ROLo
Research type
Research Study
Full title
Phase II study of ROS1 targeting with crizotinib in advanced E-cadherin negative, ER positive lobular breast cancer or diffuse gastric cancer
IRAS ID
229356
Contact name
Alicia Okines
Contact email
Sponsor organisation
Royal Marsden Hospital
Eudract number
2017-001680-20
Duration of Study in the UK
2 years, 5 months, 30 days
Research summary
Summary of Research
Crizotinib targets cancers with genetic changes in two genes called ALK and ROS1. Lung cancers with changes in these genes usually get smaller when treated with crizotinib. Fulvestrant is an established and approved anti-hormone injection which patients with breast cancers are receiving in the clinic.Laboratory work at the Institute of Cancer Research has shown that cells of a sub-type of breast cancer (lobular type) and a sub-type of stomach cancer (diffuse gastric cancer) appear to be similarly affected by crizotinib due to a mutation in a different gene called CDH1. This raises the question whether crizotinib will be similarly effective in reducing cancer growth in patients with lobular breast cancer and diffuse gastric cancer. It is possible that the combination of crizotinib and a hormonal treatment will be more effective in breast cancer than the crizotinib tablets only.
The purpose of this study is to find out how effective the combination of crizotinib and fulvestrant is in shrinking lobular breast cancer tumours and how effective crizotinib is in shrinking diffuse gastric cancer tumours. We will also be assessing the side effects of crizotinib alone and the combination of crizotinib tablets and fulvestrant injections. The side effects and the doses of crizotinib and crizotinib + fulvestrant have already been evaluated individually in large clinical trials, but this is the first time these two drugs will be combined together.
The study is being carried out at six hospitals in the UK. We aim to recruit 58 patients total (33 patients in the breast and gastric cohort each) in this study. The study will be organised and run by the Royal Marsden NHS Foundation Trust and has been funded by a grant from the charity Breast Cancer Now (BCN) and the drug company who make crizotinib, Pfizer.Summary of Results
The ROLo study: A trial looking at crizotinib for breast and stomach cancersThe ROLo study was sponsored by the Royal Marsden NHS Foundation Trust in collaboration with Breast Cancer Now and Pfizer. This was a Phase II study, which focuses on evaluating how effective a treatment is in a larger group of patients, and also looks at safety. The purpose of this study was to find out how effective the combination of two drugs, crizotinib and fulvestrant, is at treating advanced E-Cadherin negative, hormone-receptor (ER-positive) lobular breast cancer (the lobular breast cancer cohort), and also to assess how effective the drug crizotinib works on its own to treat several other types of cancer (the basket cohort).
Crizotinib is a targeted cancer drug used in lung cancer that blocks proteins called ROS1 and ALK. These proteins help cancer cells grow. Laboratory studies have shown that blocking ROS1 in models that have lost the protein E-Cadherin, can have anti-tumour effects, which is why crizotinib is being tested for these cancers. Fulvestrant is a drug that works by blocking the hormone oestrogen, which ER-positive breast cancers use to grow, helping to stop their growth.
Lobular breast cancer is a type of breast cancer that starts in the cells lining the milk-producing glands (lobules) of the breast. E-Cadherin is a protein which helps cells stick together, and in approximately 90% of patients with lobular breast cancer, this protein is lost due to changes in the CDH-1 gene. ER-positive breast cancer means the cancer cells have proteins, called receptors, for the hormone oestrogen. The basket cohort included different cancer types including triple negative lobular breast cancer, which is a type of lobular breast cancer that doesn’t have receptors for the hormones oestrogen and progesterone, or the HER2 protein; diffuse gastric cancer, a type of stomach cancer; and CDH-1 mutated solid tumours, which are cancers with a mutation in the CDH-1 gene.
This study recruited 27 patients to the ER-positive lobular breast cancer cohort, and 6 patients to the basket cohort (5 patients with triple-negative breast cancer, and 1 patient with diffuse gastric cancer) between 09/05/2019 and 01/12/2023. Patients were recruited from 5 sites across the United Kingdom: The Royal Marsden NHS Foundation Trust, The Christie NHS Foundation Trust, Guys and St Thomas’ NHS Foundation Trust, University College London Hospital NHS Foundation Trust and the Beatson West of Scotland Cancer Centre.
Safety review showed that the combination of crizotinib with fulvestrant was frequently associated with abnormal, raised liver blood tests, and was seen in 74% of patients, with 30% of the 21 patients experiencing larger increases. Other common side-effects that occurred with the combination treatment included nausea, vomiting, and diarrhoea, in up to 74%, 67%, and 48% of patients respectively. While these side-effects also occurred in patients taking crizotinib alone, they were less common - nausea in 17%, vomiting in 33%, and diarrhoea in 17% of the 6 patients.
The main aim of the trial was to see how many patients had a confirmed complete or partial response to the treatment, meaning their cancer either shrank completely or got smaller on imaging at any point during the trial. One patient out of 27 (4%) in the ER-positive lobular breast cancer cohort had a response to crizotinib and fulvestrant, however, no patients in the basket cohort responded to single-agent crizotinib. The median time from starting treatment, to signs that the cancer has started to grow again was only 1.8 months for both cohorts. Trial participants survived for a median of 17.5 months in the ER-positive lobular breast cancer cohort and just 4.4 months in the basket cohort. The study concluded that neither taking crizotinib alone, nor in combination with fulvestrant, showed any useful activity in advanced breast cancer or diffuse gastric cancer. We hope that ongoing translational research will help us understand why the treatment benefits seen in the laboratory setting did not have the same benefits for patients who took part in the clinical trial.
You can learn more about this study and the results by visiting Clinicaltrials.gov and searching for the trial using the identifier: NCT03620643.REC name
London - Fulham Research Ethics Committee
REC reference
17/LO/2025
Date of REC Opinion
29 Jan 2018
REC opinion
Further Information Favourable Opinion