Multitargeted Antifolate Research Articles

CTNI-15. PILOT STUDY OF HIGH-DOSE PEMETREXED FOR PROGRESSIVE CHORDOMA

Abstract INTRODUCTION Chordomas are ultra-rare tumors of the spine, and no systemic therapy is approved for refractory disease. Pemetrexed is a multitargeted antifolate that inhibits thymidylate synthase (TS) and other enzymes involved in nucleotide biosynthesis. Considering the majority of chordomas do not express TS, we sought to evaluate the therapeutic activity and safety of high-dose pemetrexed. METHODS Adults with previously-treated chordoma were enrolled on an open-label, single-institution, single-arm, pilot clinical trial. Pemetrexed 900 mg/m2 was administered intravenously every 3 weeks, with supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary and exploratory endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in potential tissue and blood-based biomarkers before and after treatment. RESULTS Fifteen patients with chordoma received a median of 15 (range 4-31) doses of pemetrexed. Median PFS was 10.5 months (95% CI 9 months-undetermined) and 6-month PFS was 67%. Out of 14 response-evaluable patients, two (14%) achieved a partial response and ten (71%) demonstrated stable disease. Adverse events were generally mild at grades 1-2, the most common being fatigue, rash, nausea, constipation, diarrhea, mucositis, vomiting, alopecia, pruritus, lower extremity edema, and alanine transaminase increased. One Grade 3 creatinine increase, one Grade 3 lymphopenia, and one Grade 4 lymphopenia occurred and there were no Grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities. Clinical improvement in disease-related symptoms occurred in several patients. Tumor molecular profiling revealed low mutational burden and though not statistically significant, positive TS expression trended negatively with disease progression. Cell-free microRNAs (cfmiRs) were concordantly detected in plasma and tissues and a blood cfmiR signature was identified that distinguished chordoma from health donors. CONCLUSION High-dose pemetrexed is safe and well-tolerated in chordoma patients. A phase II study is in development. (NCT03955042)

EP16.03-029 SLIT2 Expression in NSCLC With Long-Term Response to Pemetrexed

The chemotherapy including the multitargeted antifolate (pemetrexed disodium; Alimta) is indicated for the 1st line treatment of patients with advanced non-small cell lung cancer (NSCLC). It is constructed by induction and maintenance chemotherapy, and some patients have the response over 12 months. We evaluated SLIT2 expression of immunohistochemistry (IHC) in NSCLC with long-term response to pemetrexed.

Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3.

Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 µM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed.

Design, synthesis and biological evaluation of 6-substituted pyrrolo[2,3-d]pyrimidines as dual inhibitors of TS and AICARFTase and as potential antitumor agents

A new series of 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines, with an isosteric replacement of the side chain amide moiety to a sulfur atom, were designed and synthesized as multitargeted antifolates as well as potential antitumor agents. Starting from previously synthesized 2-amino-4-oxo-pyrrolo[2,3-d]pyrimidin-6-yl-acetic acid, a reduction by lithium triethylborohydride and successive mesylation afforded the key mesylate. Nucleophilic substitution by mercaptoacetic or mercaptopropionic acid methyl esters, followed by hydrolysis and condensation with pyridinyl-methylamines provided the nonclassical compounds 1–6, whereas condensation with glutamic acid diethyl ester hydrochloride and saponification afforded the classical analogs 7–8. All target compounds exhibited inhibitory activities toward KB, SW620 and A549 tumor cell lines. The most potent compounds of this series, 7 and 8, are better inhibitors against A549 cells than methotrexate (MTX) and pemetrexed (PMX). Nucleoside protection assays establish compound 8 a dual inhibitor of thymidylate synthase (TS) and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFTase) targeting both de novo thymidylate and purine nucleotide biosynthesis, which is further verified by the molecular modeling studies. Analogous to PMX, target compound 8 alternates the cell cycle of SW620 cells with S-phase accumulation and induces apoptosis, leading to cell death.

Synthesis and antitumor activity of a novel series of 6-substituted pyrrolo[2,3-d]pyrimidines as potential nonclassical antifolates targeting both thymidylate and purine nucleotide biosynthesis

A novel series of 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines were designed and synthesized as potential nonclassical antifolates targeting both thymidylate and purine nucleotide biosynthesis. Condensation of 2,4-diamino-6-hydroxypyrimidine with ethyl-4-chloroacetoacetate and subsequent hydrolysis afforded the key intermediate, 2-amino-4-oxo-pyrrolo[2,3-d]pyrimidin-6-yl-acetic acid. Coupling with various amino acid methyl esters followed by saponification and condensation with 3-(aminomethyl)pyridine provided target compounds 1–9. The new compounds exhibited micromolar to submicromolar antiproliferative potencies against a panel of tumor cell lines including KB, A549 and HepG2. Growth inhibition of compound 2 toward KB cells resulted in cytotoxicity and G1/G2-phase accumulation, and was partially protected by excess thymidine and adenosine, but was completely reversed in the combination of thymidine and adenosine, indicating both thymidylate and de novo purine nucleotide synthesis as the targeted pathway. However, 5-aminoimidazole-4-carboxamide (AICA) protection was incomplete, suggesting inhibition of both glycinamide ribonucleotide formyltransferase (GARFTase) and AICA ribonucleotide formyltransferase (AICARFTase). The results of the docking studies show that 2 could bind and inhibit both thymidylate synthase (TS) and the two folate-dependent purine biosynthetic enzymes (GARFTase and AICARFTase), which is consistent with the results of in vitro metabolic assays. Our studies establish that compound 2 is an excellent lead analog as a multitargeted antifolate for further structure optimization.

OUR EXPERIENCE WITH PEMETREXED/ CISPLATIN AS FIRST LINE CHEMOTHERAPY IN PATIENTS WITH ADVANCED NON- SQUAMOUS NON- SMALL CELL LUNG CANCER

SUMMARY: Objective: Lung cancer Pemetrexed is novel multitargeted antifolate which inhibits three key enzymes in the folate metabolic pathwaw. Methods: From May 2010 to March 2012 twenty two consecutive patients with morphologically proven advanced non- squamous non- small cell lung cancer entered the study. Treatment schedule consist of Pemetrexed 500 mg/m 2 on day 1 and Cisplatin 80 mg/m 2 with hyperhydratation administered as intravenous infusion with repetition every three weeks. Vitamins supplementation, antiemetics and Dexamethasone were administered too. Results: Overall response rate was 27,3 %, with one complete and five partial remissions obtained. The median time to progression and median overall survival time were 5,5 months and 9,6 months respectively. The main toxicity- grade 3 and 4, included neutropenia and diarrhea. Conclusions: That data suggest that chemotherapy with Pemetrexed / Cisplatin is reasonable choices for first- line chemotherapy in patients with inoperable non- squamous non- small cell lung cancer.

Thymidylate Synthase Expression Determines Pemetrexed Targets and Resistance Development in Tumour Cells

Although treatment options for cancer patients are increasing every year, the drug resistance problem remains very present. It is very difficult to find a drug that acts equally on tumours of the same histology as the individual's genetic characteristics often determine the response to treatment. Furthermore, tumours that initially respond to anti-tumour therapy are able to adapt and develop resistance to the drug, while others do not. In addition, this usually implies resistance development to agents to which the cells have not been exposed, a phenomenon called cross-resistance or multidrug resistance. Given this situation, it has been suggested that the most appropriate treatment would be able to act in parallel on multiple pathways constitutively altered in tumour cells. Pemetrexed is a multitargeted antifolate that exerts its activity against folate-dependent enzymes involved in de novo pyrimidine and purine synthesis. It is currently in use in combination with cisplatin against malignant pleural mesothelioma and non-squamous non-small cell lung cancer with favourable results. By real-time RT-PCR gene expression assays and restoration viability assays we demonstrated that Pemetrexed targets folate-dependent enzymes involved in de novo biosynthesis of purines differently depending on the intrinsic genetic characteristics of the tumour. These differences did not, however, interfere either with the initial response to the drug or with the activation of apoptotic pathways. In addition, these genetic fingerprints can differentiate two groups of tumours: those capable of developing resistance to antifolate, and not capable. These results may be useful to employ targets gene expression as resistance markers, a valuable tool for identifying patients likely to receive combination therapy to prevent the development of resistance.

Safety and efficacy of pemetrexed in gynecologic cancers: A systematic literature review

Gynecologic cancers represent a significant problem worldwide. Advanced, recurrent gynecologic cancers are often refractory to chemo-therapy, so new treatment regimens are needed. Pemetrexed is a third-generation, multi-targeted antifolate that has been approved for use in non-squamous non-small cell lung cancer and malignant pleural mesothelioma in both the United States and European Union. This paper reviews the safety and efficacy of pemetrexed in gynecologic cancers, which were defined as maligancies of the ovaries (including fallopian tubes and primary peritoneum), uterine endometrium, and uterine cervix. A search of English-language literature via PubMed and American Society of Clinical Oncology proceedings was performed from database inception to June 2012. Thirteen clinical trials involving the use of pemetrexed (alone and in combination with other agents) in gynecologic cancers were identified. These were phase I and phase II trials; there were 9 studies in ovarian cancer, 1 study in endometrial cancer, and 3 studies in cervical cancer. Pemetrexed with vitamin supplementation was tolerable in all clinical trials and had activity in ovarian and cervical cancers. Therefore, it may be reasonable to further explore the use of pemetrexed in ovarian and cervical malignancies.

Reduced Folate Carrier Independent Internalization of PEGylated Pemetrexed: A Potential Nanomedicinal Approach for Breast Cancer Therapy

Pemetrexed has been widely used as an effective chemotherapeutic agent for the treatment of a variety of cancers including breast cancer. It is a multitargeted antifolate that gets transported to cells primarily by reduced folate carrier (RFC) and exerts its action by disrupting folate-dependent metabolic processes essential for cell replication. The loss of RFC leads to impaired transport of pemetrexed, which in turn decreases its intracellular concentration and reduces its cytotoxic effect on cancer cells. Furthermore, the multidrug resistance (MDR) related proteins (MRPs) contribute to pemetrexed efflux from the cancer cells. These observations prompted us to develop PEGylated pemetrexed that follows an efficient cellular internalization route independent of RFC and simultaneously bypasses the MRP efflux mechanism for acting as an efficient chemotherapeutic agent. Thus, the present study focuses on PEGylation of pemetrexed for its superior therapeutic efficiency by evaluating its cellular uptake and retention by flow cytometry, confocal microscopy, and reversed-phase high-performance liquid chromatography (RP-HPLC) in breast cancer cell lines having RFC expression and lacking RFC expression, that is, MCF7 and MDA MB231, respectively. In addition, the treatment of PEGylated pemetrexed lead to enhanced cytotoxicity due to S-phase arrest and apoptosis in the above mentioned cell lines. Interestingly, the longer circulation time of PEGylated pemetrexed in animal model concomitant with the RFC independent uptake and enhanced cytotoxicity suggests it to be a potential candidate for cancer therapy in a clinical setting.

Phase 2 trial of pemetrexed in children and adolescents with refractory solid tumors: A Children's Oncology Group study

Pemetrexed is a multi-targeted antifolate that inhibits key enzymes involved in nucleotide biosynthesis. We performed a phase 2 trial of pemetrexed in children with refractory or recurrent solid tumors, including CNS tumors, to estimate the response rate and further define its toxicity profile. Pemetrexed, at a dose of 1910 mg/m(2) , was administered as a 10-minute intravenous infusion every 21 days. Patients also received vitamin B(12) , daily multivitamin supplementation, and dexamethasone. A two-stage design (10 + 10) was employed in each of the following disease strata: osteosarcoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, and non-brainstem high-grade glioma. Seventy-two eligible subjects (39 males) were enrolled. Median age was 11 years (range 3-23). Sixty-eight were evaluable for response. The median number of cycles administered was 2 (range 1-13). No complete or partial responses were observed. Stable disease, for a median of 5 (range 4-13) cycles, was observed in five patients (ependymoma, Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma; n = 1 each). Neutropenia (44%), anemia (35%), and elevated alanine transaminase (35%) attributable to pemetrexed were the most commonly recurring toxicities observed in patients receiving multiple cycles. Other toxicities attributed to pemetrexed occurring in ≥10% of cycles included thrombocytopenia (30%), fatigue (18%), nausea (14), hyperglycemia (13%), rash (11%), vomiting (13%), and hypophosphatemia (11%). Pemetrexed, administered as an intravenous infusion every 21 days, was tolerable in children and adolescents with refractory solid tumors, including CNS tumors, but did not show evidence of objective anti-tumor activity in the childhood tumors studied.

Pemetrexed in the treatment of relapsed/refractory primary central nervous system lymphoma

Despite initial treatment with high-dose methotrexate-based regimens, many patients with primary central nervous system lymphoma (PCNSL) relapse and die from their disease. No standard of care exists at progression or relapse, but chemotherapy and in some cases radiation are usually used. Pemetrexed is a multitargeted antifolate, similar to methotrexate, but with a broader spectrum of activity. Because methotrexate is an integral part of PCSNL treatment, the authors assessed the antitumor activity and safety of pemetrexed in recurrent PCNSL. Patients with relapsed/refractory PCNSL were enrolled in this trial. Treatment consisted of pemetrexed 900 mg/m(2) given every 3 weeks with low-dose dexamethasone, folate, and B12 supplementation. Each cycle was 6 weeks, and follow-up imaging was done before each new cycle. Treatment was continued until complete remission, progression, or toxicity. Eleven patients were treated, with a median age of 69.8 years and Karnofsky performance status of 70%; 10 of 11 patients had failed prior high-dose methotrexate. The median number of pemetrexed cycles given was 5, with an associated overall response rate of 55% and disease control rate of 91%. The 6-month progression-free survival (PFS) was 45%, median PFS was 5.7 months, and median overall survival was 10.1 months. Toxicities were primarily hematologic and infectious. Pemetrexed has single-agent activity in relapsed/refractory PCNSL. Toxicities were seen likely because of the higher than standard dose used. Further investigation of this agent or other multitargeted antifolates in PCNSL is warranted to determine optimal dose and efficacy in a more homogeneous population.

A short and efficient synthetic protocol for the synthesis of 5-substituted-4,6-dioxo-pyrrolo[2,3-d]pyrimidines

A short and efficient synthesis for 5-substituted-4,6-dioxo-pyrrolo[2,3-d]pyrimidines has been developed by the cyclocondensation of α,α-dibromoaldehydes with 2,4-diamino-6-hydroxypyrimidine under mild basic conditions in good yields. Application of this protocol has been demonstrated in the synthesis of a metabolite of Pemetrexed disodium, a novel multi-targeted antifolate.

Phase II Trial of Pemetrexed and Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer

We hypothesized that bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), will potentiate the activity of pemetrexed, a multitargeted antifolate, in squamous cell carcinoma of the head and neck (SCCHN). Patients with previously untreated, recurrent, or metastatic SCCHN were treated with pemetrexed 500 mg/m(2) and bevacizumab 15 mg/kg given intravenously every 21 days with folic acid and B(12) supplementation until disease progression. Primary end point was time-to-progression (TTP). DNA was isolated from whole blood samples for the detection of polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase (MTHFR), and VEGF. Forty patients were enrolled. The median TTP was 5 months, and the median overall survival (OS) was 11.3 months. In 37 evaluable patients, the overall response rate was 30%, including a complete response rate of 5%, and the disease control rate was 86%. Grade 3 to 5 bleeding events occurred in six patients (15%): four were grade 3, and two were fatal. Other serious toxicities in 10% or more of patients included neutropenia (10%) and infection (12.5%). One patient died of sepsis after receiving eight cycles of therapy. For the MTHFR A1298C (rs1801131) single nucleotide polymorphisms, homozygote patients with AA had worse OS (P = .034). The addition of bevacizumab to pemetrexed resulted in promising efficacy outcomes in SCCHN. Bleeding events were frequent but some may have been due to natural history of disease. Polymorphisms in MTHFR may offer potential for treatment individualization.

In vitro study on the schedule-dependency of the interaction between pemetrexed, gemcitabine and irradiation in non-small cell lung cancer and head and neck cancer cells

BackgroundBased on their different mechanisms of action, non-overlapping side effects and radiosensitising potential, combining the antimetabolites pemetrexed (multitargeted antifolate, MTA) and gemcitabine (2',2'-difluorodeoxycytidine, dFdC) with irradiation (RT) seems promising. This in vitro study, for the first time, presents the triple combination of MTA, dFdC and irradiation using various treatment schedules.MethodsThe cytotoxicity, radiosensitising potential and cell cycle effect of MTA were investigated in A549 (NSCLC) and CAL-27 (SCCHN) cells. Using simultaneous or sequential exposure schedules, the cytotoxicity and radiosensitising effect of 24 h MTA combined with 1 h or 24 h dFdC were analysed.ResultsIncluding a time interval between MTA exposure and irradiation seemed favourable to MTA immediately preceding or following radiotherapy. MTA induced a significant S phase accumulation that persisted for more than 8 h after drug removal. Among different MTA/dFdC combinations tested, the highest synergistic interaction was produced by 24 h MTA followed by 1 h dFdC. Combined with irradiation, this schedule showed a clear radiosensitising effect.ConclusionsResults from our in vitro model suggest that the sequence 24 h MTA → 1 h dFdC → RT is the most rational design and would, after confirmation in an in vivo setting, possibly provide the greatest benefit in the clinic.

Emerging role of thymidylate synthase for the pharmacogenomic selection of patients with thoracic cancer

The use of antifolate drugs, and particularly of pemetrexed, is emerging as a relevant therapeutic strategy for the treatment of some specific thoracic cancers. Pemetrexed is a novel multitargeted antifolate which has been shown in vitro to inhibit at least three different enzymes in the folate pathway: thymidylate synthase (TS), dihydrofolate reductase (DHFR) and glycinamide ribonucleotide formyl transferase (GARFT) of which TS is its main target [1]. These enzymes are involved in the synthesis of nucleotides and interference with their function will ultimately hinder the synthesis of RNA and DNA. Pre-clinical studies have demonstrated the cytotoxic activity of this agent in a broad range of tumor types including non-small cell lung cancer (NSCLC). In vitro studies indicated that tumor cell lines expressing high levels of TS or DHFR have reduced sensitivity to pemetrexed, suggesting that increased expression levels might correlate with reduced clinical efficacy [2]. In NSCLC, which accounts for more than 80% of all lung cancer, two recent independent Phase III trials showed that pemetrexed alone or in combination with cisplatin demonstrated a statistically superior activity in patients with non-squamous histotypes [3, 4]. Although histology has not consistently been associated with clinical outcomes in almost every trial testing the role of platinum-based chemotherapy in advanced NSCLC, it has now emerged as a potential predictive factor due to the evidence of the differential expression of TS between the different tumor histotypes, which seems to play an important role [3]. Preliminary molecular evidence, in fact, has previously shown that TS expression is significantly higher in squamous cell carcinoma compared with adenocarcinoma by means of both Real-Time PCR gene quantification and of immunohistochemistry for the detection of the protein levels [5]. In undifferentiated large cell carcinoma, a subsequent analysis consistently reported significantly higher TS levels in desmocollin 3 (DSC-3)-positive as compared to DSC-3negative tumors (indicating a squamous and adenocarcinoma origin of the tumors, respectively), reporting that lack of DSC-3 immunoreactivity in this histologic subtype is associated with lower TS expression [8]. In the same experimental setting, TS expression levels were tested in 22 cases having a cytological diagnosis of NSCLC with no clear histological definition, and in the corresponding histological samples obtained at the time of subsequent surgical resection. As a result, a significantly high degree of concordance in terms of TS protein expression in matched specimens was detected. This result raises the possibility of using the protein levels, evaluated by immunohistostaining on cytological specimens, to select the patients with unresectable advanced disease to be treated with TS-inhibiting agents. On the other hand, the small cell carcinoma (SCLC) group of patients, comprising approximately 13% of all lung cancers, has shown minimal response to pemetrexed in several studies including a large Phase III study [6]. Again, the explanation for these results may be found at the molecular level, in that SCLC has been shown to have very high TS expression when compared with either well-differentiated pulmonary neuroendocrine tumors or NSCLC [7]. These data once again support the hypothesis that elevated TS expression decreases the response to pemetrexed, and that the determination of TS levels can be used in to exclude those patients who are most likely to be unaffected from the treatment. A clear example of this is found in a very recent retrospective study from our group carried out on malignant pleural mesothelioma (MPM), a disease in which pemetrexed has been previously shown to be clinically active. We showed that TS protein and gene expression levels are significantly correlated with the clinical outcome in a consecutive series of 60 patients with advanced MPM treated with pemetrexed, with or without plat

Phase II randomized trial of radiotherapy (RT), cetuximab (E), and pemetrexed (Pem) with or without bevacizumab (B) in locally advanced squamous cell carcinoma of the head and neck (SCCHN).

TPS264 Background: RT and E, an anti-EGFR monoclonal antibody, has emerged as a standard nonsurgical therapy for stage III/IV SCCHN. Pem, a multitargeted antifolate that inhibits several enzymes of the folate pathway (thymidylate synthetase, dihydrofolate reductase, and other) has attributed promising results in SCCHN. We previously established the recommend doses of Pem in combination with RT plus E in SCCHN (ASCO 2008; A2540). The combination of Pem plus B has produced promising results in a phase II trial in recurrent or metastatic SCCHN (ASCO 2008; A6069). Upregulation of VEGF has been associated with E resistance, thus, adding B to the RT plus PemE regimen may enhance antitumor activity. Methods: Eligible patients have previously untreated stage III/IV SCCHN of the oropharynx, larynx or hypopharynx, ECOG performance status (PS) 0-1, no history of bleeding and not receiving therapeutic anticoagulation, and adequate laboratory parameters. Patients are randomized after stratification by stage, site, and PS to receive either: A) RT 2Gy/day to 70 Gy, E 250 mg/m2 weekly, after a loading dose of 400 mg/m2 1 week prior starting RT, and Pem 500 mg/m2 every 21 days × 3 cycles (PemE), or B) the same regimen plus B 15 mg/kg every 21 days × 3 cycles during RT (B-PemE) followed by B maintenance × 8 cycles (24 weeks). All patients receive folic acid and B12, and antibiotic prophylaxis with cycles 2 and 3. Placement of prophylactic gastrostomy tube is strongly recommended. The primary endpoint is the progression-free survival (PFS) at 2 years. We target a 2-year PFS of 64% assuming 46% as historical control. 40 patients will be accrued per arm. Secondary objectives include local PFS, distant PFS, overall survival, toxicities, and quality-of-life. 14 pts have been enrolled in this ongoing trial (6 in arm A; 8 in arm B). No significant financial relationships to disclose.

Antitumor activity of pemetrexed (Pem) in second-line advanced/metastatic osteosarcomas: A multicenter phase II study.

10076 Background: Osteosarcoma (OS) is the most common primary malignant bone tumor in young adults. Despite improved prognosis, resistance to chemotherapy remains responsible for failure of OS treatment. The search for new agents in OS is mandatory. Pem is a multitargeted antifolate, with a mode of action similar to methotrexate, coupled with a broader range of action, which provided the rational for this study. Methods: This open-label, single-arm study enrolled patients (pts) with high-grade locally advanced/metastatic osteosarcoma, not amenable to surgery. Eligible pts had one prior chemotherapy regimen for advanced disease, and ECOG performance status 0 to 2. Pem 500 mg/m2 was given over 10 min on day 1 of a 21 day cycle with folic acid and vitamin B12 supplementation until progression. RECIST was used to evaluate response every two cycles. Primary endpoint was response rate (RR). At least five tumor responses over 32 were required to consider further investigations. Secondary endpoints were duration of response, progression-free survival (PFS), overall survival (OS) and safety profile. Results: Between September 07 and March 09 a total of 32 pts were entered, and received at least one cycle of Pem. Their mean age was 42.1 years, baseline ECOG performance status ≤1 in 93.8%, and 2 for one patient (3.1%). 90.6% of pts had metastatic sites in the lung. Median number of administered cycles was 2 [range 1 - 14]. Over 32 pts, one partial response was observed (RR: 3.1% (95% CI [0.1, 16.2])), 15.6% had stable disease. Most common possibly related grade 3/4 treatment-emergent adverse events were (N=32 pts): 9.4% asthenia, 9.4% elevated ALT, 9.4% leukopenia, 6.3% febrile neutropenia, 6.3% neutropenia, and 6.3% anemia. One patient died due to multiorgan failure possibly related to study drug. Conclusions: The response rate of Pem as a second-line treatment in advanced or metastatic osteosarcoma did not meet expectations required by the protocol. Patients are continuing in the follow-up period. PFS and OS will be analyzed at the end of the study. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Novartis, PharmaMar Novartis Lilly

The Role of Pemetrexed Combined with Gemcitabine for Non-Small-Cell Lung Cancer

Pemetrexed is a multitargeted antifolate that inhibits at least three folate dependent enzymes involved in DNA synthesis. Gemcitabine is a broadly active pyrimidine nucleoside antimetabolite that is incorporated into DNA and causes chain termination. Both pemetrexed and gemcitabine, as single agents, have shown antitumor activity in a wide range of solid tumors, including non-small-cell lung cancer (NSCLC). Based on preclinical in vitro and in vivo synergism of the combination of pemetrexed and gemcitabine, the 2 drugs were studied in several phase I and II trials in patients with advanced NSCLC. The published studies found response rates between 13 to 31%, with overall survival times similar to established standard chemotherapy regimens. The grade 3 or 4 toxicities with this combination are mainly haematologic, dermatologic and transaminitis. In this paper, we review the pemetrexed-gemcitabine combination in the treatment of NSCLC patients with regards to the rationale, clinical activity as well as the future directions for this new 2-drug combination.

Pemetrexed for the treatment of non-small-cell lung cancer

Pemetrexed is a novel multi-targeted antifolate that is used in the treatment of both malignant pleural mesothelioma and non-small-cell lung cancer (NSCLC). Lung cancer is the most common cancer in the world and NSCLC represents approximately 80% of all lung cancers. Pemetrexed is the first NSCLC drug for which ‘treatment-by-histology’ has been determined. This refers to the greater efficacy of pemetrexed in patients with advanced NSCLC other than of predominantly squamous-cell histology. The advent of treatment-by-histology represents a significant step forward in the treatment of lung cancer, allowing physicians to tailor therapies to the individual patient. Ongoing trials aim to establish the place of pemetrexed in maintenance, in combination with other ‘targeted agents’, in adjuvant therapy in early NSCLC and in concurrent radio/chemotherapy.

9122 Phase I study with pemetrexed, cisplatin and concurrent radiotherapy in limited-stage small cell lung cancer (LS-SCLC)

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.