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Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent.

Jameson MB, Thompson PI, Baguley BC, Evans BD, Harvey VJ, Porter DJ, McCrystal MR, Small M, Bellenger K, Gumbrell L, Halbert GW, Kestell P, Phase I/II Trials Committee of Cancer Research - Br. J. Cancer (2003)

Bottom Line: DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen.The results of PK and PD studies are reported separately.DMXAA has antitumour activity at well-tolerated doses.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Oncology, Auckland Hospital, Private Bag 92024, Auckland, New Zealand. jameson@waikatodhg.govt.nz

ABSTRACT
The antitumour action of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is mediated through tumour-selective antivascular effects and cytokine induction. This clinical phase I trial was conducted to examine its toxicity, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). A secondary objective was to assess its antitumour efficacy. DMXAA was administered every 3 weeks as a 20-min i.v. infusion. Dose escalation initially followed a modified Fibonacci schema but was also guided by PK and toxicity. A total of 63 patients received 161 courses of DMXAA over 19 dose levels ranging from 6 to 4900 mg m(-2). DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen. Rapidly reversible dose-limiting toxicities were observed at 4900 mg m(-2), including confusion, tremor, slurred speech, visual disturbance, anxiety, urinary incontinence and possible left ventricular failure. Transient prolongation of the corrected cardiac QT interval was seen in 13 patients evaluated at doses of 2000 mg m(-2) and above. A patient with metastatic cervical carcinoma achieved an unconfirmed partial response at 1100 mg m(-2), progressing after eight courses. The results of PK and PD studies are reported separately. DMXAA has antitumour activity at well-tolerated doses.

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Related in: MedlinePlus

Tumour response in a patient with metastatic squamous carcinoma of cervix treated with DMXAA 1100 mg m−2. Tumour size was calculated as the sum of the products of bidimensional measurements of three clinically measurable metastatic neck nodes.
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fig3: Tumour response in a patient with metastatic squamous carcinoma of cervix treated with DMXAA 1100 mg m−2. Tumour size was calculated as the sum of the products of bidimensional measurements of three clinically measurable metastatic neck nodes.

Mentions: A total of 60 patients were evaluable for response. One partial response was seen in a patient with metastatic squamous carcinoma of cervix treated at 1100 mg m−2 and previously treated with bleomycin, etoposide and cisplatin chemotherapy, then carboplatin. The response was unconfirmed because two small neck nodes increased in size transiently after the third course then subsequently regressed again and overall tumour response was maintained for eight courses (Figure 3Figure 3


Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent.

Jameson MB, Thompson PI, Baguley BC, Evans BD, Harvey VJ, Porter DJ, McCrystal MR, Small M, Bellenger K, Gumbrell L, Halbert GW, Kestell P, Phase I/II Trials Committee of Cancer Research - Br. J. Cancer (2003)

Tumour response in a patient with metastatic squamous carcinoma of cervix treated with DMXAA 1100 mg m−2. Tumour size was calculated as the sum of the products of bidimensional measurements of three clinically measurable metastatic neck nodes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2741109&req=5

fig3: Tumour response in a patient with metastatic squamous carcinoma of cervix treated with DMXAA 1100 mg m−2. Tumour size was calculated as the sum of the products of bidimensional measurements of three clinically measurable metastatic neck nodes.
Mentions: A total of 60 patients were evaluable for response. One partial response was seen in a patient with metastatic squamous carcinoma of cervix treated at 1100 mg m−2 and previously treated with bleomycin, etoposide and cisplatin chemotherapy, then carboplatin. The response was unconfirmed because two small neck nodes increased in size transiently after the third course then subsequently regressed again and overall tumour response was maintained for eight courses (Figure 3Figure 3

Bottom Line: DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen.The results of PK and PD studies are reported separately.DMXAA has antitumour activity at well-tolerated doses.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Oncology, Auckland Hospital, Private Bag 92024, Auckland, New Zealand. jameson@waikatodhg.govt.nz

ABSTRACT
The antitumour action of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is mediated through tumour-selective antivascular effects and cytokine induction. This clinical phase I trial was conducted to examine its toxicity, maximum tolerated dose, pharmacokinetics (PK) and pharmacodynamics (PD). A secondary objective was to assess its antitumour efficacy. DMXAA was administered every 3 weeks as a 20-min i.v. infusion. Dose escalation initially followed a modified Fibonacci schema but was also guided by PK and toxicity. A total of 63 patients received 161 courses of DMXAA over 19 dose levels ranging from 6 to 4900 mg m(-2). DMXAA was well tolerated at lower doses and no drug-related myelosuppression was seen. Rapidly reversible dose-limiting toxicities were observed at 4900 mg m(-2), including confusion, tremor, slurred speech, visual disturbance, anxiety, urinary incontinence and possible left ventricular failure. Transient prolongation of the corrected cardiac QT interval was seen in 13 patients evaluated at doses of 2000 mg m(-2) and above. A patient with metastatic cervical carcinoma achieved an unconfirmed partial response at 1100 mg m(-2), progressing after eight courses. The results of PK and PD studies are reported separately. DMXAA has antitumour activity at well-tolerated doses.

Show MeSH
Related in: MedlinePlus