Phase 1/2 Dose Escalating Study of Twice-Monthly Pemetrexed and Gemcitabine in Patients with Advanced Cancer and Non-small Cell Lung Cancer

Dudek, Arkadiusz Z.; Larson, Timothy; McCleod, Michael; Schneider, Daniel J.; Dowell, Jonathan E.; Banerjee, Tarit K.; Pandya, Kishan J.; Bromund, Jane; Chen, Ruqin; Monberg, Matthew J.; Obasaju, Coleman K.

doi:10.1097/jto.0b013e318169cdc4

Cited by 17 publications

(8 citation statements)

References 24 publications

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“…Pemetrexed pharmacokinetic studies in NSCLC patients have suggested that thymidylate synthase inhibition is short-lived, especially with concurrent vitamin B 12 and folic acid supplementation, suggesting that an every 2-week schedule may be optimal [20,23]. Administration of accelerated doses of pemetrexed (500 mg/m 2 every 2 weeks) has been shown to be feasible and well tolerated in NSCLC patients [24].…”

Section: Discussionmentioning

confidence: 98%

“…Although it is known that folate antimetabolites are often schedule dependent, being more active when administered more frequently, the duration of target enzyme inhibition by pemetrexed was unknown [19]. In view of this, and also based on preliminary findings from a phase I study by Dudek and colleagues exploring the combination of pemetrexed plus gemcitabine given on a bi-weekly schedule to patients with advanced tumors [20], we hypothesized that a shorter interval between doses (14 days) might result in superior antitumor activity. Accordingly, we undertook this study to evaluate the activity of single-agent pemetrexed in a biweekly schedule, as the first-line treatment for advanced or MBC.…”

Section: Introductionmentioning

confidence: 97%

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Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer

Robert

Conkling

O’Rourke

et al. 2010

Breast Cancer Res Treat

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Palliation is the primary goal in metastatic breast cancer (MBC), and safe, efficacious, new single-agent options are needed. Pemetrexed, an antifolate, inhibits several folate-dependent enzymes involved in purine biosynthesis. The primary goal of this study was to determine the objective response rate in patients with advanced or MBC given pemetrexed as a first-line, dose-dense, every 2-week chemotherapy. Women with HER2-negative advanced or MBC, without prior cytotoxic treatment for this stage of disease, were treated with intravenous pemetrexed 600 mg/m² on Day 1 of each 14-day cycle. Standard dexamethasone, folic acid, and vitamin B(12) premedications were given. 37 patients enrolled; 36 received ≥ 1 dose of pemetrexed and 35 were evaluable for response. Median age of patients was 61.4 years, 76% were hormone receptor positive (ER+ and/or PR+). Prior treatment included adjuvant chemotherapy (57%) and/or endocrine (65%). Patients received a median of 6 cycles of pemetrexed (range, 1-21). Based on 35 evaluable patients, the overall response rate (ORR) was 26% (1 CR and 8 PR), and the clinical benefit rate (CR+ PR+ stable disease [SD] ≥ 6 months) was 40%. Median progression-free survival (PFS) was 4.1 months (range, <1-22.4). Median overall survival (OS) was 18.9 months (range, <1-27.7). Grades 3-4 treatment-related toxicities included: neutropenia (36%), leukopenia (17%), fatigue (14%), and anemia (14%). Grade 1/2 alopecia was seen in 8% of patients. This phase II study of dose-dense, single-agent pemetrexed showed moderate activity in the first-line setting with acceptable toxicity and no significant alopecia.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 97%

Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer

Robert

Conkling

O’Rourke

et al. 2010

Breast Cancer Res Treat

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“…However, prior investigations of both drugs suggested that synergy as a result of sequencing may vary from one in vitro system to another 10–12. In a phase I trial of G immediately followed by P given biweekly, the maximum tolerated doses were 1500 mg/m 2 and 500 mg/m 2 respectively 13. The regimen produced a response rate of 21% in untreated patients with advanced NSCLC, and it was well tolerated 13…”

Section: Introductionmentioning

confidence: 99%

Clinical Efficacy and Predictive Molecular Markers of Neoadjuvant Gemcitabine and Pemetrexed in Resectable Non-small Cell Lung Cancer

Bepler

Sommers

Cantor

et al. 2008

Journal of Thoracic Oncology

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Background A trial of neoadjuvant gemcitabine and pemetrexed (GP) chemotherapy in patients with resectable non-small cell lung cancer was conducted. The goal was to achieve a disease response rate of 50% and to determine if the expression levels of genes associated with gemcitabine and pemetrexed metabolism are predictive of response. Methods Patients had staging with a computed tomography (CT) scan, whole body F-18 fluorodeoxyglucose positron emission tomography (PET), and mediastinoscopy. Four biweekly cycles of GP were given. Patients were restaged, and those with resectable stage IB-III disease had thoracotomy. Fresh frozen tumor specimens were collected before and after chemotherapy and the mRNA levels of 14 target genes determined by real-time reverse transcriptase polymerase chain reaction (RTPCR). Results Fifty-two patients started therapy. The radiographic disease response rate was 35% (95% confidence interval [CI] 21.7 to 49.6%), and the progression rate was 6%. Forty-six patients had a thoracotomy. The complete tumor resection rate was 77% (40/52). There were no perioperative deaths or deaths related to chemotherapy. Tumor response to chemotherapy was inversely correlated with the level of expression of RRM1 (p ≤ 0.001; regulatory subunit of ribonucleotide reductase) and TS (p = 0.006; thymidylate synthase); i.e., the reduction in tumor size was greater in those with low levels of expression. Conclusions Neoadjuvant GP is well tolerated and produces an objective response rate of 35%. Tumoral RRM1 and TS mRNA levels are predictive of disease response and should be considered as parameters for treatment selection in future trials with this regimen.

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“…The results of several of these studies can be found in Table 4. [35][36][37][38][39][40] vinorelbine Vinorelbine is a semi-synthetic vinca alkaloid that has shown activity in NSCLC as part of a platinum-based combination regimen. 41 A combination regimen of vinorelbine and pemetrexed was evaluated in a phase I/II clinical trial reported in 2005.…”

Section: Gemcitabinementioning

confidence: 99%

Tailoring treatment of nonsmall cell lung cancer by tissue type: role of pemetrexed

Powell¹,

Dudek

2009

PGPM

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Pemetrexed (ALIMTA, LY231514, MTA) is a novel multitargeted antifolate that is currently approved for the treatment of metastatic nonsmall cell lung cancer (NSCLC). Recent evidence reveals that the drug's efficacy is limited to nonsquamous lung cancer histology. As we further understand the drug's mechanisms of action, new genomic and proteomic evidence is shedding light on why some patients respond while others do not. The first goal of this review is to briefly review pemetrexed's mechanism of action, resistance patterns, toxicity profile, and pharmacokinetics. We will also review the clinical trials that led to its use in NSCLC, with special attention to data showing that pemetrexed has greater efficacy in nonsquamous histologies of NSCLC. Furthermore, we will discuss the hypotheses for the genomic and proteomic basis for this variation in efficacy. Finally, we will report the future directions for pemetrexed as a personalized agent for nonsquamous NSCLC.

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Phase 1/2 Dose Escalating Study of Twice-Monthly Pemetrexed and Gemcitabine in Patients with Advanced Cancer and Non-small Cell Lung Cancer

Abstract: Twice-monthly gemcitabine and pemetrexed was well tolerated, with overall survival and clinical benefit indicating disease activity in NSCLC patients.

Cited by 17 publications

References 24 publications

Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer

Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer

Clinical Efficacy and Predictive Molecular Markers of Neoadjuvant Gemcitabine and Pemetrexed in Resectable Non-small Cell Lung Cancer

Tailoring treatment of nonsmall cell lung cancer by tissue type: role of pemetrexed

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