treatment cycle might be feasible for pemetrexed. CONCLUSION: For population PK/PD models, to provide useful information for the practicing clinician or the clinical development team, it is not sufficient to look only at influences of covariates on model parameters. Rather, the modeling results need to be carefully investigated in terms of clinically relevant measures.

Adult↗
PubMed2006

Phase II trial of pemetrexed as second-line therapy in patients with metastatic urothelial carcinoma.

PURPOSE: The purpose of this single-center phase II study was to determine the activity of pemetrexed administered as second-line therapy in patients with advanced urothelial carcinoma. METHODS: Patients with advanced urothelial carcinoma that had relapsed after receiving perioperative chemotherapy, or progressed on first-line chemotherapy for metastatic disease, were eligible for enrollment. Patients received pemetrexed 500 mg/m(2) every 21 days along with folic acid and vitamin B12 supplementation. RESULTS: A total of 13 patients were enrolled. An objective response was achieved in 1/12 evaluable patients for an overall response rate of 8% (90% upper limit 29%). This level of activity did not meet criteria for expansion based on the pre-defined optimal 2-stage Simon design and the trial was concluded. Treatment was generally well tolerated, however, 2/13 patients developed febrile neutropenia. Non-hematologic grade > or = 3 toxicity was rare. CONCLUSIONS: Pemetrexed as second-line therapy in advanced urothelial carcinoma is associated with modest activity. The role of this novel antifolate in chemotherapy-naïve patients warrants further investigation.

Administration, Oral↗
PubMed2006

Pemetrexed-induced edema of the eyelid.

Pemetrexed is a novel antimetabolite that targets multiple enzymes in the folate pathway, and has exhibited clear antitumor activities in the treatment of malignant pleural mesothelioma and non-small cell lung cancer. Although many adverse events of pemetrexed, such as bone marrow suppression, have been reported, edema of the eyelid has been previously reported in only one case (0.2%, n=519), according to the Pemetrexed Clinical Investigator's Brochure, April 2005 version. We experienced a patient who developed the valuable edema of the eyelid. We believe that medical oncologists should be aware of this rare adverse event, although the mechanism responsible for it is not yet known.

Adenocarcinoma↗
PubMed2001

Gemcitabine and pemetrexed disodium combinations in vitro and in vivo.

Pemetrexed disodium (ALIMTA) is a novel antimetabolite that inhibits at least three folate-dependent enzymes, thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed disodium is broadly active in a wide variety of solid tumours, including non-small cell lung, breast, bladder, head and neck and ovarian cancers. Gemcitabine is a broadly active pyrimidine nucleoside antimetabolite, which is approved for the treatment of pancreatic and non-small cell lung cancers. Three preclinical studies have been reported that show cytotoxic synergy between gemcitabine and pemetrexed. Clinical activity with this combination has been observed in a phase I study, with partial responses in three of five patients previously treated for non-small cell lung cancer. An international phase II study of this combination in non-small cell lung cancer is ongoing.

Animals↗
PubMed2002

Activity of pemetrexed (alimta), a new antifolate, against non-small cell lung cancer.

Chemotherapy for non-small cell lung cancer (NSCLC) has developed within the past decade into an important part of treatment with palliative aims as well as part of curative combined-modality treatment. Furthermore, second-line treatment has become an accepted part of the palliative approach as well. Pemetrexed (alimta) is one of the recently introduced agents that have been evaluated for efficacy against NSCLC. In single-agent phase II studies in previously untreated NSCLC, pemetrexed resulted in a response rate of around 20%. In combination with cisplatin, response rates of 40% were achieved. As a second-line single agent in-patients with early progression after first-line treatment, the response rate is 9%. Toxicity is mainly hematologic and can be reduced by supportive measures. Overall, pemetrexed is an active agent that further improves the chemotherapeutic options of physicians involved in the treatment of NSCLC.

Adult↗
PubMed2001

Highly sensitive analysis of the antifolate pemetrexed sodium, a new cancer agent, in human plasma and urine by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatography method was developed and validated for the quantitation of pemetrexed (LY231514, ALIMTA) in human urine and plasma. Plasma samples were spiked with the internal standard lometrexol and extracted using Certify II columns. Pemetrexed was assayed in diluted urine by an external calibration method. A C8 column was used for the separation of analytes with a mobile phase composed of sodium formate buffer and acetonitrile. Between- and within-day precision and accuracy were acceptable down to the limit of quantitation of 5 ng/ml in plasma. This method was used successfully for an investigation of the disposition of pemetrexed in patients receiving 500 mg/m2 as a 10-min infusion.

Antineoplastic Agents↗
PubMed2001

A phase II study of pemetrexed disodium (LY231514) in patients with locally recurrent or metastatic breast cancer.

A phase II study was conducted to evaluate the activity of pemetrexed in patients with locally recurrent or metastatic breast cancer. 38 patients, median age 52 years (range 36-71 years), were given pemetrexed 600 mg/m(2) as a 10-min intravenous (i.v.) infusion every 3 weeks. Median time from diagnosis to study entry was 48 months (range 14.7-310 months). 33 of 38 patients had prior chemotherapy; 16 adjuvant, 12 metastatic and 5 in both settings. Sites of disease included skin and soft tissue (19/38) nodes (18/38), lung (17/38), liver (13/38) and bone (3/38). An overall response rate of 28% (95% confidence interval (CI): 14.2-45.2%) in 10/36 evaluable patients (1 complete response (CR), 9 partial responses (PR)), included reductions in hepatic and pulmonary metastases. 5 of 10 responders had received taxoid or anthracycline therapy for metastatic disease; 3 of these 5 had also received adjuvant chemotherapy. Median duration of response was 8 months (range 1.6-14+ months), and median survival was 13 months (95% CI 9.56-17.38 months). 167 courses were given (median five per patient; range 1-9), with 37 reductions and 33 delays. Reasons for reduction included neutropenia (11%) and mucositis (5%), with delays due to raised LFTs (21%), neutropenia (12%) and other non-treatment related events. The major haematological toxicities (Common Toxicity Criteria) (CTC) were grade 3/4 neutropenia (47%) and thrombocytopenia (15.7%) of patients. There was one report of a grade 3 infection. Non-haematological toxicities (all grades 2/3) included elevated transaminases (92%), vomiting (34%), nausea (34%) and mucositis (32%). One episode of grade 4 diarrhoea was reported. Other toxicities included a skin rash, grade 2 (42%), 3 (5%) and 4 (13%), which was ameliorated by the use of prophylactic dexamethasone. These results suggest that pemetrexed has significant antitumour activity in advanced breast cancer with responses in patients who had previously received anthracyclines and taxoids.

Adult↗
PubMed2003

A phase II trial of pemetrexed in patients with metastatic renal cancer.

BACKGROUND: Metastatic renal cell carcinoma (RCC) is rising in incidence but remains difficult to treat. This clinical trial evaluated the effects of pemetrexed (multitargeted antifolate, ALIMTAR) for the treatment of metastatic RCC. PATIENTS AND METHODS: Patients were required to have histological diagnosis of metastatic RCC with measurable disease and no prior chemotherapy. In addition, patients were required to have a World Health Organization (WHO) performance status of 0-2 and adequate bone marrow reserve. Patients received pemetrexed at a dose of 600 mg/m2 as a 10 min infusion every 3 weeks. Patients did not receive folic acid or vitamin B12 supplementation. RESULTS: Thirty-nine patients were enrolled and thirty two were evaluable for response. Three patients had a partial response for a response rate of 9% (95% CI 2-25%). The median time to progressive disease was 10.5 months. Of the nonresponders, twenty two had stable disease (median duration was 5.8 months; range 1.5-27.7) and seven had progressive disease (median time to progression was 5.4 months). Median time to progression for all qualified patients was 5.7 months. Common toxicities experienced were diarrhea and infection. Fatigue, stomatitis, and rash were also reported. The most common hematologic toxicity was grade 3/4 lymphopenia in 76% of patients. Leukopenia, granulocytopenia, and thrombocytopenia were also frequently reported. CONCLUSION: Single-agent pemetrexed has moderate activity in the treatment of metastatic RCC and should be investigated in combination with other potential active agents, as first-line treatment.

Aged↗
PubMed2005

Pemetrexed (Alimta) in small cell lung cancer.

Small cell lung cancer (SCLC) comprises approximately 13% of all lung cancers. In limited stage (LS)-SCLC, combined-modality therapy represents the standard of care. Therapy should be approached curatively in fit patients with a good performance status because 5-year survival rates approach 26% in aggressively treated patients. In contrast, cure is not possible in extensive stage (ES)-SCLC with median 2-year survival rates with current therapy remaining at less than 10%. Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a novel, multi-targeted antifolate that inhibits several folate-dependent enzymes involved in purine and pyrimidine synthesis, and is active as a single-agent or in combination with a platinum in both non-small cell lung cancer and malignant pleural mesothelioma. Pemetrexed/platinum combinations appear active in ES-SCLC based on objective response rates observed in a randomized phase II trial. However, no survival data is yet available from this trial. The toxicity profile of both cisplatin and carboplatin in combination with pemetrexed was extremely favorable, as was the ability to deliver full doses of each of the component drugs. Given the limited options available for patients in the relapsed setting, the activity of single-agent pemetrexed is interesting. Also, preliminary data indicates that full doses of carboplatin/pemetrexed can be administered with thoracic radiation therapy, supporting a future clinical trial initiative in LS-SCLC.

Antimetabolites, Antineoplastic↗
PubMed2002

Pemetrexed in the treatment of selected solid tumors.

The novel agent pemetrexed inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Significant activity has been seen in completed phase II trials of pemetrexed in non-small cell lung cancer and breast cancer. Pemetrexed is also active in combination with other agents such as gemcitabine, cisplatin, and carboplatin. In addition, this agent shows promising activity in bladder, head and neck, esophageal, renal, and cervical carcinomas. Preliminary results of studies in these tumor types are reviewed.

Antimetabolites, Antineoplastic↗
PubMed2002

Pemetrexed: a promising new treatment for breast cancer.

Metastatic breast cancer is a chemotherapy-responsive disease, and significant palliation of cancer-related symptoms can be achieved with effective treatment. New treatments are needed because patients with metastatic breast cancer commonly out-live the effectiveness of currently available cytotoxic and hormonal treatments. Pemetrexed is a novel antimetabolite that inhibits three enzymes critical in purine and pyrimidine biosynthetic pathways: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Several phase II studies of pemetrexed have showed objective response rates of more than 30% in minimally pretreated metastatic breast cancer patients and approximately 20% in more heavily pretreated patients. Pemetrexed is associated with limited toxicity when administered with folic acid and vitamin B(12) supplementation and is therefore a promising agent both for palliative treatment of metastatic disease and for incorporation into combination regimens for treating newly diagnosed metastatic and early-stage breast cancer.

Antimetabolites, Antineoplastic↗
PubMed2002

Incorporation of pemetrexed (Alimta) into the treatment of non-small cell lung cancer (thoracic tumors).

Lung cancer is the leading cause of cancer death in the United States and throughout the world. The overall 5-year survival rate for lung cancer is dismal: 14% in the United States and even lower in other parts of the world. Recent developments in the armamentarium of chemotherapeutic agents for lung cancer have shown that two-drug combinations improve survival, relieve symptoms, and improve quality of life; however, complete response rates are still approximately 1% in stage IV disease and less than 20% of advanced stage patients survive 2 years. Therefore, improved therapeutic agents that increase efficacy are sorely needed. Most lung cancers overexpress thymidylate synthase and a variety of genes involved in cell cycle regulation. Previous studies have shown that some inhibitors of DNA synthesis (eg, gemcitabine) can improve the survival of advanced lung cancer patients, especially when combined with other agents such as cisplatin. The multitargeted antifolate, pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) was developed because it inhibits multiple enzymes involved in DNA synthesis including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyl transferase. The early studies of pemetrexed showed that the important dose-limiting toxicities were myelosuppression, mucositis, and diarrhea, all of which are common with any antimetabolite. Subsequent studies described in this article will show that these toxicities can be significantly reduced by the use of vitamin supplementation with folate and B12, and that pemetrexed has considerable activity in non-small cell lung cancer and mesothelioma.

Antimetabolites, Antineoplastic↗
PubMed2002

Pemetrexed: single-agent and combination phase I study overview.

Pemetrexed is a novel folic acid antimetabolite that exerts its activity by the inhibition of multiple enzyme targets. It has been evaluated in a series of phase I clinical trials that explored different administration schedules. The schedule that has been carried forward into phase II trials involves the administration of pemetrexed as a 10-minute intravenous infusion every 21 days with no standard pretreatment with folic acid or vitamin B(12). When given in this manner, the dose-limiting toxicities were neutropenia and thrombocytopenia. Other toxicities included mucositis, rash, and fatigue. The recommended phase II dose was 600 mg/m(2) administered intravenous every 21 days, although this was subsequently modified to 500 mg/m(2) when several early patients experienced toxicities requiring dose reduction in phase II studies. On the basis of preclinical studies suggesting additive or synergistic effects, pemetrexed has also been evaluated in phase I studies in combination with several other agents including cisplatin, carboplatin, oxaliplatin, irinotecan, the taxanes, and anthracyclines. Encouraging anticancer activity has been observed in many of these studies.

Antimetabolites, Antineoplastic↗
PubMed2002

Pemetrexed safety and dosing strategy.

Pemetrexed is a novel antifolate/antimetabolite that inhibits several folate-dependent enzymes, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide transformylase. As a class, antifolates have been associated with sporadic severe myelosuppression with gastrointestinal toxicity. Although infrequent, a combination of such toxicities carries a high risk of potentially life-threatening complications. Severe toxicity from pemetrexed-based therapy has become more predictable using the vitamin deficiency marker homocysteine and, to a lesser extent, methylmalonic acid. Evidence now suggests that reducing total plasma homocysteine levels by supplementation with folic acid and vitamin B(12) leads to a better safety profile for pemetrexed, while not adversely affecting its efficacy.

Antimetabolites, Antineoplastic↗
PubMed2002

The role of pemetrexed in the treatment of colorectal cancer.

Advanced colorectal cancer is a leading cause of cancer-related morbidity and mortality. Chemotherapeutic options, however, have recently expanded with concomitant improvements in survival. Through the 1980s and early 1990s research focused mainly on the major fluoropyrimidine, 5-fluorouracil, a thymidylate synthase inhibitor, and methods to enhance its activity through scheduling changes or by biochemical modulation. Pemetrexed is a novel antifolate that inhibits several folate-dependent enzymes in addition to thymidylate synthase. This agent has theoretical and preclinical advantages over fluoropyrimidines and specifically acting antifolates. Phase II studies have shown a broad spectrum of activity in solid tumors, including colorectal cancer. Further studies at higher doses with the use of vitamin supplementation may be desirable. Combinations of pemetrexed with irinotecan and oxaliplatin have also proven feasible. Pemetrexed is a promising new drug for the treatment of colorectal cancer.

Antimetabolites, Antineoplastic↗
PubMed2002

Pemetrexed in bladder, head and neck, and cervical cancers.

Pemetrexed is a novel multitargeted antifolate analog. The drug has shown encouraging activity in a wide range of solid tumors, including cervix, head and neck, and bladder carcinomas, which are the focus of this review. Toxicity, particularly hematologic, is higher in patients with these tumor types than in other populations exposed to pemetrexed. Supplementation with folic acid and vitamin B(12) appears to effectively reduce the incidence of severe toxicity and may optimize the therapeutic index of pemetrexed in patient subsets with poor nutritional status. The role of this agent in the management of these and other tumor types, as a single agent or in combination, shall be determined by randomized phase III studies.

Animals↗