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

Our plain-English summary of Phase I and pharmacologic study of CT-2584 HMS, a modulator of phosphatidic acid, in adult patients with solid tumours, by S.L. Cheeseman, M. Brannan, A. McGown, et al (British Journal of Cancer, 2000).

The study

• Authors: S.L. Cheeseman, M. Brannan, A. McGown, P. Khan, C. Gardner, L. Gumbrell, D. Dickens, M. Ranson
• Journal: British Journal of Cancer
• Published: 2000;83(12):1599-606
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

Copyright 2000 Cancer Research Campaign.

In plain English

This was a Phase I (early dose-finding) trial of an experimental cancer drug, CT-2584 HMS. It did not study asbestos exposure. In a UK trial, the authors enrolled 30 adults (13 men and 17 women) with solid tumours that had not responded to standard therapy or had no standard therapy. Six of the 7 patients who had never had chemotherapy or radiotherapy had advanced inoperable mesothelioma. The drug was given as a 6-hour infusion daily for 5 days every 3 weeks, at doses from 65 to 585 mg/m2. Dose increases stopped at 585 mg/m2, where two of three patients stopped treatment because of drug-related toxicity. The limiting side effect was malaise (feeling generally unwell), sometimes with nausea and headache. Two patients at 455 mg/m2 had drug-related heart events. Of 26 patients evaluable for response, one man with pleural mesothelioma treated at the lowest dose had a partial response, confirmed by CT scan, that lasted 8 months. Five others had stable disease for 12 weeks or longer. The article's conclusion proposed 500 mg/m2 for Phase II testing, while its summary names 520 mg/m2.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I dose-escalation and pharmacokinetic trial of an experimental anticancer drug (no comparison group)
• Who was studied: 30 adult patients (13 male, 17 female) in a UK study with solid tumours that were refractory to conventional therapy or had no standard therapy. The patients included people with pleural and peritoneal mesothelioma. Study dates are not stated.
• Exposure: No asbestos exposure was studied. The exposure was the drug CT-2584 HMS, given intravenously at dose levels of 65, 130, 215, 325, 455, 520 and 585 mg/m2 daily for 5 days every 3 weeks.
• Main results:
  • At 585 mg/m2, two of three patients discontinued treatment because of drug-related toxicity, and the study was not continued at that dose.
  • 28 of the 30 patients (93%) experienced malaise. In 73% of instances it was attributed to the study drug.
  • At 520 mg/m2, 4 of 6 patients developed grade 2 or 3 malaise.
  • Two patients treated at 455 mg/m2 had drug-related cardiac events. No further cardiac side effects were seen at higher doses.
  • 26 patients were evaluable for response.
  • One male patient with pleural mesothelioma (Butchart stage I), treated at 65 mg/m2 for 6 cycles, had a partial response. It was confirmed by CT scan and continued for 8 months.
  • Five further patients had stable disease for 12 weeks or longer.
  • The drug did not cause significant suppression of the bone marrow.
  • On day 1, plasma elimination half-life ranged from 5.4 to 9.6 hours (mean 7.3) and did not depend on dose.
• The authors' conclusion: The authors concluded that the treatment-limiting toxicity was malaise, sometimes with nausea and headache. In the conclusion section they proposed a dose of 500 mg/m2 for Phase II testing.
• Limitations the authors state:
  • Pharmacokinetic samples from 4 patients thawed during shipment, and analysis failed for 2 patients.
  • Serum samples intended for fatty acid analysis were damaged in transit.
  • Phosphatidic acid expression was not measured in the patient who responded, so the response could not be linked to the drug's proposed mechanism.
  • Routine steroid premedication was not given, which may have increased hypersensitivity reactions and resulting withdrawals from the study.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma.

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