MADRID, Spain—A cancer research lab operated by the Spanish government has published the findings of its first clinical trial, and the data suggest potential for a new method of treating breast cancer. The Phase 1 clinical trial at the Spanish National Cancer Research Center (Centro Nacional de Investigaciones Oncológicas, or CNIO) found that the experimental drug nintedanib, combined with standard chemotherapy with paclitaxel, caused a total remission of tumors in 50 percent of patients suffering from early HER2-negative breast cancer. The study, which was carried out by CNIO ́s Breast Cancer Clinical Research Unit, was published in the British Journal of Cancer in September.
“The drug combination of paclitaxel and nintedanib has turned out to be a complete success, given that it is proved to be safe and that the pathologic complete response was 50 percent, which doubles the response compared to patients treated with standard therapy with paclitaxel,” said Dr. Miguel Ángel Quintela, head of CNIO’s Breast Cancer Clinical Research Unit.
CNIO’s study was focused specifically on patients with HER2-negative breast cancers, which tend to grow and spread more slowly than HER2-positive breast cancers, which involve higher than normal levels of a protein called human epidermal growth factor receptor 2 (HER2).
Researchers at CNIO launched their study as part of an effort to target abnormalities of the tumor stroma, a complex mixture of healthy cells that constitute the blood and lymphatic vessels of the tumor and the intercellular molecules that serve as scaffold for the normal cells and the tumor cells. Tumors have the capacity to reprogram the normal stroma, causing abnormalities in blood and lymphatic vessels as well as the intercellular scaffold molecules. Quintela says that nintedanib seemed to be a drug that was especially well-suited to targeting this phenomenon. “This reprogramming occurs through several signaling axes aberrantly functioning in breast cancer,” Quintela tells DDNews. “We had available mouse models for this purpose, and nintedanib had activity against all these aberrations, so it was the ideal partner for our research.”
The positive outcome of the study has already led CNIO to launch a Phase 2 clinical trial to validate the results in a large group of patients. The Phase 2 trial incorporates two types of potential biomarkers for testing. One is a non-invasive misonidazole PET, an imaging test that will enable researchers to identify the patients for whom nintedanib is normalizing the stroma and enabling blood vessels to allow chemotherapy to be effectively delivered in the tumor microenvironment. The second biomarker test is a phosphoproteomic screening, which helps researchers identify which signaling molecules it will be necessary to modulate in combination with nintedanib to revert intrinsic drug resistance in patients with low chance of presenting a positive response.
“We know from large trials in other pathology that nintedanib is a very powerful drug,” Quintela says. “What is unknown, and constitutes the main flaw for targeted therapies, is in whom the drug is going to work beforehand.” Developing an effective predictive test is especially important, says Quintela, due to the high cost of the drug and the time potentially needed to determine if it is effective in a patient. CNIO expects to release the results of the Phase 2 trial by early 2015.
CNIO has also just completed a second Phase 1 clinical trial using dovitinib, a drug from the same family as nintedanib. The study has been tested in metastatic patients with different primary tumors such as breast, colon and lung cancer. The results, still in a preliminary stage, show that patients with a specific variant in the RET gene, which CNIO reports is present in 15 percent of Caucasian people, could be more sensitive to this drug. The findings have been published by Molecular Oncology. If the data are confirmed, this genetic variant could be used as a reliable biomarker in personalized medicine that selects the best-suited candidates to receive the drug.
The studies of nintedanib and dovitinib were inspired by recent theories suggesting that a possible solution to cancer might be to suffocate tumors by blocking the formation of new blood vessels surrounding them. The mechanism of action of both experimental drugs CNIO studied involves that precise process. The drugs block the formation of new blood vessels, or angiogenesis, which can lead to retardation in tumor growth rates and limit its viability. “Nintedanib is an improved antiangiogenic drug compared to previous angiogenesis inhibitors, given that it prevents angiogenesis in a more efficient way and with lower toxicity than its predecessors,” says Quintela.
The clinical trials of nintedanib and dovitinib are part of CNIO’s strategy to undertake a comprehensive project for excellence in oncology research. “The clinical trials we are presenting are the first organized by CNIO, to whom several pharmaceutical companies have entrusted complete development of the previously mentioned experimental drugs,” says Quintela. “This wouldn’t have been possible without the fluid collaboration of hospitals from the Spanish National Health System, and the Spanish Breast Cancer Research Group.”
The institution aims to conduct many more similar clinical trials for cancer patients through its Clinical Research Program. “Doing this type of study is critical to be able to test hypotheses formulated in the laboratory on patients without commercial pressures,” says Manuel Hidalgo, director of the program. “These studies show that it is possible to create a network of research centers and hospitals to carry out clinical trials with a strong scientific component.”
