Update on Survival in a Phase 1b/2 Study of DMXAA (AS1404)

[RandyW]

Update on Survival in a Phase 1b/2 Study of DMXAA (AS1404) Combine With Carboplatin and Paclitaxel in Non-Small-Cell Lung Cancer: Presented at AACR-NCI-EORTC

By Chris Berrie

PRAGUE, CZECH REPUBLIC -- November 9, 2006 -- Addition of the vascular-disrupting agent DMXAA (AS1404) to standard doses of carboplatin and paclitaxel results in a well-tolerated way to increase survival for patients with locally advanced and metastatic non-small-cell lung cancer (NSCLC).

These findings, from a multicentre, randomised, open-label, integrated phase 1b/2 study, were presented here on November 8th at the American Association for Cancer Research 18th Symposium on Molecular Targets and Cancer Therapeutics - National Cancer Institute - 18th European Organisation for Research and Treatment of Cancer (AACR-NCI-EORTC).

For many patients presenting with late-stage NSCLC, standard treatment is platinum-based chemotherapy in combination with the taxane paclitaxel. However, with none of the frequently used platinum-based therapies showing specific benefits over the others, there remains the need for new approaches to the treatment of these patients, said Joachim von Pawel, MD, principal investigator for Germany and head, department of oncology, Asklepois Hospital, Gauting, Munich, Germany.

Vascular-disrupting agents like DMXAA act by selectively disrupting tumour blood vessels. Previous randomised, controlled trials have indicated additive effects of DMXAA when combined with platinum compounds and taxanes for patients with lung, prostate and ovarian cancers.

Following the initial phase 1b trial, the main objective of the phase-2 stage was determination of safety, tolerability and efficacy of DMXAA plus carboplatin and paclitaxel, as compared with standard carboplatin and paclitaxel.

The study design allowed for initial phase 1b testing of 3 incremental doses of DMXAA (600, 1200 and 1800 mg/m2; 20-minute IV infusion) in combination with carboplatin (AUC 6 mg/mL.min; 30-minute IV infusion) and paclitaxel (175 mg/m2; 3-hour IV infusion) for tolerability and potential drug interactions.

The phase 1b patients on the DMXAA 1200 mg/m2 combination (n = 6) then continued into phase 2 for direct comparison of this three-agent combination (DMXAA+ST; n = 37; mean age, 59.4 years; male, 62.2%) with carboplatin and paclitaxel alone (ST alone; n = 36; mean age, 61.0 years; male, 66.7%), every 21 days for up to 6 cycles.

The study enrolled adults with histologically confirmed stage IIIb or IV NSCLC who were previously untreated with chemotherapy. Tumour response was evaluated according to the Response Evaluation Criteria in Solid Tumours (RECIST) criteria.

Baseline characteristics across the DMXA+ST and ST alone patient groups were well balanced for NSCLC type, stage, and Karnofsky performance status.

No patients showed a complete response. Response rate (complete plus partial response) showed benefits of DMXAA+ST with 31.3% versus 22.2% with ST alone, although stable disease showed 65.6% versus 70.4%, respectively.

Some benefit for DMXAA+ST was seen for time to tumour progression (5.4 months vs 4.4 months, hazard ratio

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, 0.86; 95% confidence interval [CI], 0.50-1.40), and mean survival time (14.0 months vs 8.8 months, HR, 0.73; 95% CI, 0.39-1.38), with the latter thus providing a 27% reduction in risk of death.

These data are consistent with preliminary findings that showed increased response rates in hormone-refractory prostate cancer and recurrent ovarian cancer when DMXAA was added to chemotherapy, which also provided the first proof of concept for a vascular-disrupting agent in a randomised controlled study.

"Although this represents small groups, the main message is that you have a much better survival [in these DMXAA-combination patients], and the intention is to go forward to a phase 3 trial, to include non-small-cell lung cancer and ovarian cancer," Dr. von Pawel said.

He presented the findings on behalf of the AS1404-201 Study Group Investigators. The study was sponsored by Antisoma.

[Presentation title: Update on Survival in a Phase 1b/2 Study of DMXAA (AS1404) Combine With Carboplatin and Paclitaxel in Non-Small-Cell Lung Cancer (NSCLC). Abstract 40]