Phase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours.

2.50
Hdl Handle:
http://hdl.handle.net/10541/86688
Title:
Phase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours.
Authors:
Cheeseman, S L; Brannan, M; McGown, Alan T; Khan, P; Gardner, C; Gumbrell, L; Dickens, D; Ranson, Malcolm R
Abstract:
CT-2584 HMS, 1-(11-dodecylamino-10-hydroxyundecyl)-3, 7-dimethylxanthine-hydrogen methanesulphonate, is a modulator of intracellular phosphatidic acid. We treated 30 patients as part of a Phase I and pharmacokinetic study to determine the maximum-tolerated dose of CT-2584 HMS, toxicity profiles, pharmacokinetic profile and antitumour effects at escalating dose levels. CT-2584 HMS was given as a continuous infusion for 6 hours for 5 consecutive days every 3 weeks. Plasma samples for pharmacokinetic studies were analysed using a validated high-performance liquid chromatographic assay. Mean C(max)and AUC values for each dose group were similar on days 1 and 5 and increases in plasma concentration (C(max)and AUC) appeared proportional to the dose. CT-2584 HMS had a mean elimination half-life of 7.3 hours. Values of V(d)and clearance were independent of dose and duration of treatment. Dose escalation was halted at 585 mg/m(2)because of malaise and lethargy, which was sometimes accompanied by nausea and headache. 26 patients were evaluable for response, one patient with pleural mesothelioma achieved a partial response to treatment confirmed by CT scanning. A dose level of 520 mg/m(2)daily x 5 days would be suitable for Phase II testing. Alternative schedules of CT-2584 HMS to overcome the limiting toxicity of malaise would be worthy of examination.
Affiliation:
CRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK.
Citation:
Phase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours. 2000, 83 (12):1599-606 Br. J. Cancer
Journal:
British Journal of Cancer
Issue Date:
Dec-2000
URI:
http://hdl.handle.net/10541/86688
DOI:
10.1054/bjoc.2000.1503
PubMed ID:
11104552
Type:
Article
Language:
en
ISSN:
0007-0920
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorCheeseman, S Len
dc.contributor.authorBrannan, Men
dc.contributor.authorMcGown, Alan Ten
dc.contributor.authorKhan, Pen
dc.contributor.authorGardner, Cen
dc.contributor.authorGumbrell, Len
dc.contributor.authorDickens, Den
dc.contributor.authorRanson, Malcolm Ren
dc.date.accessioned2009-11-23T12:06:06Z-
dc.date.available2009-11-23T12:06:06Z-
dc.date.issued2000-12-
dc.identifier.citationPhase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours. 2000, 83 (12):1599-606 Br. J. Canceren
dc.identifier.issn0007-0920-
dc.identifier.pmid11104552-
dc.identifier.doi10.1054/bjoc.2000.1503-
dc.identifier.urihttp://hdl.handle.net/10541/86688-
dc.description.abstractCT-2584 HMS, 1-(11-dodecylamino-10-hydroxyundecyl)-3, 7-dimethylxanthine-hydrogen methanesulphonate, is a modulator of intracellular phosphatidic acid. We treated 30 patients as part of a Phase I and pharmacokinetic study to determine the maximum-tolerated dose of CT-2584 HMS, toxicity profiles, pharmacokinetic profile and antitumour effects at escalating dose levels. CT-2584 HMS was given as a continuous infusion for 6 hours for 5 consecutive days every 3 weeks. Plasma samples for pharmacokinetic studies were analysed using a validated high-performance liquid chromatographic assay. Mean C(max)and AUC values for each dose group were similar on days 1 and 5 and increases in plasma concentration (C(max)and AUC) appeared proportional to the dose. CT-2584 HMS had a mean elimination half-life of 7.3 hours. Values of V(d)and clearance were independent of dose and duration of treatment. Dose escalation was halted at 585 mg/m(2)because of malaise and lethargy, which was sometimes accompanied by nausea and headache. 26 patients were evaluable for response, one patient with pleural mesothelioma achieved a partial response to treatment confirmed by CT scanning. A dose level of 520 mg/m(2)daily x 5 days would be suitable for Phase II testing. Alternative schedules of CT-2584 HMS to overcome the limiting toxicity of malaise would be worthy of examination.en
dc.language.isoenen
dc.subjectCanceren
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshArea Under Curve-
dc.subject.meshArrhythmias, Cardiac-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshFatigue-
dc.subject.meshFemale-
dc.subject.meshHematuria-
dc.subject.meshHumans-
dc.subject.meshHypersensitivity-
dc.subject.meshHypotension-
dc.subject.meshInfusions, Intravenous-
dc.subject.meshMale-
dc.subject.meshMiddle Aged-
dc.subject.meshMyocardial Ischemia-
dc.subject.meshNausea-
dc.subject.meshNeoplasms-
dc.subject.meshPhosphatidic Acids-
dc.subject.meshProteinuria-
dc.subject.meshTreatment Outcome-
dc.subject.meshVomiting-
dc.subject.meshXanthines-
dc.titlePhase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours.en
dc.typeArticleen
dc.contributor.departmentCRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK.en
dc.identifier.journalBritish Journal of Canceren

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