Phase II study of 10-ethyl-10-deaza-aminopterin (10-EdAM; CGP 30 694) for stage IIIB or IV non-small cell lung cancer

Lee, Jin S.; Libshitz, Herman I.; Murphy, William K.; Jeffries, Diane; Hong, Waun Ki

doi:10.1007/bf00171841

Cited by 32 publications

(2 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A randomized trial comparing vinorelbine with 5-FU and leucovorin concluded that 5-FU had negligible activity against NSCLC (3%) in patients with stage IV disease (Crawford et al, 1996). Three phase II trials of edatrexate showed response rates of 32% (Shum et al, 1988), 13% (Souhami et al, 1992) and 10% (Lee et al, 1990). A subsequent phase III trial in 673 patients, which compared edatrexate, mitomycin and vinblastine (EMV) with mitomycin and vinblastine (MV), failed to show improved survival in patients treated with EMV, although the response rate in the EMV arm was higher (24% compared with 16%) (Comis et al, 1994).…”

Section: The Future For Mtamentioning

confidence: 99%

Clinical studies with MTA

Calvert

Walling²

1998

Br J Cancer

View full text Add to dashboard Cite

Summary MTA (LY231514), a multi-targeted antifolate, is a classical antifolate undergoing intracellular polyglutamation. Polyglutamated MTA is a potent thymidylate synthase (TS) inhibitor and inhibits other folate-dependent enzymes, including dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. Multifocal antifolates may overcome antifolate resistance, but it is not known whether the antitumour activity of MTA depends on its TS inhibition, its primary locus of action, or whether other loci contribute. MTA was examined in three phase trials using different schedules: a 1 0-min i.v. infusion given once every 3 weeks, once weekly for 4 weeks every 6 weeks or daily for 5 days every 3 weeks. Dose-limiting toxicities were neutropenia and thrombocytopenia. Other consistently seen side-effects, which were manageable, included mucositis, skin rashes and transient elevations of transaminases. Toxicity was highly schedule dependent: the recommended dose for the 3-weekly schedule (600 mg m-2) was 30 times that for the daily x 5 schedule (4 mg m-2 day-'). The 3-weekly dosing schedule was chosen for phase 11 evaluation. Phase II trials are underway to investigate the activity and toxicity of MTA in several tumour types, including colorectal, pancreas, breast, bladder and non-small-cell lung cancer (NSCLC) Further phase trials will investigate MTA in combination with other agents, including gemcitabine, cisplatin, 5-fluorouracil and folate. Preliminary phase 11 trials results are encouraging; responses were seen in colorectal, pancreas, NSCLC and breast cancer.

show abstract

Section: The Future For Mtamentioning

confidence: 99%

Clinical studies with MTA

Calvert

Walling²

1998

Br J Cancer

View full text Add to dashboard Cite

show abstract

“…In phase II testing, EdAM produced encouraging objective responses in breast cancer (17%-41%) [62][63][64][65], non-small cell lung cancer (7%-32%) [66][67][68][69], malignant mesothelioma (18%) [70], head and neck cancer (6%-38%) [71][72][73][74], and soft-tissue sarcomas (6%-14%) [75,76] (Table 3). Its activity was particularly promising in malignant fibrous histiocytomas, inducing partial responses in five of seven patients treated (71%) [76].…”

Section: Edatrexatementioning

confidence: 99%

New Antifolates: Pharmacology and Clinical Applications

Takimoto

1996

The Oncologist

View full text Add to dashboard Cite

Many new antifolate compounds with unique clinical properties are currently in clinical development. Some of these agents have been rationally designed to circumvent known mechanisms of resistance to methotrexate, the most useful and extensively studied antifolate in clinical practice. Resistance to methotrexate can result from decreased active transport into cells, decreased polyglutamation resulting in enhanced drug efflux from cells, mutations in dihydrofolate reductase which reduce drug binding affinity, and increased expression of dihydrofolate reductase due to gene amplification or increased translational efficiency. As a consequence, the newer antifolates may differ from methotrexate because of increased lipid solubility, improved cellular uptake or increased ability to undergo polyglutamation. Several of these newer agents also uniquely target specific folate-dependent enzymes such as thymidylate synthase or glycinamide ribonucleotide transformylase. Antifolates currently in clinical development include trimetrexate, edatrexate, piritrexim, ZD1694, lometrexol, AG337, LY231514 and 1843U89. This report summarizes the basic pharmacology and potential clinical applications of these promising new agents.

show abstract

Edatrexate improves the antitumor effects of cyclophosphamide and cisplatin against non-small cell lung cancer

Lee

Libshitz

Fossella

et al. 1991

Cancer

View full text Add to dashboard Cite

The authors treated 32 patients with Stage IIIB or IV non‐small cell lung cancer (NSCLC) with an outpatient regimen of edatrexate (10‐ethyl‐10‐deaza‐aminopterin) (10‐EdAM) on days 1 and 8, cyclophosphamide on day 1, and cisplatin on day 1, repeated every 3 weeks with dose modification. The 22 men and 10 women (median age, 57 years of age) had no prior chemotherapy and a Zubrod performance status less than or equal to 2. A schedule with initial doses of 80 mg/m2, 800 mg/m2, and 80 mg/m2, respectively, yielded a 47% major response rate with two complete responses (95% confidence interval [CI], 25% to 70%), but it also yielded significant stomatitis and myelosuppression. A schedule with reduced starting doses (70 mg/ m2, 700 mg/m2, and 70 mg/m2) was better tolerated, but dropped the major response rate to 27% with no complete responses (95% CI, 11% to 52%). Median survival time was 39 weeks for all 30 evaluable patients without a significant difference between the treatment groups (which were comparable in patient characteristics). Major response, however, was associated with longer survival time than minor response or no change (P = 0.024) or progressive disease (P = 0.001) (median survival times, 55, 39, and 27 weeks, respectively). When the doses delivered were compared, patients treated with the reduced dose schedule received less mean 10‐EdAM per course (P = 0.01), although the doses of cyclophosphamide and cisplatin were comparable to the original dose schedule for the second course and thereafter. These results suggest that this three‐drug regimen may have synergistic antitumor effects, with a steep dose‐response relationship, particularly with 10‐EdAM. With amelioration of the dose‐limiting stomatitis of 10‐EdAM, it seems possible to maximize the antitumor effects of this regimen.

show abstract

Phase II study of 10-ethyl-10-deaza-aminopterin (10-EdAM; CGP 30 694) for stage IIIB or IV non-small cell lung cancer

Cited by 32 publications

References 13 publications

Clinical studies with MTA

Clinical studies with MTA

New Antifolates: Pharmacology and Clinical Applications

Edatrexate improves the antitumor effects of cyclophosphamide and cisplatin against non-small cell lung cancer

Contact Info

Product

Resources

About