Chemotherapy treatment patterns, costs, and outcomes of patients with gastric cancer in the United States: a retrospective analysis of electronic medical record (EMR) and administrative claims data.

BACKGROUND: The aim of this study was to conduct a retrospective database analysis to describe the chemotherapy treatment patterns and outcomes of patients with gastric cancer. METHODS: Individuals diagnosed with gastric cancer were identified from the IMS Oncology Database, which contains electronic medical record (EMR) data collected from a variety of community practices, and the Truven Health MarketScan(®) Research database, an administrative claims database. Eligible patients were 18 years of age or older and had an ICD-9 code 151.0-151.9. Patients were excluded if they had evidence of cancer within 6 months of the index diagnosis. RESULTS: There were 5257 eligible patients identified in EMR data: 1982 (37.7 %) of these patients also had data regarding chemotherapy treatments. Of the 1982 patients who received first-line therapy, 42.3 %, 18.1 %, and 7.9 % went on to receive a second, third, and fourth line of chemotherapy, respectively. There were 11891 eligible patients identified in the administrative database; 5299 (44.6 %) had data regarding chemotherapy. Of those initiating chemotherapy, 2888 (54.5 %) received a second line and 1598 (30.2 %) received a third line of treatment. The average total cost of care during first-line therapy was $40,811 [standard deviation (SD) = $49,916], which was incurred over an average of 53.5 (SD = 63.4) days. A similar pattern was evident in second-line treatment (mean/SD, $26,588/$33,301) over 41.2 (SD = 55.7) days. CONCLUSIONS: Costs and duration of care received vary among gastric cancer patients in the U.S. There is a need to understand which regimens may be associated with better health outcomes and to standardize treatment as appropriate.

Phase I study of enzastaurin and bevacizumab in patients with advanced cancer: safety, efficacy and pharmacokinetics.

PURPOSE: Given distinct mechanism of actions of enzastaurin and bevacizumab, preclinical studies suggest enhanced antitumor activity in combination. This phase I study assessed the combination's safety and efficacy. PATIENTS AND METHODS: Six advanced cancer patients could be enrolled in each of 11 cohorts. Patients received an enzastaurin loading dose. Oral enzastaurin (500 mg once daily [QD], 250 mg twice daily [BID], 375 mg BID, 500 mg BID, and 750 mg BID) was escalated in each cohort in combination with bevacizumab dosed at 5 mg/kg every 2 weeks, 10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks until a dose-limiting toxicity (DLT) occurred in 2 of 6 patients in any cohort. RESULTS: Sixty-seven patients (31, ovarian cancer [ovcar]) were evaluable for safety and efficacy. Six treatment-related DLTs occurred: grade 3 fatigue (n=4), grade 4 cerebral hemorrhage, and grade 3 elevated aspartate transaminase. Common drug-related toxicities included change in color of urine and stool, fatigue, pain, diarrhea, and nausea. The maximum tolerated dose of enzastaurin was 750 mg BID in combination with any tested bevacizumab dose/schedule. Overall response rate was 19.4 % (32.3 % ovcar). Median time to progression was 3.7 months (95 % confidence interval [CI], 2.7-5.5), with 8.3 months (95 % CI, 3.7-11.1) in ovcar. Overall, 35.9 % (50.4 % ovcar) of patients remained without disease progression after 6 months. CONCLUSION: The recommended phase II doses of enzastaurin were 500 mg QD up to 500 mg BID with any tested dose/schedule of bevacizumab. This combination demonstrated encouraging clinical activity, particularly in ovcar.

A double-blind, randomized, placebo-controlled, phase 2 study of maintenance enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab after first-line therapy for metastatic colorectal cancer.

BACKGROUND: Enzastaurin and bevacizumab have demonstrated synergistic antitumor effects and, in phase 1 studies, the combination was well tolerated. This phase 2 study assessed enzastaurin with 5-fluorouracil/leucovorin plus bevacizumab as maintenance therapy for metastatic colorectal cancer (MCRC). METHODS: Patients with locally advanced or MCRC and stable or responding disease after completing 6 cycles of first-line chemotherapy randomly received a loading dose of enzastaurin 1125 mg, followed by 500 mg/d subsequent doses or placebo. Both arms received 5-fluorouracil/leucovorin (leucovorin 400 mg/m(2) intravenously [IV], 5-fluorouracil 400-mg/m(2) bolus, 5-fluorouracil 2400 mg/m(2) IV) plus bevacizumab 5 mg/kg IV, every 2 weeks. The primary endpoint was progression-free survival (PFS), from randomization. Overall survival (OS) and PFS were also assessed from start of first-line therapy. Enrollment was stopped, and the final analysis was conducted after 73 PFS events. RESULTS: Fifty-eight patients were randomized to enzastaurin and 59 to placebo. For the enzastaurin and placebo arms, respectively, the median cycles received were 9 and 10, and the median PFS was 5.8 and 8.1 months (hazard ratio [HR], 1.35; 95% confidence interval [CI], 0.84-2.16; P = .896). Median OS was not calculable because of high censoring (77.6% enzastaurin; 91.5% placebo). The median PFS from start of first-line therapy was 8.9 months for enzastaurin and 11.3 months for placebo (HR, 1.39; 95% CI, 0.86-2.23; P = .913). More enzastaurin patients developed thrombosis or embolism compared with placebo (15.8% and 1.7%; P = .008). One possibly enzastaurin-related death occurred because of arrhythmia. CONCLUSIONS: Enzastaurin combined with bevacizumab-based therapy is tolerable, but does not improve PFS during maintenance therapy in patients with MCRC compared with bevacizumab-based therapy alone.

Multicenter, randomized phase II trial of bevacizumab plus folinic acid, fluorouracil, gemcitabine (FFG) versus bevacizumab plus folinic acid, fluorouracil, oxaliplatin (FOLFOX4) as first-line therapy for patients with advanced colorectal cancer.

PURPOSE: To assess safety and efficacy of folinic acid, 5-fluorouracil, gemcitabine (FFG) and folinic acid, fluorouracil, oxaliplatin (FOLFOX4) regimens with added bevacizumab as first-line treatment in patients with advanced colorectal cancer (CRC). PATIENTS AND METHODS: Patients with Stage III unresectable or Stage IV adenocarcinoma of the colon or rectum were randomly assigned to either FFG weekly for 6 weeks of an 8-week cycle or FOLFOX4 every 2 weeks. After FDA approval, bevacizumab 5 mg/kg was added every 2 weeks. Treatment continued until disease progression. Planned enrollment was 190 patients. Primary endpoint was overall response rate (ORR); secondary endpoints included evaluation of adverse events, time to progression (TTP), and overall survival (OS). Disease Control Rate (DCR; % of patients with complete or partial responses or stable disease) was a post hoc analysis. RESULTS: The trial was stopped prematurely due to low enrollment. Of 84 enrolled patients (42 to each arm), 36 patients (18 in each arm) received bevacizumab. ORR was greater (P = .002) for FOLFOX4 (17/42; 40.5%) than for FFG (4/42; 9.5%); however, TTP, OS, and DCR results were not statistically different comparing FOLFOX4 and FFG. Peripheral neuropathy was more frequent (P = <.001) with FOLFOX4 (18/42; 42.9%) than with FFG (1/42; 2.4%). CONCLUSIONS: FFG and FOLFOX4 were generally well tolerated. Based on ORR, FOLFOX4 was superior to FFG. However, differences in TTP and OS comparing regimens were inconclusive. General use of gemcitabine as a biomodulator of 5-fluorouracil in CRC cannot be recommended at this time and the regimen remains investigational.

A phase I study of pemetrexed in patients with relapsed or refractory acute leukemia.

PURPOSE: To investigate the toxicity profile, activity, pharmacokinetics, and pharmacodynamics of pemetrexed in leukemia. PATIENTS AND METHODS: Patients with refractory or relapsed acute leukemia were eligible. A phase I 3+3 design was implemented. Pemetrexed was infused intravenously (IV) over 25 min with vitamin supplementation. Courses were repeated every 3 to 4 weeks according to toxicity and efficacy. The starting dose of 900 mg/m² was escalated by approximately 33% until the dose-limiting toxicity (DLT) was determined. RESULTS: Twenty patients with acute myeloid (AML) or lymphocytic (ALL) leukemia received therapy. The main non-hematologic adverse event was liver dysfunction at several dose levels, including 2 DLTs at 3,600 mg/m². One patient with ALL (3,600 mg/m² dose level) achieved a partial response. Pemetrexed pharmacokinetics were linear with escalated dosing. Elevated plasma deoxyuridine was observed in a subset of patients following pemetrexed infusion, but was not correlated with dose levels. Changes in the nucleotide pools of circulating mononuclear cells were observed, but were variable. CONCLUSIONS: The recommended phase II dose of pemetrexed for future leukemia studies is 2,700 mg/m(2) IV over 25 min every 3 to 4 weeks with vitamin supplementation. Deoxyuridine levels did not increase with increasing pemetrexed dose, suggesting pemetrexed inhibition of thymidylate synthase (TS) may be saturated by the 900 mg/m² dose level. However, no firm conclusion can be made regarding TS saturation in tumor cells. While tolerable, pemetrexed monotherapy had limited activity in this highly refractory population. Exploration of pemetrexed in combination with other active agents in leukemia is a reasonable future endeavor.

Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: results of a phase II, randomized, noncomparative study.

PURPOSE: Gemcitabine (G) is standard therapy for pancreatic cancer. Enzastaurin (E) inhibits PKCß and PI3K/AKT signaling pathways with a dose-dependent effect on growth of pancreatic carcinoma xenografts. Data suggest that the GE combination may improve clinical outcomes. METHODS: Primary objective was overall survival (OS); secondary objectives assessed progression-free survival (PFS), response rate (RR), quality of life (QOL), toxicity, and relationships between biomarker expression and clinical outcomes. Patients were randomly assigned (2:1) to GE or G treatment; GE arm: E 500 mg p.o. daily; loading-dose (1200 mg; Day 1 Cycle 1 only) and G 1000 mg/m(2) i.v. Days 1, 8, and 15 in 28-day cycles; G arm: G as in GE. Biomarker expression was assessed by immunohistochemistry. RESULTS: Randomization totaled 130 patients (GE = 86, G = 44); 121 patients were treated (GE = 82, G = 39). GE/G median OS was 5.6/5.1 months; median PFS was 3.4/3.0 months. GE responses: 1 complete response (CR, 1.2%), 6 partial response (PR, 7.4%), and 33 stable disease (SD, 40.7%); disease control rate (DCR=CR+PR+SD, 49.4%). G responses: 2 PR (5.3%) and 16 SD (42.1%); DCR (47.4%). No QOL differences were noted between arms. GE/G Grade 3-4 toxicities included: neutropenia (18.3%/28.2%); thrombocytopenia (14.6%/25.6%); and fatigue (11.0%/7.7%). No statistically significant relationships between biomarker expression and outcomes were observed. However, patients with low expression of cytoplasmic pGSK-3ß trended toward greater OS with GE treatment. CONCLUSIONS: OS, PFS, QOL, and RR were comparable between arms. Adding E to G did not increase hematologic toxicities. GE does not warrant further investigation in unselected pancreatic cancer patients.

Challenges of Using ICD-9-CM and ICD-10-CM Codes for Soft-Tissue Sarcoma in Databases for Health Services Research.

Objectives: Soft-tissue sarcoma (STS) is a heterogeneous group of rare solid tumors that arise from various soft tissues in the body, such as muscle, fat, nerves, and blood vessels. Current International Classification of Diseases (ICD) coding systems include a set of nonspecific codes for malignancies of connective and soft tissue (ICD-9-CM code 171 and ICD-10-CM code C49). The goal of this study was to evaluate the use of these codes for health services research involving patients with a diagnosis of this rare malignancy. Methods: Two databases were utilized to explore ICD coding for STS: claims data from Truven MarketScan and electronic medical records (EMRs) from Flatiron Health. Eligible patients from claims data were those with at least two ICD-9-CM codes of 171.x on two different days between July 1, 2004, and March 30, 2014. The treatment patterns of these cases were evaluated for consistency with known therapeutic approaches for STS. Eligible patients from the Flatiron EMR system were those who received olaratumab (a drug indicated only for use in patients diagnosed with STS) after its US Food and Drug Administration approval in October 2016 through the end of the data set (November 2017). ICD-10-CM codes were evaluated for this known STS cohort. Results: In claims data, 4,159 patients were eligible for inclusion. Although national treatment guidelines include only a limited number of drugs used to treat STS, 98 unique anticancer drugs were identified as being used to treat patients in a claims data cohort. Only 7.7 percent of patients had claims for doxorubicin-based therapy and 3.8 percent had claims for ifosfamide-based therapy as initial treatment for STS, despite these being a standard of care. In the EMR data, 350 patients were eligible; only 170 patients (48.6 percent) had any evidence in the database of a connective or soft-tissue ICD-10-CM malignancy code within 60 days before or after initiation of olaratumab. Conclusions: ICD coding for STS using the "Malignant neoplasm of connective and soft tissue" code is not reliable as a method to identify patients diagnosed with STS. Although codes reflecting the primary site of disease may have clinical relevance, lack of consistency in ICD coding for the diagnosis and treatment of this disease is a limiting factor in the ability to conduct real-world observational research of this rare disease. In the absence of consistent use of this code, an algorithm needs to be developed and validated to accurately identify patients with STS in these databases.

Patient and Oncologist Preferences for the Treatment of Adults with Advanced Soft Tissue Sarcoma: A Discrete Choice Experiment.

BACKGROUND: There has been no single standard-of-care treatment of patients with advanced/metastatic soft tissue sarcoma (STS). This study was designed to understand patient and oncologist preferences in the advanced/metastatic setting. METHODS: Adult patients diagnosed with STS and oncologists treating patients with STS completed discrete choice experiment surveys. Study participants chose between pairs of hypothetical treatment profiles for advanced STS characterized by varying levels of overall survival (14, 20, or 26 months), progression-free survival (3, 5, or 7 months), objective tumor response rate (12, 18, or 26%), risk of hospitalization due to side effects (12, 30, or 46%), and days/month to administer treatment (1, 2, or 4 days). A hierarchical Bayes model was used to estimate preferences and relative importance of attributes. RESULTS: Seventy-six patients (23.7% male, mean age 52.8 years) and 160 oncologists (73.8% male, mean 16.9 years in practice) completed the surveys. Among patients, overall survival had the highest relative importance (39.5%, standard deviation [SD] 18.2%), followed by response rate (21.2%, SD 10.4%), and hospitalization (19.8%, SD 12.5%). Among oncologists, overall survival had the highest relative importance (44.6%, SD 16.0%), followed by hospitalization (18.4%, SD 8.3%). CONCLUSIONS: Both patients with STS and oncologists preferred a treatment that maximizes the life of patients while avoiding hospitalizations.

Treatment patterns and survival among older adults in the United States with advanced soft-tissue sarcomas.

BACKGROUND: To describe patient and tumor characteristics, treatments, and survival among older adults in the United States with advanced soft-tissue sarcoma (STS), across and by categories of specifically defined histologic subtypes. METHODS: We conducted a retrospective cohort analysis using the SEER. The study population comprised patients ≥ 65 years old with advanced STS (excluding osteosarcoma, Kaposi sarcoma, and gastrointestinal stromal tumors) diagnosed from January 1, 2001 to December 31, 2011. RESULTS: Of 4274 study patients, 2103 (49.2%) were male. Mean age was 77.8 years, and 1539 (36.0%) had distant disease at initial diagnosis. The most common histologic categories were leiomyosarcoma (922[21.6%]), undifferentiated pleomorphic sarcoma (652[15.3%]), and liposarcoma (554[13.0%]). Overall, 1227 (28.7%) patients received first-line systemic therapy. Among these patients, 325 (26.5%) received docetaxel plus gemcitabine and 231 (18.8%) received doxorubicin alone. Only 476 patients received second-line therapy (11.1%), most commonly doxorubicin alone (n = 101). Median overall survival (95% confidence interval) from advanced STS diagnosis was 8.9 (8.3, 9.7) months. CONCLUSIONS: Although previous studies of younger populations reported anthracycline-based therapy predominated in first line, our study of older advanced STS patients found that docetaxel plus gemcitabine was most commonly used. Despite variation by histologic category, prognosis remains poor for older adult patients with advanced STS.

Pemetrexed and oxaliplatin for metastatic colorectal cancer: results of a phase I Mayo Cancer Center Research Consortium trial, MC0248.

PURPOSE: Pemetrexed, an antifolate involved in purine and pyrimidine formation, is a potential alternative to fluoropyrimidines in the treatment of colorectal cancer. A phase I trial was performed to establish the maximum tolerated dose (MTD) of pemetrexed and oxaliplatin when B(12) and folate supplementation is used. PATIENTS AND METHODS: Patients with metastatic colorectal cancer received folate (> 350 microg) daily and vitamin B(12) (1000 microg) every 9 weeks starting 7 days before chemotherapy. Pemetrexed over 10 minutes and oxaliplatin over 2 hours were given every 3 weeks in escalating dose cohorts. RESULTS: Twenty-two patients were entered on 6 dose levels. The MTD was established at the highest dose level, pemetrexed 900 mg/m(2) and oxaliplatin 130 mg/m(2). Toxicities related to treatment at the MTD included grade 3 neutropenia and thrombocytopenia. For all dose levels combined, grade 3/4 toxicities included hematologic, neurologic, and gastrointestinal. Nine of 21 evaluable patients responded overall (response rate, 43%). The time to tumor progression was 11.9 months. CONCLUSION: The MTD was determined to be pemetrexed 900 mg/m(2) and oxaliplatin 130 mg/m(2) every 21 days when folate and B (12) supplementation are used. Because of the observed tolerability and activity of this regimen, further evaluation is warranted.

The Patient Experience with Soft Tissue Sarcoma: A Systematic Review of the Literature.

BACKGROUND: Soft tissue sarcomas (STS) are a heterogenous group of rare tumors that involve the connective tissue in the body (e.g. muscle, tendons). As with many rare tumors, little is known about the impact of STS on patient well-being. OBJECTIVE: The aim of this review was to better understand current knowledge related to patient experience and quality of life (QOL) following diagnosis of STS. METHODS: A systematic review of English-language articles published from 2005 to 2015 was conducted in the PubMed/MEDLINE, Embase, PsychINFO, and Evidence-Based Medicine databases. The review included recent conference proceedings and advocacy websites. Articles were eligible if they included adult STS patient-reported outcomes (PROs) or details on patient experience. RESULTS: Overall, 3430 articles were identified and 20 were eligible for inclusion. Of these, 14 were clinical studies that included PRO measures, 1 summarized PRO measures used in STS studies, and 5 described the STS patient experience. Patients with STS report a range of impacts on QOL, including emotional well-being, body image, functional deficit following surgery, and practical considerations such as child care and work. CONCLUSIONS: Few studies have published either qualitative or quantitative data on the patient experience with STS. While STS has a measurable impact on QOL, there is a lack of detailed information in the published literature. Although PROs are used in clinical studies of STS, they are not STS-specific and may not capture the unique needs of this population. There is a need for qualitative research to better understand both patient and caregiver experiences in STS.

KRAS testing of patients with metastatic colorectal cancer in a community-based oncology setting: a retrospective database analysis.

BACKGROUND: In 2009, treatment guidelines were updated to recommend KRAS testing at diagnosis for patients with metastatic colorectal cancer (mCRC). We investigated KRAS testing rates over time and compared characteristics of KRAS-tested and not-tested patients in a community-based oncology setting. METHODS: Adult patients with a diagnosis of mCRC from 2008-2011 were selected from the ACORN Data Warehouse (ACORN Research LLC, Memphis, TN). Text mining of physician progress notes and full chart reviews identified KRAS-tested patients, test dates, and test results (KRAS status). The overall proportion of eligible patients KRAS-tested in each calendar year was calculated. Among KRAS-tested patients, the proportion tested at diagnosis (within 60 days) was calculated by year. Univariate and multivariate analyses were used to compare patient characteristics at diagnosis between tested and not-tested cohorts, and to identify factors associated with KRAS testing. RESULTS: Among 1,363 mCRC patients seen from 2008-2011, 648 (47.5%) were KRAS-tested. Among newly diagnosed mCRC patients, the rate of KRAS testing increased from 5.9% prior to 2008, to 13.9% in 2008, and then jumped dramatically to 32.3% in 2009, after which a modest yearly increase continued. The proportions of KRAS-tested patients who had been diagnosed in previous years but not tested previously increased from 17.7% in 2008 to 27.0% in 2009, then decreased to 19.0% in 2010 and 17.6% in 2011. Among patients who were KRAS-tested, the proportions tested at the time of diagnosis increased annually (to 78.4% in 2011). Patients more likely to have been tested included those with lung metastases, poor performance status, more comorbidities, and mCRC diagnosis in 2009 or later. CONCLUSIONS: The frequency of KRAS testing increased over time, corresponding to changes in treatment guidelines and epidermal growth factor receptor inhibitor product labels; however, approximately 50% of eligible patients were untested during the study period.

A multi-institutional phase II trial of gemcitabine plus paclitaxel in patients with locally advanced or metastatic urothelial cancer.

The purpose of the study was to evaluate response and survival in patients with metastatic urothelial cancer treated with combination gemcitabine and paclitaxel administered on a biweekly schedule at doses of 3000 mg/m2 and 150 mg/m2, respectively. Patients with adequate organ function and performance status were accrued through 7 institutions, stratified by prior therapy status, and treated as noted. Response was evaluated by 1979 bi-dimensional World Health Organization (WHO) criteria. Of 55 eligible patients, 17 had a partial and 5 had a complete response rate for an overall response rate of 40% (27-54%). One complete response and one partial response were observed in the 6 previously treated patients. Overall median survival was 11.8 months (11.9 months in the chemonaive cohort). Grade 3 or 4 myelosuppression occurred in 56%, but only 4 serious infections were observed. We conclude that because of a lower than expected complete response rate, even when corrected for prognostic groupings, this regimen is not recommended for routine use in patients with metastatic urothelial cancer. Insufficient patients with poor renal function or prior therapy were accrued to reach conclusions regarding its utility in these subgroups.

Metastatic colorectal cancer treatment patterns according to kirsten rat sarcoma viral oncogene homolog genotype in U.S. Community-based oncology practices.

INTRODUCTION: In 2008, the National Comprehensive Cancer Network guidelines were revised in light of the identification of the Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) gene as a biomarker of nonresponse to epidermal growth factor receptor inhibitors. This study sought to describe and compare real-world treatment patterns of metastatic colorectal cancer (mCRC) according to KRAS genotype in community-based oncology practices in the United States. MATERIALS AND METHODS: Data from the ACORN (ACORN LLC, Memphis, TN) electronic medical record data warehouse, containing data of approximately 180,000 patients from 12 oncology practices across the United States were used. Records of adult patients with mCRC who had undergone KRAS testing between January 2008 and December 2011 were evaluated. Patient demographic characteristics, KRAS genotype, and treatment patterns were identified and compared. RESULTS: Six hundred forty-eight mCRC patients who were tested for KRAS were identified. Of these, 48.1% had wild type (WT), 42.3% mutant, and 9.6% unknown genotypes. Most patients (72.1%) were tested in 2009 or later, after the guideline revision. Bevacizumab-containing combinations were the most common first-line regimens in KRAS mutant and WT patients. Approximately 90% of patients received at least 1 line of therapy, however, WT patients received significantly more lines of therapy than KRAS mutant patients (2.6 ± 1.5 vs. 2.1 ± 1.2; P < .001). CONCLUSIONS: KRAS WT and mutant genotypes had similar first-line regimens; however, WT patients received more lines of therapy. Although there does not appear to be a lag between changes in guidelines and treatment practice, professional and government organizations must keep up with the changing science and disseminate this information to oncologists in a timely manner.

Phase I dose-escalating study of biweekly fixed-dose rate gemcitabine plus pemetrexed in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD) and the recommended phase II dose and to identify the dose-limiting toxicities (DLTs) of gemcitabine, administered by fixed-dose rate (FDR) infusion, combined with the antifolate agent pemetrexed in patients with advanced solid tumors. METHODS: Eligible patients were entered into this open label, phase I trial. Using a 3 + 3 dose escalation design, patients received intravenous pemetrexed 300-800 mg/m(2) followed by FDR gemcitabine 900-1,500 mg/m(2) at 10 mg/m(2)/min on Day 1 every 2 weeks. All patients received folic acid and vitamin B(12) supplementation. Patients continued until DLT or disease progression. RESULTS: A total of 33 patients were treated at 7 dose levels with a total of 230 cycles (median: 4 cycles; mean: 7 cycles; range: 1-35 cycles). The MTD of the combination was pemetrexed 800 mg/m(2) and gemcitabine 1,500 mg/m(2) over 150 min. DLTs were febrile neutropenia and grade 3 renal failure. Of the 28 patients evaluable for response, 3 patients experienced a partial response (10.7%) and 13 patients had stable disease (46.4%); the disease control rate was 57.1%. CONCLUSIONS: The recommended phase II dose for biweekly pemetrexed with FDR gemcitabine is 800 mg/m(2) and 1,200 mg/m(2) × 120 min, respectively. This regimen allows good dose intensity of both drugs to be administered on a simple schedule with an excellent tolerability profile. This regimen showed moderate activity in a diverse phase I population, possibly greater than either single agent. Further assessment of the combination in a phase II setting is suggested.

Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma.

This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

Enzastaurin plus temozolomide with radiation therapy in glioblastoma multiforme: a phase I study.

We conducted a phase I study to determine the safety and recommended phase II dose of enzastaurin (oral inhibitor of the protein kinase C-beta [PKCbeta] and the PI3K/AKT pathways) when given in combination with radiation therapy (RT) plus temozolomide to patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Patients with Karnofsky performance status > or =60 and no enzyme-inducing anti-epileptic drugs received RT (60 Gy) over 6 weeks, concurrently with temozolomide (75 mg/m(2) daily) followed by adjuvant temozolomide (200 mg/m(2)) for 5 days/28-d cycle. Enzastaurin was given once daily during RT and adjuvantly with temozolomide; the starting dose of 250 mg/d was escalated to 500 mg/d if < or =1/6 patients had dose-limiting toxicity (DLT) during RT and the first adjuvant cycle. Patients continued treatment for 12 adjuvant cycles unless disease progression or unacceptable toxicity occurred. Twelve patients enrolled. There was no DLT in the first 6 patients treated with 250 mg enzastaurin. At 500 mg, 2 of 6 patients experienced a DLT (1 Grade 4 and 1 Grade 3 thrombocytopenia). The patient with Grade 3 DLT recovered to Grade <1 within 28 days and adjuvant temozolomide and enzastaurin was reinitiated with dose reductions. The other patient recovered to Grade <1 toxicity after 28 days and did not restart treatment. Enzastaurin 250 mg/d given concomitantly with RT and temozolomide and adjuvantly with temozolomide was well tolerated and is the recommended phase II dose. The proceeding phase II trial has finished accrual and results will be reported in 2009.

A phase II study of pemetrexed in patients with advanced hepatocellular carcinoma.

Pemetrexed has demonstrated activity in hepatocellular carcinoma (HCC) cell lines, and has a manageable toxicity profile in clinical trials, suggesting its potential as a treatment for HCC patients. A multicenter, Phase II community-based study was conducted to assess the response rate and toxicity profile of single-agent pemetrexed in first-line patients with advanced or metastatic HCC. Patients premedicated with folic acid, vitamin B(12), and dexamethasone were administered pemetrexed 600 mg/m(2) IV on day 1 of each 21-day cycle until disease progression. This nonrandomized study employed Simon's 2-stage design, enrolling 21 eligible patients in the first stage, stopping accrual if < or =2 responders were observed. Responses were four stable disease, 14 progressive disease, and three not evaluable: two had early toxicities (renal/liver failure, sepsis) and one was noncompliant. The most common grade 3 hematological toxicities were neutropenia 6 of 21 (29%) and thrombocytopenia 3 of 21 (14%); with no grade 4 toxicities. Thirteen patients died on-study: 12 PD and one liver failure; none were drug-related. The median survival was 5.2 months (range, <1-12.2). The planned second stage was cancelled, and the trial was closed owing to lack of response. While pemetrexed was tolerated in this patient population, it was not active.

Phase I trial of pemetrexed plus oxaliplatin administered every other week in patients with metastatic cancer.

PURPOSE: To identify the maximum tolerated dose (MTD) and describe dose-limiting toxicities (DLT) of pemetrexed and oxaliplatin given on a once-every-2-week schedule in patients with metastatic cancer. PATIENTS AND METHODS: Twenty-five patients were enrolled. Due to toxicities observed at the first dose level in unselected patients, a second MTD was determined in patients who had received zero to two prior chemotherapy regimens. RESULTS: DLT was observed at dose level 1-pemetrexed 400 mg/m(2) and oxaliplatin 85 mg/m(2)-in the form of grade 3 fatigue in two of six patients. Enrollment was then limited to lightly pretreated patients and DLT was observed at dose level 2-pemetrexed 500 mg/m(2) and oxaliplatin 85 mg/m(2)-in the form of neutropenic fever in one of five patients. Complete response was confirmed in one patient (squamous cell carcinoma of the head and neck) and partial response was confirmed in three patients. CONCLUSIONS: The combination of pemetrexed and oxaliplatin can be safely administered at doses of 400 to 500 mg/m(2) of pemetrexed and 85 mg/m(2) in patients without extensive prior therapy and 300 and 85 mg/m(2), respectively, every 2 weeks in patients with more extensive prior therapy. Based on promising results observed in this study, a phase II trial in patients with recurrent head and neck cancer has been initiated.

Phase I study of a 3-drug regimen of gemcitabine/cisplatin/pemetrexed in patients with metastatic transitional cell carcinoma of the urothelium.

OBJECTIVES: Gemcitabine (G) plus cisplatin (C) is standard care for metastatic transitional cell carcinoma (TCC) of the urothelium. Pemetrexed (P), alone or in combination with G, is active in metastatic TCC. However, the safety and efficacy of P combined with GC therapy is unknown. This phase I trial was designed to determine the maximum tolerated dose (MTD) of GC followed by P+G in patients with metastatic TCC. METHODS: Cohorts of 3 to 6 patients received escalating doses 28-day cycles (maximum 6 cycles): G 800-1,000 mg/m2 on days 1 and 15; P 400-500 mg/m2 on day 15; and C 50-70 mg/m2 on day 1. All patients received folic acid, vitamin B12, and full supportive care. The 3+3 standard phase I escalation rule was used to determine MTD. RESULTS: Fifteen patients registered: 13/15 white males; median age 70 years (range, 53-82); 11/15 had KPS>or=90. At dose level 0, 2/4 patients experienced unrelated DLTs, and 1 patient was replaced (completed<1 cycle). Dose escalation proceeded to dose level 1. At level 1, 4/6 patients experienced DLTs; dosing decreased to level 0 and 4/5 patients experienced DLTs. The MTD was not determined. The 2 patients that completed 6 cycles both had partial responses. Grades 3-4 hematologic toxicities included neutropenia (60%), leukopenia (20%), and febrile neutropenia (13%). CONCLUSION: Adding P to the standard GC regimen as first-line therapy for metastatic TCC produced no benefit. The MTD exceeded therapeutic gemcitabine and cisplatin doses for urothelial cancer and thus the study was aborted.