WINTHER is the first trial of the WIN Consortium and is addressed to stage IV cancer patients with solid tumors. WINTHER offers personalized treatment to patients who harbor advanced metastatic malignancies of lung, breast, colon, head and neck, kidney, liver, and rhabdomyosarcomas. It remains the most advanced trial worldwide. Although there are some navigational trials such as PREDICT or MAP that are assigning patients to a therapy matched to their structural genomic profile (using Next Generation Sequencing), no trial so far has been adding the functional genomics dimension (mRNA gene expression) of the transcriptome.
DNA aberrations (such as mutations, amplifications, deletions) that can be addressed by targeted therapies have proven to be limited to a subset of the population, leaving the majority of the patients without any biologically matched treatment option. By incorporating RNA information from the patient and his or her tumor, WINTHER is able to address many more patients and gain knowledge about the role of the transcriptome in selecting targeted therapies for patients.
WINTHER Key Innovative Concepts (*)
i. Dual biopsy of metastasis and matched normal tissue (*) (NSCLC metastatic location and bronchial mucosa for Normal for instance)
ii. Next Generation Sequencing of the metastasis, CGH and CNV
iii. Gene expression arrays of metastasis and normal tissue (*) for assessment of the genetic distance in expression of messenger RNA between tumor tissue and normal, enabling the study to discard genetic variability and reduce noise
iv. Integration into an innovative family of algorithms developed and patented by WIN(*), based on tumor vs. normal gene expression, predicting the efficacy of all marketed drugs or experimental targeted drugs in trial for the individual patient
v. Creation of web based tools for use by the clinicians to discuss therapeutic choice for each patient
(*) Unique innovative feature of the trial
The WINTHER algorithm converts the differential levels of expression of the metastasis (tumor) and the non-tumoral (normal matched tissue) into useful information for therapeutic decision. In a nutshell, it is hypothesized that the bigger the difference in expression of a gene, the higher the chances are that a drug that targets the gene will be effective. As a consequence, the algorithm enables the identification of the best drug that matches the biology of the tumor.
− If a DNA aberration is detected by NGS done at Foundation Medicine and there is a matched and safe drug, the patient enters in Arm A and is treated with the matched drug
− If there is no actionable DNA aberration, the patient enters in Arm B and is treated based on gene expression data and algorithm
− For both arms, the Principal Investigators discuss in web-conferenced clinical management committees
− Provide personalized therapy to all patients: (Arm A & Arm B)
− Demonstrate that the efficacy of treatments in Arm B is equivalent to Arm A.
WINTHER Key Achievements To Date
• Trial conducted across four countries
• Genomics and tumor/normal transcriptomics successful
• Tumor and normal biopsies safe
• Weekly transcontinental clinical management committee calls with investigators from across the globe discussing patients
• Weekly Laboratory teleconferences of all laboratory staff across all centers – to discuss hurdles, share solutions, ensure training, improve SOP, discuss each patient biopsies and other quality controls
• Onsite laboratory training
• Data reporting, quality assurance etc. established
• Funding and regulatory hurdles recognized
• Patients have multiple aberrations
• EU has selected WINTHER as the Success Story of the EU FP7
WINTHER in Annals of Oncology
"Challenges in initiating and conducting personalized cancer therapy trials: perspectives from WINTHER, a Worldwide Innovative Network (WIN) Consortium trial"
June 1, 2015
Senior Vice President, Head of Oncology Innovative Medicines, MedImmune, USA
Chief, Division of Hematology & Oncology, Sr. Deputy Center Director for Clinical Science, University of California San Diego Moores Cancer Center (USA)
Chief Scientific and Operating Officer, WIN Consortium
Clinical Head and Co-Director, Research Unit for Molecular Therapy of Cancer; Head, Early Clinical Drug Development Group, Vall d'Hebron Institute of Oncology, VHIO (Spain)
Associate Professor, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center
Director, Institute of Oncology, Sheba Medical Center (Israel)
Director, Laboratory Research, Clinical Research Unit, Developmental Therapeutics Program, and Professor, Division of Oncology, Segal Cancer Center, Jewish General Hospital
Phase 1, Clinical Research Manager, Sheba Medical Center
Professor of Medicine, Université Claude Bernard; Scientific Director, Canceropole Lyon Rhône Alpes, Centre Léon Bérard (France)