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
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.
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 chemotherapy OR unsuitable for chemotherapy in the
opinion of the investigator (for example patient choice not to have chemotherapy, or no
suitable chemotherapy agent).
- 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.
- 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.
NOTE: it is only considered highly effective if the patient is refraining from sexual
intercourse during the entire period of risk associated with the study treatments
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.
- 18 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
- Pre-/peri-menopausal ER+ lobular breast cancer patients must be willing to receive
gosarelin injections every 28 days.
- Signed and dated informed consent.
- Patients willing and able to comply with scheduled visits, treatment plans, laboratory
tests, and other procedures.
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.
