Phase 3 Trial of Motesanib in Non-Small-Cell Lung Cancer Suspended

Zosia Chustecka

November 21, 2008

November 21, 2008 — A phase 3 clinical trial of non-small-cell lung cancer (NSCLC) patients has been temporarily suspended after a planned safety review showed more deaths with the investigational drug than with placebo.

The drug is motesanib (also known as AMG 706), an oral angiogenesis inhibitor that acts by targeting vascular endothelial growth-factor receptor (VEGFR)1, VEGFR2, and VEGFR3. It is being developed by Amgen, Takeda, and Millennium, and the companies announced the finding in a joint press release.

This is the second such compound that has run into safety problems while being investigated in NSCLC patients.

Immediate Discontinuation in Squamous NSCLC

The company-sponsored trial, known as MONET1, was evaluating motesanib in combination with paclitaxel and carboplatin for the first-line treatment of advanced NSCLC. It included patients with both squamous and nonsquamous type NSCLC, and the trial was almost fully enrolled (1100 of a planned total of 1240 patients).

The safety-data review involved 600 patients and was carried out by an independent Data Monitoring Committee. The review found higher early mortality rates in the motesanib group than in the placebo group, the companies announced. In addition, there was a higher incidence of hemoptysis with motesanib than with placebo among patients with squamous NSCLC. Because of this, the Data Monitoring Committee recommended immediate discontinuation of the drug among this patient population. However, the committee did not recommend discontinuation of the drug in patients with nonsquamous NSCLC (about two thirds of the patients enrolled in the trial).

"While we are disappointed in this outcome, it is consistent with data seen with some other anti-VEGF therapies and appears to constitute a class effect of these types of agents," commented Roger Perlmutter, MD, PhD, executive vice president of research and development at Amgen.

Earlier this year, safety concerns stopped a similar trial with a very similar investigational product, cediranib (Recentin, formerly AZD2171), a highly potent oral inhibitor of VEGFR1, 2, and 3, under development by AstraZeneca. This drug is also being investigated in colorectal cancer. The trial that was halted was a phase 2/3 study investigating the addition of cediranib to a combination of carboplatin and paclitaxel in the first-line treatment of NSCLC. An interim analysis suggested an imbalance of toxicity in the cediranib group, as previously reported by Medscape Oncology.

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