Crizotinib in Lobular Breast, Diffuse Gastric and Triple Negative Lobular Breast Cancer or CDH1-mutated Solid Tumours (ROLo)

  • End date
    Jul 1, 2024
  • participants needed
  • sponsor
    Royal Marsden NHS Foundation Trust
Updated on 9 February 2022
measurable disease
hormone therapy
cancer chemotherapy
solid tumour


The purpose of this study is to find out how effective the combination of crizotinib and fulvestrant is in shrinking lobular breast cancer tumours. The investigators will also be assessing the side effects of the combination of crizotinib tablets and fulvestrant injections. The side effects and the doses of crizotinib and fulvestrant have already been evaluated in large clinical trials, but this is the first time these two drugs will be combined together.


This clinical study is looking at whether a drug called crizotinib, which is used in some patients with lung cancer, is effective in a sub-type of breast cancer, called lobular breast cancer. As the majority of lobular breast cancers are oestrogen receptor positive (ER+ve), crizotinib will be combined with a second drug, fulvestrant, to try to block tumour growth that is driven by oestrogen.

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. Laboratory work at the Institute of Cancer Research has shown that lobular breast cancer cells, due to a mutation in a different gene called CDH1, appear to be similarly affected by crizotinib.

Fulvestrant is an oestrogen receptor down regulator and blocks the effects of oestrogen on oestrogen receptor positive (ER+ve) breast cancer cells. Fulvestrant is an established and approved anti-hormone therapy which patients with breast cancers are receiving in the clinic. It is possible that the combination of crizotinib and an anti-oestrogen agent will shrink the tumour(s) more effectively and prevent further growth. Because fulvestrant is only effective in post-menopausal women, if participants have not yet gone through the menopause, participants will need to start (or continue to receive) a monthly injection under the skin to temporarily stop the function of the participants ovaries to be eligible to take part in the trial.

This injection is called goserelin and has to be started at least 4 weeks before the first day of treatment on the trial.

The overall aims of this clinical study are to find out:

  • The proportion of patients whose tumour(s) shrink when they are treated with crizotinib and fulvestrant
  • The safety and tolerability of fulvestrant in combination with crizotinib, to determine that they can be given together without unacceptable side effects
  • What the drugs do to the tumours, which will help us decide which patients may benefit from this combination in the future

Condition Lobular Breast Carcinoma, Gastric Cancer, Triple Negative Breast Cancer, CDH1 Gene Mutation
Treatment Crizotinib Oral Capsule [Xalkori], Fulvestrant 50 MG/ML Prefilled Syringe [Faslodex], Fulvestrant 50 MG/ML Prefilled Syringe [Faslodex or generic]
Clinical Study IdentifierNCT03620643
SponsorRoyal Marsden NHS Foundation Trust
Last Modified on9 February 2022


Yes No Not Sure

Inclusion Criteria

Patients with histological diagnosis of E-cadherin negative inoperable or metastatic diffuse gastric cancer (basket cohort), Or inoperable or metastatic triple negative lobular breast cancer (basket cohort) Or inoperable or metastatic CDH1-mutated solid tumour with allele fraction 20% (basket cohort) Or recurrent inoperable locally advanced ER positive/HER2 negative lobular breast cancer (breast cohort)
Assessment of E-cadherin, ER and HER2 status as per local assessment
Lobular breast cancer patients previously treated with at least one prior line of therapy including at least one prior line of hormone therapy for advanced disease, but no more than three prior lines of chemotherapy for advanced disease
Measurable disease (RECIST 1.1)
Haematological and biochemical indices within the ranges shown in protocol. These measurements must be performed within one week (Day -7 to Day 1) before the patient goes in the trial
Gastric cancer, triple negative lobular breast cancer or CDH1-mutated solid
tumour patients previously treated with at least one prior therapy for
advanced disease OR relapsing within one year of completing (neo) adjuvant
NOTE: it is only considered highly effective if the patient is refraining from
chemotherapy OR unsuitable for chemotherapy in the opinion of the investigator
sexual intercourse during the entire period of risk associated with the study
(for example patient choice not to have chemotherapy, or no suitable
chemotherapy agent)
The oral contraceptive pill may be ineffective when taken with crizotinib so
is not an acceptable means of contraception for female patients during this
study but can be used by female partners of male patients
Female patients with child-bearing potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial. Both male and female patients of reproductive potential must agree to use two forms of highly effective contraception (see below) for 2 weeks before starting the study treatment, throughout the treatment period and for 90 days after discontinuation of treatment with crizotinib and 2 years after the last dose of fulvestrant
years of age or over with written (signed and dated) informed consent and be capable of co-operating with treatment and follow-up
World Health Organisation (WHO) performance status 0,1 or 2
Estimated life expectancy of at least 3 months in the opinion of the investigator
Signed and dated informed consent
Patients willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other procedures
Pre-/peri-menopausal ER+ lobular breast cancer patients must be willing to receive gosarelin injections every 28 days

Exclusion Criteria

Systemic chemotherapy or investigational medicinal products during the previous four weeks, or hormonal therapy within 7 days except luteinizing hormone-releasing hormone (LHRH) analogues for ovarian suppression. Bisphosphonates or RANK ligand antagonists are permitted for the management of bone metastases
Previous treatment with any agent that inhibits ROS1
Mixed ductal/lobular breast cancer, unless both ductal and lobular components are CDH1 negative by local assessment
Major surgery (excluding minor procedures, e.g. placement of vascular access) within 4 weeks or radiation therapy within 14 days prior to study entry
Patients with known symptomatic brain metastases requiring steroids, untreated brain metastases or spinal cord compression
Any of the following within 12 months prior to study entry: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, or transient ischemic attack. Uncontrolled hypertension or cardiac dysrhythmia including atrial fibrillation
QT interval, corrected >470 ms or the use of bradycardic agents, drugs which prolong the QT interval and/or anti-arrhythmic agents within 12 days before the first dose of crizotinib or during study treatment
Use of drugs that are known potent cytochrome P450 (CYP) 3A4 inhibitors or moderate or strong CYP 3A4 inducers within 12 days before the first dose of crizotinib. Us of CYP3A4 substrates with a narrow therapeutic index (such as ciclosporin) is also not permitted within 12 days prior or during the study treatment
Patients on warfarin. Patients requiring anticoagulation for rate-controlled AF or previous venous thromboembolism should be switched to low-molecular weight heparin
Known HIV or AIDS-related illness, active infection requiring systemic therapy, or positive HBV or HCV test indicating acute or chronic infection
Inability or unwillingness to swallow pills, or (for patients receiving fulvestrant) receive IM injections
Other severe acute or chronic medical condition or psychiatric condition, recent or active suicidal ideation or behaviour, or end stage renal disease on haemodialysis, or laboratory abnormality that may increase the risk associated with study participation or investigational products administration or may interfere with the interpretation of results and, in the judgment of the Investigator, would make the patient inappropriate study entry
Persisting toxicity related to prior therapy >Grade 1 (except for stable peripheral neuropathy grade 2 or alopecia grade 2)
Pregnancy or lactation
Diagnosis of other malignancy within 5 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or cervix, or low-grade (Gleason 6) prostate cancer
Is a participant or plans to participate in another interventional clinical trial, whilst taking part in this study. Participation in an observational trial would be acceptable
Immunocompromised status due to current known active infection with HIV or due to the use of immunosuppressive therapies for other conditions
Known prior or suspected hypersensitivity to investigational products or to any of the excipients
Patients at risk for gastrointestinal perforation (due to e.g., history of diverticulitis)
Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical trial
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