Drug combination lengthens lives of metastatic colorectal cancer patients

                         fluoropyrimidine                    TAS-102

 Capecitabine

A drug developed 50 years ago and abandoned because it was considered to be too toxic has gained a second life in an international clinical trial. Research led by scientists at Dana-Farber Cancer Institute showed the drug and a potentiating agent lengthened the lives of patients with metastatic colorectal cancer, all of whom had exhausted available standard treatments.

In a paper published online today by the New England Journal of Medicine, investigators at Dana-Farber and research centers around the world found that the drug combination - given as a single pill known as TAS-102 - not only extended patients' overall survival, but also delayed the advance of the disease and did so with very few side effects.

According to the study authors, the results are especially impressive because half of the patients had just finished treatment with the standard class of chemotherapy agents - fluoropyrimidines (e.g. 5-fluorouracil [5-FU] or capecitabine [Xeloda]) but had failed to benefit from them. The fact that TAS-102 temporarily halted the disease in many of these patients suggests that it operates through a different biochemical pathway than 5-FU, and therefore may serve as an alternative to standard therapy.

"Colorectal cancer is the second most common cause of cancer deaths [after lung cancer] in the United States and is an enormous health problem around the world," said the study's lead author, Robert J. Mayer, MD, faculty vice president for academic affairs, medical oncologist and colorectal cancer researcher at Dana-Farber. "To have a well-tolerated, effective new drug in a cancer that is so prevalent is good news for patients."

The trial, a phase 3 study involving major cancer research institutions in Europe, the United States, Australia and Japan, enrolled 800 patients with metastatic colorectal cancer that was progressing despite previous treatment. Participants were randomly assigned to receive TAS-102 or a placebo pill...

More : http://www.nejm.org/doi/full/10.1056/NEJMoa1414325

Drug combination lengthens lives of metastatic colorectal cancer patients

New small molecule inhibitor could be a safe and first-line treatment for metastatic breast cancer

Mesupron® (see structure below) is a new small molecule inhibitor, taken as a pill, that inhibits the uPA system. The results from a recent phase II clinical study suggest that the drug could be a safe and first-line treatment that extends progression-free survival for metastatic breast cancer patients, when combined with the chemotherapeutic drug Capecitabine.

The study included 132 patients with metastatic breast cancer from 20 centers in five countries. In the trial, patients who took Mesupron combined with Capecitabine went without the return of disease for a median 8.3 months after the therapy. Patients who only took Capecitabine had a progression-free survival of 7.5 months.

"The combination of oral agents was convenient for and well tolerated by the patients," says Goldstein. "Plans for future studies are ongoing."

The drug was developed by WILEX, a German pharmaceutical company that focuses on the development of small molecule inhibitors and other new targeted cancer drugs designed to give patients treatment options with fewer side effects than traditional chemotherapy. In the Phase II study, Goldstein and her collaborators also investigated the safety and efficacy of the drug, as well as the objective response rate  the patient population who had no sign of disease after a specific amount of time.

Nine percent of the patients who received only Capecitabine had a complete objective response after 24 weeks. The objective response rate among the patients taking the combination therapy was nearly twice that, at 17 percent. The researchers also looked at different subgroups of participants to try to identify which patients might receive the most benefit from a combination therapy involving Mesupron. Among 109 Caucasian patients, the progression free survival was 7.5 months for patients who received Capecitabine alone, and 9.1 months for those who also received Mesupron.

The drug also showed a significant improvement for patients who had previously received treatment  before their disease became metastatic. In the subgroup of patients (n=95) who received adjuvant chemotherapy following the primary diagnosis of breast cancer, progression free survival improved from 4.3 months in the Capecitabine alone group to 8.3 months in the Mesupron combination group.....

Ref : http://www.fccc.edu/information/news/press-releases/2012/2012-12-07-SABC-Goldstein-WILEX.html

New small molecule inhibitor could be a safe and first-line treatment for metastatic breast cancer

Capecitabine combination therapy reduces early breast cancer recurrence...

Capecitabine, is an orally-administered chemo therapeutic agent used in the treatment of metastatic breast and colorectal cancers.

Mode of action :

Capecitabine is a prodrug, that is enzymatically converted to 5-fluorouracil in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue. The activation of capecitabine follows a pathway with three enzymatic steps and two intermediary metabolites, 5'-deoxy-5-fluorocytidine (5'-DFCR) and 5'-deoxy-5-fluorouridine (5'-DFUR), to form 5-fluorouracil. Its being used (& FDA approved) in the treatment of adjuvant in colorectal cancer, metastatic colorectal cancer and Metastatic breast cancer - used in combination with docetaxel, after failure of anthracycline-based treatment. Also as monotherapy, if the patient has failed paclitaxel-based treatment, and if anthracycline-based treatment has either failed or cannot be continued for other reasons.

Recently, Finnish Breast Cancer Group and published in The Lancet Oncology shows women at intermediate to high-risk of early breast cancer recurrence who received capecitabine as part of their chemotherapy regimen had a 34% reduction in the risk of the disease returning or death, compared with those taking the chemotherapy combination regimen without capecitabin. The pre-planned three-year interim analysis of a randomised, prospective trial compared adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for the treatment of early breast cancer with the standard, non-capecitabine regimen (docetaxel, epirubicin, cyclophosphamide and fluorouracil). The analysis also found that patients taking the capecitabine-containing regimen were significantly less likely to have their cancer spread (distant metastasis) to another part of the body (a 36% reduction in risk was observed). This is the first phase III randomised trial to report efficacy of capecitabine combination therapy in the adjuvant treatment of early breast cancer.

Though capecitabine, has already been shown to be effective in patients with advanced breast cancer, but the most important conclusion the researchers have arrived is "capecitabine-containing regimen in the early stages of breast cancer may offer survival benefits for women".....

Source :http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2809%2970307-9/fulltext