Abstract
The dose limiting toxicities of the short infusion trial of the dacarbazine analog, CB10-277, were nausea and vomiting which appeared to be related to the peak plasma level of the parent drug. In addition, based on mouse studies, these dose limiting toxicities occurred at a less than optimal level of the monomethyl metabolite, the presumed species required for antitumour activity. An alternative schedule that would avoid the parent drug peak plasma levels of short infusion, while possibly allowing an increase in the amount of monomethyl metabolite produced was considered. Thus, a 24 h continuous infusion schedule, repeated every 21 days was explored. Twenty-two patients received 42 courses with a dose range of 4,700-15,000 mg m-2. The dose limiting toxicity was myelosuppression (leucopenia and thrombocytopenia). Although nausea and vomiting also occurred, it was manageable with routine antiemetic therapy. Other toxicities included diarrhoea, hallucinations, malaise, muscle ache, headache and flushing and all were < or = WHO grade 2. Pharmacokinetic studies were performed with 13 courses which included all dose levels. The mean t1/2 of the parent drug was 178 min. Area under the concentration x time curve (AUC) at the highest dose for the parent drug and the monomethyl metabolite were 2,350 and 9 mM x minutes, respectively. This monomethyl metabolite AUC and the associated myelosuppression showed a more favourable comparison to the preclinical data determined in mice than the results from the short infusion trial of CB10-277. Therefore, the recommended Phase II dose and schedule of this drug was 12,000 mg m-2 given by 24 h continuous infusion.
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- Buchheit K. H., Costall B., Engel G., Gunning S. J., Naylor R. J., Richardson B. P. 5-Hydroxytryptamine receptor antagonism by metoclopramide and ICS 205-930 in the guinea-pig leads to enhancement of contractions of stomach muscle strips induced by electrical field stimulation and facilitation of gastric emptying in-vivo. J Pharm Pharmacol. 1985 Sep;37(9):664–667. doi: 10.1111/j.2042-7158.1985.tb05109.x. [DOI] [PubMed] [Google Scholar]
- Buesa J. M., Gracia M., Valle M., Estrada E., Hidalgo O. F., Lacave A. J. Phase I trial of intermittent high-dose dacarbazine. Cancer Treat Rep. 1984 Mar;68(3):499–504. [PubMed] [Google Scholar]
- Cowan D. H., Bergsagel D. E. Intermittent treatment of metastatic malignant melanoma with high-dose 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (NSC-45388). Cancer Chemother Rep. 1971 Apr;55(2):175–181. [PubMed] [Google Scholar]
- Cubeddu L. X., Hoffman I. S., Fuenmayor N. T., Finn A. L. Antagonism of serotonin S3 receptors with ondansetron prevents nausea and emesis induced by cyclophosphamide-containing chemotherapy regimens. J Clin Oncol. 1990 Oct;8(10):1721–1727. doi: 10.1200/JCO.1990.8.10.1721. [DOI] [PubMed] [Google Scholar]
- Gralla R. J., Itri L. M., Pisko S. E., Squillante A. E., Kelsen D. P., Braun D. W., Jr, Bordin L. A., Braun T. J., Young C. W. Antiemetic efficacy of high-dose metoclopramide: randomized trials with placebo and prochlorperazine in patients with chemotherapy-induced nausea and vomiting. N Engl J Med. 1981 Oct 15;305(16):905–909. doi: 10.1056/NEJM198110153051601. [DOI] [PubMed] [Google Scholar]
- Grunberg S. M., Stevenson L. L., Russell C. A., McDermed J. E. Dose ranging phase I study of the serotonin antagonist GR38032F for prevention of cisplatin-induced nausea and vomiting. J Clin Oncol. 1989 Aug;7(8):1137–1141. doi: 10.1200/JCO.1989.7.8.1137. [DOI] [PubMed] [Google Scholar]
- Johnson R. O., Metter G., Wilson W., Hill G., Krementz E. Phase I evaluation of DTIC (NSC-45388) and other studies in malignant melanoma in the Central Oncology Group. Cancer Treat Rep. 1976 Feb;60(2):183–187. [PubMed] [Google Scholar]
- Moore G. E., Meiselbaugh D. Letter: DTIC (NSC-45388) toxicity. Cancer Treat Rep. 1976 Mar;60(3):219–219. [PubMed] [Google Scholar]
- Pritchard K. I., Quirt I. C., Cowan D. H., Osoba D., Kutas G. J. DTIC therapy in metastatic malignant melanoma: a simplified dose schedule. Cancer Treat Rep. 1980 Oct-Nov;64(10-11):1123–1126. [PubMed] [Google Scholar]
- Stables R., Andrews P. L., Bailey H. E., Costall B., Gunning S. J., Hawthorn J., Naylor R. J., Tyers M. B. Antiemetic properties of the 5HT3-receptor antagonist, GR38032F. Cancer Treat Rev. 1987 Dec;14(3-4):333–336. doi: 10.1016/0305-7372(87)90026-0. [DOI] [PubMed] [Google Scholar]