Phase I trial of edatrexate in advanced breast and other cancers

Philip Kuriakose, David R Gandara, Edith A. Perez

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Edatrexate (EDX) (10-ethyl-10-deazaaminopterin or 10-EDAM) is an analogue of methotrexate with improved pre-clinical antitumor activity, more selective cellular uptake, and with more extensive formation of intracellular polyglutamate metabolites. A phase I trial in advanced cancer using EDX was initiated to determine the toxicities associated with the use of a biweekly schedule of intravenous EDX, and to carry out a dose escalation to define the maximum tolerated dose employing this schedule. Thirty-four patients were enrolled in this phase I trial. Thirty-three patients were treated in cohorts of at least three patients (except at one dose level 210 mg m-2, where there were only two patients). Dose escalations of EDX were administered 2 starting with 100 mg m-2, and progressing through 120, 140, 160, 180, 210, 240, and 270 mg m-2. Edatrexate was administered by intravenous infusion over 20 min, and cryotherapy using ice chips was given prophylactically for 5 min before, during, and 15 min after each EDX treatment. The dose-limiting toxicity could not be reached in this study because it had to be closed on account of competing protocols using EDX in combination regimens. Of note though, was that the delivered dose intensity at the 160 mg m-2 week-1, was higher than the previously used or recommended phase II doses. Anemia was mild and white blood corpuscle toxicity was mostly of grade 1 or 2. One patient had grade 4 neutropenia and one had grade 3 thrombocytopenia. Of the non-hematological toxicities, nausea, vomiting, and diarrhea were mild and tolerable. Mucositis, which was the dose-limiting toxicity in previous studies, was seen in 30% of the patients, but was predominantly a grade 1 toxicity. This could have been due to either the different schedule of EDX used in this study or the use of cryotherapy. Substantial antitumor effects were noted, with two near-complete complete responses at the 120 and 160 mg m-2 levels. Additionally, six partial responses and one minor response were observed, and stable disease was observed in seven patients. Despite achieving antitumor activity at different dose levels, a clear-cut dose response was not evident at the levels tested. We feel that the biweekly EDX schedule is a tolerable regimen, which allows a higher dose intensity than weekly administration, and that EDX is an active agent for the treatment of patients with metastatic cancer.

Original languageEnglish (US)
Pages (from-to)473-479
Number of pages7
JournalCancer Investigation
Volume20
Issue number4
DOIs
StatePublished - 2002

Fingerprint

Breast Neoplasms
Appointments and Schedules
Cryotherapy
edatrexate
Polyglutamic Acid
Mucositis
Maximum Tolerated Dose
Ice
Proxy
Neutropenia
Intravenous Infusions
Methotrexate
Nausea
Vomiting
Anemia
Diarrhea
Neoplasms
Leukocytes
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Phase I trial of edatrexate in advanced breast and other cancers. / Kuriakose, Philip; Gandara, David R; Perez, Edith A.

In: Cancer Investigation, Vol. 20, No. 4, 2002, p. 473-479.

Research output: Contribution to journalArticle

Kuriakose, Philip ; Gandara, David R ; Perez, Edith A. / Phase I trial of edatrexate in advanced breast and other cancers. In: Cancer Investigation. 2002 ; Vol. 20, No. 4. pp. 473-479.
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abstract = "Edatrexate (EDX) (10-ethyl-10-deazaaminopterin or 10-EDAM) is an analogue of methotrexate with improved pre-clinical antitumor activity, more selective cellular uptake, and with more extensive formation of intracellular polyglutamate metabolites. A phase I trial in advanced cancer using EDX was initiated to determine the toxicities associated with the use of a biweekly schedule of intravenous EDX, and to carry out a dose escalation to define the maximum tolerated dose employing this schedule. Thirty-four patients were enrolled in this phase I trial. Thirty-three patients were treated in cohorts of at least three patients (except at one dose level 210 mg m-2, where there were only two patients). Dose escalations of EDX were administered 2 starting with 100 mg m-2, and progressing through 120, 140, 160, 180, 210, 240, and 270 mg m-2. Edatrexate was administered by intravenous infusion over 20 min, and cryotherapy using ice chips was given prophylactically for 5 min before, during, and 15 min after each EDX treatment. The dose-limiting toxicity could not be reached in this study because it had to be closed on account of competing protocols using EDX in combination regimens. Of note though, was that the delivered dose intensity at the 160 mg m-2 week-1, was higher than the previously used or recommended phase II doses. Anemia was mild and white blood corpuscle toxicity was mostly of grade 1 or 2. One patient had grade 4 neutropenia and one had grade 3 thrombocytopenia. Of the non-hematological toxicities, nausea, vomiting, and diarrhea were mild and tolerable. Mucositis, which was the dose-limiting toxicity in previous studies, was seen in 30{\%} of the patients, but was predominantly a grade 1 toxicity. This could have been due to either the different schedule of EDX used in this study or the use of cryotherapy. Substantial antitumor effects were noted, with two near-complete complete responses at the 120 and 160 mg m-2 levels. Additionally, six partial responses and one minor response were observed, and stable disease was observed in seven patients. Despite achieving antitumor activity at different dose levels, a clear-cut dose response was not evident at the levels tested. We feel that the biweekly EDX schedule is a tolerable regimen, which allows a higher dose intensity than weekly administration, and that EDX is an active agent for the treatment of patients with metastatic cancer.",
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