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The CNIO-BR clinical trials and studies Last update October/2016
Concept and vision

The Breast Cancer Clinical Research Unit is not just a research laboratory. The concepts originated in the bench have to be translated quickly to the patients. Some of us are actually medical oncologists with clinical practice in some of the Madrid area Hospitals. Many of our associate researchers are oncologists form other hospitals of Spain. In addition, in our daily routine practice, several questions arise, from the experiences of patients failing to conventional treatments, from cases with atypical disease course, and in general, from the vast heterogeneity that this disease shows. All these "bedside" questions require a quick design of preclinical models to get practical answers, that then can be brought back to clinical implementation. This model of activity ("Bench-to-the-bedside and back-to-the-bench) led to the CNIO-BR Clinical Network and the CNIO-BR-initiative, in collaboration with Pharmaceutical Companies and Philanthropy.

Completed and ongoing studies

CNIO-BR-001 trial

-Status: concluded and published.

-This study was part of an initiative to understand the acquired resistance to small-molecule antiangiogenics. In preclinical models we had observed that the signaling nodes increasing their activities upon short exposure to molecular targeted therapeutics could be used as potential future targets for the resistant phenotypes. A future study (003) would try to prove this concept, but first, toxicity and preliminary efficacy should be explored. We conducted this phase I study of the combination of nintedanib, a small molecule that inhibits the receptors of the VEGFR, PDGFR and FGFR family, with conventional chemotherapy. The trial demonstrated an excellent tolerability, and achieved an unprecedented 50% pathologic complete response rate, enriched in the triple-negative phenotype.

-The publication can be consulted in the following link: http://www.ncbi.nlm.nih.gov/pubmed/25058346

CNIO-BR-002 trial

-Status: concluded and published

-This study was framed as well within the initiative to understand better the role of antiangiogenics in cancer. Coupled with a preclinical study, we aimed to develop a non-invasive biomarker that early during treatment could segregate the patients experience benefit from small-molecule antiangiogenics from the remainder. Based on the hypothesis of vascular normalization, we assumed that tumors experiencing this phenomenon would also normalize tumor hypoxia; this feature was proved in preclinical models by using the tracer 18F-misonidazole. This tracer can be monitored by PET-scan. Prior to launch a pilot trial of 18F-misonidazole-PET in predicting efficacy of the small-molecule antiangiogenic dovitinib plus chemotherapy, we first completed this phase I trial studying the safety and preliminary efficacy of the combination. Plus, several genetic biomarkers were assessed as well. This trial defined a phase II recommended dose of dovitinib 200 mg/day (5 days per week) plus 65 mg/m2 IV per week of paclitaxel, for further testing in the pilot trial with the PET-tracer. In addition, we found that the benefit of dovitinib was mostly concentrated in patients that harbored a variant in the RET oncogene, G2071A.

The trial is registered in clinicaltrials.gov under the following number: NCT01548924.

-The publication can be found in the following link: http://www.ncbi.nlm.nih.gov/pubmed/25103625

CNIO-BR-003 trial

-Status: concluded and published.

-This trial is exploring 2 hypothesis: 1) the kinome reprogramming in response to BIBF1120 in early breast cancer, as a means to define potential signaling nodes involved in acquired resistance against antiangiogenics. It is based on the dose-finding trial CNIO-BR-001 trial; 2) the role of Misonidazole - PET (a technique that we have demonstrated that it can trace whether a tumor is oxygenating or not in response to antiangiogenics) in predicting the response to neoadjuvant nintedanib.

The trial recruited 130 patients and randomized them to standard chemotherapy or the same treatment plus nintedanib. We found that among hormone-receptor positive patients, the response rate doubled by adding nintedanib. In addition, the patients that did not oxygenate their tumors in response to short-course nintedanib had adverse outcomes, suggesting that for this type of agents to work some sort of normalization is necessary. Currently we are studying which signaling pathways account for the resistance in those patients developing the hypoxic adaptation.

The trial is registered in clinicaltrials.gov under the following number: NCT01484080

-The first publication can be found in the following link: https://www.ncbi.nlm.nih.gov/pubmed/27587436

CNIO-BR-004 study

-Status: archival samples taxonomy - concluded and published

-This study is a multicentric initiative to pinpoint breast cancer genetic mutations accounting for relapse of hormone-receptor positive cases. Plenty of literature describes the mutations of the driver genes of this disease, and the most frequent genetic alterations of the incident cases. However, due to the relatively low incidence of distant failure, the genes present in the cases with distant relapse, and whether these mutations are stable or not from the primary to the metastatic lesions, are yet unclear. We have collected pairs of primary+metastatic tumors and are currently analyzing these questions in a set of samples where 100% of the cases have experienced distant relapse. We have found that a signature composed by alterations in MYC, KMT2C and EPHA7 induces a triple risk of relapse of hormone-receptor positive breast cancer, and that when these genes are mutated, they are associated to resistance to hormonal therapy.

-The publication can be found in the following link: https://www.ncbi.nlm.nih.gov/pubmed/27195705

CNIO-BR-005 trial

-Status: Prospective clinical trial pending Ethics Board and Spanish Drug Agency approval.

-This trial will assess the role of High-Intensity Focused Ultrasound in advanced cancer in combination with chemotherapy. The trial registration in clinicaltrials.gov will soon be available.

CNIO-BR-006 study

-Status: correlative study in archival samples – under analysis.

-This study involved a huge effort of gathering a sample collection of more than 400 samples with annotated clinical follow-up in breast cancer units of the Madrid area. The objective is to establish a phosphoproteomic taxonomy of triple-negative breast cancer, the most malignant variant. We hypothesize that all the genetic aberrations that make each cancer unique converge in a certain number of patterns of activation of the signaling pathways that can be tackled with our taxonomy. This would allow dividing the disease into several functional subtypes on the basis of this taxonomy; however, what it is more important is that the signaling nodes that constitute this taxonomy are targets on themselves. Thus, this taxonomy would allow not only building accurate prognostic scores but also defining which therapies do the patients falling in the adverse prognostic cluster need.

-The publication link will be updated as soon as it is available.

CNIO-BR-007 trial

Status: Prospective clinical trial. Recruiting.

-This clinical trial is a phase 0 / phase I trial that is based on the findings of the CNIO-BR-006 study. One of the oncogenic-addiction drivers of hormone-receptor positive breast cancer, FGFR, can be blocked by nintedanib, but it is only effective in combination with hormonal blockade. Thus, we are going to conduct a clinical trial of the combination of letrozole plus nintedanib. The objectives of this phase are to find the recommended dose for phase II (phase I part) and to re-assure pharmacodynamic modulation of the targets (suppression of FGFR signaling and estrogen levels) at such dose (phase 0 part).

The trial is registered in clinicaltrials.gov under the following number: NCT02619162

-The publication link will be updated as soon as it is available.

CNIO-BR-008 trial

-Status: prospective clinical trial. Recruiting

We have recently found in our animal models that tumors can develop resistance against antiangiogenics through two pathways. One involves normalization of tumor hypoxia followed by metabolic changes. The second involves hypoxia increase followed by immune-suppression changes. Both pathways are reversible. We are studying the combined effect of adding the anti-PD-L1 agent durvalumab to patients experiencing disease progression after chronic bevacizumab administratio.

This trial is registered in clinicaltrials.gov under the following number: NCT02802098

-The publication link will be updated as soon as it is available.

CNIO-BR-009 trial

-Status: prospective clinical trial. Recruiting

-This trial complements the 008 trial - the 008 is exploring the therapeutic benefits of reverting the adaptive mechanisms occurring during hypoxia. This one adds a mitochondrial inhibitor in order to try to delay the resistance acquired through metabolic adaptation when the antiangiogenic treatment normalizes hypoxia.

This trial is registered in clinicaltrials.gov under the following number: NCT02806817

-The publication link will be updated as soon as it is available.

Our collaborators

-Dr. Encarna Adrover
Medical Oncology Department, Hospital de Albacete.

-Dr. Emilio Alba
Medical Oncology Department, Hospital Virgen de la Victoria.

-Dr. Isabel Calvo
Medical Oncology Department, Hospital de Madrid.

-Dr. Javier Cortes
Medical Oncology Department, Hospital Vall d’Hebron.

-Dr. Ana Lluch
Medical Oncology Department, Hospital Clinico Valencia.

-Dr. Luis Manso
Medical Oncology Department, Hospital 12 de Octubre.

-Dr. Noelia Martinez
Medical Oncology Department, Hospital Ramon y Cajal.

-Dr. Ramon Colomer
Medical Oncology Department, Hospital La Princesa.

Our partners/funders/sponsors

Fundación CRIS contra el cáncerLa Fundación CRIS contra el cáncer is a private non-for-profit organization that donates for Research Projects and act as sponsor of clinical studies of CNIO. For more information: www.criscancer.org

Boehringer IngelheimBoehringer Ingelheim has been collaborating since 2010 with the CNIO in several studies that evaluate the effectiveness of Nintedanib, an oral triple angiokinase inhibitor which simultaneously inhibits VEGFR, PDGFR and FGFR signalling pathways, the three receptors crucially involved in angiogenesis, tumour growth and metastasis. Nintedanib belongs to the pipeline of Boehringer Ingelheim and it’s being investigated in patients with various solid tumours including NSCLC, colorectal cancer, liver cancer (hepatic cell carcinoma), and early breast cancer HER-2-negative type.

These investigations have shown the potential of nintedanib* with paclitaxel for the treatment of early HER2-negative breast cancer. The combination of these two drugs provides a pathological complete response rate [complete cure rates] of 50%, twice the one obtained with the standard monotherapy with paclitaxel. The trial included ten patients with HER2-negative breast cancer, all in early stages of the disease.

The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 142 affiliates and a total of more than 47,400 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.

Taking social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative “Making more Health” and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.

For more information please visit www.boehringer-ingelheim.com

avonAvon is, so far, the largest corporate ally in the fight against Breast Cancer.

In response to the needs of women and their families, Avon Foundation against Breast Cancer takes more than a decade raising funds and promoting awareness, prevention and cure for this cancer that is diagnosed in more than one million women to year.

The Crusade against Breast Cancer Avon has raised and donated more than $ 815 million in 50 countries around the world.

For more information please visit www.avon.es

NovartisNovartis has been supporting CNIO since 2011 in several studies that evaluate the effectiveness of dovitinib.

For more information please visit www.novartis.com