AmpliMed Corporation

Tucson, AZ, United States

AmpliMed Corporation

Tucson, AZ, United States
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Weber J.S.,H. Lee Moffitt Cancer Center and Research Institute | Samlowski W.E.,Nevada Cancer Institute | Gonzalez R.,University of Colorado at Denver | Ribas A.,University of California at Los Angeles | And 8 more authors.
Cancer | Year: 2010

BACKGROUND: Imexon (Amplimexon) is an aziridine compound that increases reactive oxygen species, disrupts mitochondrial membranes, and induces apoptosis. Preclinical studies showed activity against melanoma cell lines and models in mice, and synergy with dacarbazine. The authors evaluated standard doses of dacarbazine combined with increasing doses of imexon to determine the maximal tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy. METHODS: Sixty-eight chemotherapy-naive melanoma patients (1 inoperable stage III and 67 stage IV) were treated with dacarbazine (250 mg/m2) and imexon (570-1300 mg/m2), both daily for 5 days every 3 weeks. RESULTS: There were 18 patients in the phase 1, and 50 in the phase 2 component of the study. The MTD of imexon with dacarbazine was 1000 mg/m2. Dose-limiting toxicities were pulmonary edema and hepatorenal failure. At the MTD, therapy was well tolerated. The most common toxicities (any grade) were vomiting, diarrhea, anemia, thrombocytopenia, anorexia, fever, and constipation. Among 68 patients, there were 7 treatment-related serious adverse events. Partial response and stable disease rates were 5.9% and 25% for all subjects and 2% and 30% for the phase 2 patients, respectively. Median progression-free and overall survival of all patients were 2.0 and 11.7 months and 2 and 7.5 months for the phase 2 patients, respectively. Overall survival of the 31 patients with normal lactate dehydrogenase levels was >22.5 months. Pharmacokinetics of both drugs were similar to previous reports. CONCLUSIONS: Imexon plus dacarbazine was well tolerated. The survival data suggest further evaluation in a randomized phase 2 study. © 2010 American Cancer Society.

Remers W.A.,AmpliMed Corporation | Iyengar B.S.,AmpliMed Corporation | Dorr R.T.,AmpliMed Corporation | Dorr R.T.,Arizona Cancer Center | And 2 more authors.
Journal of Heterocyclic Chemistry | Year: 2015

Three types of compounds were synthesized from carbendazim (1), a benzimidazole derivative (Scheme 1). They included a group of esters at N1 prepared by treating carbendazim with isocyanates bearing ester groups (2a-2c), carboxyalkyl-1,2,3,4-tetrahydro-s-triazino[1,2-a]benzimidazole-2,4-dione esters (3a and 3d) formed by cyclization of two of these esters, and related hydrophilic amides 3b and 3c derived from 3a. The antitumor potencies of the N1 esters were in the range of 7 to 40 mM, which compares favorably with carbendazim, but their water solubilities were low. The s-triazine derivatives showed activity against pancreatic tumor cells, and one of them (3b) was active in mice, but they were not effective against other tumor types. Treatment of carbendazim with 3-bromopropionyl chloride produced 1-methoxycarbonyl- 4-oxo-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (4), which gave 1-(3-aminopropionyl)benzimidazole 2-methylcarbamates, substituted on the amino nitrogen (5a, 5b, and 5d), when treated with amines. These products showed some antitumor activity in cell cultures, and an ethoxy derivative (5c), obtained by treating 1-methoxycarbonyl-4-oxo-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole with sodium ethoxide, was active in the 67-150 mM range. Some of the new compounds had good water solubility. Carbendazim kills tumor cells by inhibiting tubulin; however, s-triazine 3b, which differs from it in size and functional groups, does not act by this mechanism. © 2014 HeteroCorporation.

Moulder S.,University of Texas M. D. Anderson Cancer Center | Dhillon N.,University of Texas M. D. Anderson Cancer Center | Ng C.,University of Texas M. D. Anderson Cancer Center | Hong D.,University of Texas M. D. Anderson Cancer Center | And 8 more authors.
Investigational New Drugs | Year: 2010

Summary: Purpose Imexon is an iminopyrrolidone that induces apoptosis and has synergistic activity with docetaxel in preclinical models. This trial was designed to establish the maximum tolerated dose (MTD) of imexon given with docetaxel in breast, prostate and non-small cell lung cancer (NSCLC). Patients and Methods 34 patients received protocol therapy. 26 patients received escalating doses of imexon given intravenously over 60 min on days 1-5 every 21 days. Docetaxel was administered intravenously at a fixed dose of 75 mg/m 2 immediately following imexon on day 1 every 21 days. A 3+3 design was used with eight additional patients treated at MTD. Response was measured using RECIST. Results Seven dose levels of imexon were evaluated (390 mg/m 2 to 1,700 mg/m2). The MTD was imexon 1,300 mg/m 2 IV on days 1-5 in combination with docetaxel. Dose limiting toxicities were grade 3 non-cardiac chest pain and grade 3 diarrhea. Activity was seen in 4 patients [2 partial responses (NSCLC (PR=1), prostate cancer (PR=1)), 2 minor responses (MR=breast, NSCLC)]. Eleven patients had stable disease by RECIST (including the patients with MR; prostate cancer=6, NSCLC=3). Six (one with breast cancer, two with prostate cancer and three with NSCLC) demonstrated stable disease (SD) for ≥ 3 months. Conclusion The MTD of combination therapy is imexon 1,300 mg/m2 IV on days 1-5 with docetaxel 75 mg/m2 IV on day 1 of a 21 day treatment cycle. Demonstrated responses warrant further investigation in phase II trials of which a phase II trial in NSCLC is planned. © 2009 Springer Science+Business Media, LLC.

Remers W.A.,AmpliMed Corporation | Remers W.A.,Arizona Cancer Center | Remers W.A.,AmplMed Corporation | Dorr R.T.,AmpliMed Corporation | And 2 more authors.
Current Medicinal Chemistry | Year: 2012

Following the demonstration that addition of a 2-cyano group to aziridines prevented DNA alkylation and thus reduced toxicity, many novel 2-cyanoaziridines were synthesized and evaluated as immunomodulating and antitumor agents. They typically reacted with thiols such as cysteine, depleting them and allowing the accumulation of reactive oxygen species. Two of these compounds, azimexon and ciamexon, showed activity against tumors in clinical trials. Imexon was produced by cyclization of 2-cyanoaziridine-1-carboxamide in the presence of hydroxide ions. The two enantiomers were prepared by a process involving chiral chromatography. They were equipotent against cultured tumor cells. Imexon also reacts with thiols and it is especially potent against multiple myeloma in cell cultures. An efficient chemical synthesis and a lyophilization formulation of imexon as a water soluble, injectible drug, were developed. In Phase I and I/II clinical trials imexon showed hints of activity against a variety of tumors, but a randomized double-blind Phase II trial of imexon plus gemcitabine versus gemcitabine alone in pancreatic cancer showed no enhancement of activity above that of gemcitabine alone. This result was disappointing because in cell culture and mice the two compounds were synergistic. Based on a complete response in a Phase I trial, a new Phase II clinical trial of imexon is underway in non-Hodgkins lymphoma. © 2012 Bentham Science Publishers.

Cohen S.J.,Chase Medical | Zalupski M.M.,University of Michigan | Modiano M.R.,Arizona Clinical Research Center | Conkling P.,Us Oncology Phase I Group | And 7 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2010

Purpose: Imexon is an aziridine-derived iminopyrrolidone which has synergy with gemcitabine in pancreatic cancer cell lines. Gemcitabine is a standard therapy for pancreatic cancer. We performed a phase I trial of imexon and gemcitabine to evaluate safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) in patients with advanced pancreatic cancer. Methods: Patients with untreated locally advanced or metastatic pancreatic adenocarcinoma received therapy in sequential cohorts on regimen A (n = 19; imexon 200 or 280 mg/m2 intravenously (IV) over 30 min days 1-5, 15- 19 and gemcitabine 800 or 1,000 mg/m2 IV over 30 min on days 1,8,15 every 28 days) or regimen B (n = 86; imexon 280-1,300 mg/m2 IV over 30-60 min days 1, 8, and 15 and gemcitabine 1,000 mg/m2 IV over 30 min on days 1, 8, and 15 every 28 days). Results: One hundred five patients received 340 treatment cycles (median 2, range 1-16). Patient characteristics: median age 63, 61% male, ECOG PS 0/1 50%/50%, 93% metastatic. DLT was abdominal cramping and pain, often with transient, acute diarrhea. Best response was confirmed partial response (PR) in 11.4%, 8.9% unconfirmed PR, and 48.1% with stable disease. There was a dose proportional increase in imexon AUC across the doses tested with terminal half life 69 min at the MTD and no alteration of gemcitabine pharmacokinetics. Conclusions: The recommended phase II dose of imexon is 875 mg/m2 with gemcitabine 1,000 mg/m2. DLT was acute abdominal pain and cramping. Encouraging antitumor responses support further evaluation of this combination in advanced pancreatic cancer.

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