ABSTRACT: Patients with metastatic colorectal cancer who progress on standard chemotherapy have limited treatment options. New and effective drugs are needed for these patients. Romidepsin is a histone deacetylase inhibitor that can alter chromatin structure and gene transcription leading to multiple changes in cellular protein production. This may result in cell cycle arrest and tumor growth inhibition. Romidepsin has shown anti-proliferative activity in vitro against multiple mouse and human tumor cell lines and in vivo in human tumor xenograft models.
Patients were required to have pathologically verified, measurable, metastatic or locally advanced colorectal cancer that was surgically unresectable. They must have failed either one or two prior chemotherapy regimens, had performance status of 0-1, adequate bone marrow, renal and hepatic function, and no significant cardiac disease. Patients were treated with romidepsin at a dose of 13 mg/m(2) as a 4-h iv infusion on days 1, 8, and 15 of a 28-day cycle. The study had a two stage design. The primary objective of the study was to determine the confirmed response probability in this group of patients treated with romidepsin.
Twenty-eight patients were registered to the study, two of whom were ineligible. One eligible patient refused all treatment and was not analyzed. For the 25 remaining patients, performance status was 0 in 16 patients and 1 in nine patients. Ten patients had received one prior chemotherapy regimen and fifteen 2 prior regimens. Out of the 25 eligible and analyzable patients accrued in the first stage of the protocol, no objective responses were observed and the study was permanently closed. Four patients had stable disease as the best response. Twenty-five patients were assessed for toxicity. No grade 4 or greater toxicities were seen. Fourteen of the 25 patients experienced grade 3 toxicities the most common of which were fatigue or anorexia.
Romidepsin at this dose and schedule is ineffective in the treatment of patients with metastatic colorectal cancer after prior chemotherapy. Future trials might evaluate combinations of romidepsin with chemotherapeutic or other agents.
Investigational New Drugs 11/2008; 27(5):469-75. · 3.36 Impact Factor
ABSTRACT: Imexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers.
Forty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days (one course) every other week (days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays.
There were 13 dose levels evaluated, from 20 mg/m2/d to 1,000 mg/m2/d. The MTD recommended for phase II studies was 875 mg/m2/d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m2/d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose- and area under the curve-dependent decrease in cystine levels 8 hours after dosing at 750 mg/m2/d.
The phase II recommended dose of imexon is 875 mg/m2/d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure.
Journal of Clinical Oncology 06/2007; 25(13):1779-84. · 18.37 Impact Factor
ABSTRACT: Based upon the hypothesis that prolonged exposure to the S-Phase specific agent topotecan would be more efficacious in the treatment of soft tissue sarcomas than a conventional 5-day schedule of the drug, the Southwest Oncology Group performed a Phase II trial of topotecan administered as a continuous infusion in adult patients with advanced soft tissue sarcomas.
Patients who had received no prior chemotherapy for advanced disease were treated with topotecan at a dose of 0.50 mg/m2/day on days 1-21 of repeated 28 day cycles.
Twenty-two patients were enrolled on the study, of whom 21 were eligible. No objective responses were observed (95% confidence interval of 0-16%). The median survival was 12 months (95% confidence interval of 5-16 months).
We conclude that topotecan, given either according to a 5-day or a 21-day schedule, has minimal activity in the treatment of adult soft tissue sarcomas.
Investigational New Drugs 03/2002; 20(1):129-32. · 3.36 Impact Factor