Re: FDA Approves Votrient for Advanced Soft Tissue Sarcoma...

In continuation of my update on Pazopanib..


U.S. Food and Drug Administration, approved Votrient (pazopanib) to treat patients with advanced soft tissue sarcoma who have previously received chemotherapy. Soft tissue sarcoma is a cancer that begins in the muscle, fat, fibrous tissue, and other tissues.

Votrient is a pill that works by interfering with angiogenesis, the growth of new blood vessels needed for solid tumors to grow and survive.


A rare cancer with many subtypes, soft tissue sarcoma occurs in about 10,000 cases annually in the United States. More than 20 subtypes of sarcoma were included in the clinical trial leading to approval of Votrient. The drug is not approved for patients with adipocytic soft tissue sarcoma and gastrointestinal stromal tumors.

"Soft tissue sarcomas are a diverse group of tumors and the approval of Votrient for this general class of tumors is the first in decades," said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "Drug development for sarcomas has been especially challenging because of the limited number of patients and multiple subtypes of sarcomas."

The safety and effectiveness of Votrient was evaluated in a single clinical study in 369 patients with advanced soft tissue sarcoma who had received prior chemotherapy. Patients were randomly selected to receive Votrient or a placebo. The study was designed to measure the length of time a patient lived without the cancer progressing (progression-free survival). The disease did not progress for a median of 4.6 months for patients receiving Votrient, compared with 1.6 months for those receiving the placebo.

The most common side effects in Votrient-treated patients were fatigue, diarrhea, nausea, weight loss, high blood pressure, decreased appetite, vomiting, tumor and muscle pain, hair color changes, headache, a distorted sense of taste, shortness of breath, and skin discoloration.

Votrient carries a boxed warning alerting patients and health care professionals to the potential risk of liver damage (hepatotoxicity), which can be fatal. Patients should be monitored for liver function and treatment should be discontinued if liver function declines.

Ref : http://www.gsk.com/media/pressreleases/2009/2009_pressrelease_10113.htm

MK 1775 shows promise against sarcomas..........

   2-Allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6- (4-(4-methyl- piperazin-1-yl)phenylamino)-1H-pyra -zolo [3,4-d]pyrimidin-3(2H)-one.  

MK 1775 (see structure), a small, selective inhibitor molecule, has been found to be active against many sarcomas when tested by researchers at Moffitt Cancer Center in Tampa, Fla. Researchers found that MK1775 treatment induces apoptopic cell death in four sarcoma cell lines at clinically relevant doses.

To further prove that inhibition of Wee1 by MK1775 leads to mitotic cell death in sarcomas cells, the researchers performed additional studies, including studies on sarcomas related to mutations, such as with the p53 gene. They also showed that MK1775 was an active inhibitor of Wee1 regardless of the p53 mutation status of the tumors in the cell lines tested.

"The cytotoxic effect of Wee1 inhibition on sarcoma cells appears to be independent of p53 mutation status following our testing sarcoma cell lines with different p53 mutations," he said. "All of them were highly sensitive to MK1775, suggesting that Wee1 inhibition may represent a novel approach in the treatment of sarcomas."

Researchers concluded that their laboratory tests on sarcoma cell lines suggest that MK1775 is effective as a monotherapy even in the cell lines that include p53 wild, p53 null and p53 mutant statuses.

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