Phase II evaluation of echinomycin (NSC-526417) in patients with central nervous system malignancies

Abstract

The objective of this trial was to determine the efficacy of echinomycin (1.2 mg/m2) administered on a weekly times four schedule in the treatment of patients with recurrent or progressive central nervous malignancies despite adequate radiotherapy. Thirty-five patients were registered on study. The majority of patients (20) had glioblastoma multiforme. Ten had anaplastic astrocytoma. Eight patients had received prior nitrosoureas. SWOG performance status was 1 in 11 patients and 2 in 22. The median age was 51 years (25-75 years). One patient had a partial remission (3%:95% confidence interval: 1%-16%). Twenty two patients had progressive disease. The median survival was 5.9 months. Toxicity was primarily gastrointestinal with nausea and vomiting in 13 patients and nausea only in 11 patients. Hepatotoxicity occurred in 10 patients. Echinomycin given at this dose and schedule is not effective in treating patients with recurrent or progressive glioblastoma multiforme or anaplastic astrocytomas.

Echinomycin protects mice against relapsed acute myeloid leukemia without adverse effect on hematopoietic stem cells

“…The drug development was halted as it showed minimal therapeutic effect for terminal patients with solid tumors, although it has not been tested in patients with hematologic malignancies. [38][39][40][41][42][43][44][45] In fact, dose escalation studies indicated that grade I toxicity was observed starting after doses of 180 mg/m 2 , with no toxicity found at doses of 60 and 120 mg/m 2 . 46 By showing that a low dose of echinomycin (30 mg/m 2 ) eliminates AML LICs without a significant effect on the HSCs, our data, along with our recent data on primary AML samples, 17 provide a foundation for further clinical development of the drug for treatment of both primary and relapsed AML.…”

Liposomal formulation of HIF-1α inhibitor echinomycin eliminates established metastases of triple-negative breast cancer

“…Echinomycin is a potent small-molecule inhibitor of HIF-1α, which functions through sequence-specific binding to HRE to competitively inhibit HIF-1α binding to its target genes 9 . Before HIF-1α was identified as molecular target of echinomycin, the drug was tested in multiple phase I and II trials for treatment of solid tumors [10][11][12][13][14][15][16][17][18][19][20][21] . However, clinical development was discontinued because echinomycin was not found to be effective for patients with solid tumors that were refractory to all available treatments.…”

“…In earlier clinical trials, echinomycin was formulated with Cremophor EL® (CrEL). CrEL has been under scrutiny for its allergenic activity and, in clinical trials with CrEL-echinomycin, hypersensitivity reactions were observed 12,18,19,[21][22][23] CrEL-echinomycin also caused severe nausea and vomiting, constituting its dose-limiting toxicity 11,12,[15][16][17][18][19][20][21] .…”

DNA as a target for antimicrobials

“…3) has been tested in a number of phase I and II clinical trials against different types of cancer, but the majority of those did not show a significant [10][11][12]. One of the exceptions was a study on colorectal cancer, where a moderate activity was observed [13].…”