WINTHER Trial Aims to Offer Improved Cancer Care

Rationally-selected therapeutics, based on the analysis of matched tumour and normal biopsies, for patients with advanced malignancies

The WINTHER trial was heralded at the WIN (Worldwide Networking in personalised medicine) Symposium as a new generation personalised medicine study that aims to provide biology-oriented therapy to patients with advanced solid tumours. The patients currently remain excluded from the successes obtained with targeted cancer therapies, which are effective only in the 30 to 40% of patients whose tumours express corresponding actionable targets. The Symposium was held in Paris from the 10th to 12th of July, 2013 and was sponsored by the WIN Consortium, which also planned this hallmark trial around the ambitious goal of extending personalised approaches to the 60 to 70% of patients with advanced malignancies whose tumours do not express drugable targets.

The WINTHER trial is planned to be simultaneously conducted at multinational locations under the coordination of lead investigator, Professor Jean-Charles Soria of the Department of Medicine, Institute Gustave Roussy (IGR), Villejuif, France who provided information during the Symposium on the design and rationale of the trial together with initial data from patients enrolled at this site.

The WINTHER study design

According to Professor Soria, the trial will provide biology-guided therapy to the majority of the proposed 200 patients to be enrolled in this non-randomised molecular triage study by comparing biopsies taken from each patient’s tumour and normal matched tissue. Initially an analysis of structural DNA changes found in the tumour that include mutations, translocations and copy number variations (CNV) will be done using next generation sequencing (NGS) to select an estimated 80 patients whose tumours express molecules that can be targeted by currently available drugs (arm A). Arm A patients will receive treatment with agent(s) relevant to the DNA lesions found; it is anticipated that about 20 patients will receive labelled targeted therapies and 60 will be given targeted therapies within a clinical trial.

Arm B of the WINTHER study will be comprised of the majority of patients whose tumours express unknown actionable target. RNA and microRNAs analyses will be done on matched biopsies in these patients to assess the transcriptional distance between the normal and tumour tissue of each patient; alterations in the transcribed proteins within the tumour will be pinpointed against which drugs have some activity. For example, one primary target of imatinib is the BCR/ABL gene; in lieu of this expression by the tumour there are other therapeutically relevant molecular targets for imatinib and its efficacy should increase proportionally to the number of times these moieties occur in molecules within the tumour. Information on the genetic distance determined from the matched biopsies will be converted into relevant drug-target gene matches using a paradigm ranking the proposed efficacy of available drugs. Therefore, an estimated 100 patients in arm B will receive ‘off label’ therapy with drugs that are primarily indicated for other tumour types and the standard of care will be administered to an estimated 20 patients.

Patients in each trial arm will be treated upon disease progression following standard therapy and the trial endpoint is a comparison of progression-free survival (PFS) within the trial (PFS2) with the PFS of the last therapeutic line given prior to trial entrance and treatment (PFS1), with the aim of achieving PFS2/PFS1 greater than 1.5 in 50% of arm A patients and PFS2/PFS1 greater than 1.5 in 40% of arm B patients.

The study recruitment plan

At the time of the Symposium, enrollement had begun at the Sheba Medical Center in Tel Hashomer, Israel and was expected to begin shortly at MD Anderson Cancer Center in Houston, USA, Hospital Vall d'Hebron in Barcelona, Spain, the Segal Cancer Center Canada at McGill University in Montreal, Canada and at the University of California-San Diego, (UCSD) Moores Cancer Center, San Diego, USA. Biological investigations will be centralised at the Foundation Medicine and at the IGR, with data analysis being done at Ben Gurion University.

Initial results presented

Professor Soria reported that the first patient was enrolled at IGR on April 23rd 2013 and patient accrual had progressed rapidly at the rate of 2 to 3 patients per week since then.  As of the 2nd of July, 32 consenting patients were enrolled at IGR. Cancers of the head and neck, breast, lung, renal and colon/ rectum were confirmed in 6, 5, 7, 7, and 2 patients, respectively and 5 patients had sarcoma. Five screening failures occurred, 8 biopsies were yet to be processed and 19 successful biopsies had been performed; of these, there were 7 logistical failures, 3 biopsies awaited analysis and 9 had already been analysed.

The most frequent DNA alterations (n=5 each) were p53 mutations and deletion of CDNKN2A/B followed by amplification of CCND1 and EGFR (n=2 each), with one alteration each observed in 14 other genes. MET, VEGFA and HER3 were identified as transcriptome-based targets. Contrary to initial estimates, 5 patients were determined to have structural DNA alterations and were placed on arm A while just 3 patients showed transcriptome alterations and entered arm B.

Professor Soria underscored the innovation of the WINTHER trial design, which Includes patients with or without actionable genetic aberrations and informs treatment based on both DNA and RNA analyses. Dual biopsy of tumour and matched normal tissue of same histology allows for the evaluation of the genetic distance between tumour and normal tissue, eliminates variability factors between individual patients, limits the number of irrelevant aberrations and decreases noise. He estimated that these factors may increase the statistical factor of the study by 16-fold.

The WINTHER project was funded by an FP7 grant from the European Union (this recognition by an independent European jury is a guarantee of the value of the scientific concept and methodology of the project), plus grants from the National Cancer Institute, Agilent Technologies, Foundation Medicine, Novartis and Pfizer.