The purpose of this study was to find out how effective the combination of crizotinib and fulvestrant was in shrinking lobular breast cancer tumours. The investigators also assessed the side effects of the combination of crizotinib tablets and fulvestrant injections. The side effects and the doses of crizotinib and fulvestrant had already been evaluated in large clinical trials, but this was the first time these two drugs had been combined together.
This clinical study was looking at whether a drug called crizotinib, which is used in some patients with lung cancer, was 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 was 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 had not yet gone through the menopause, participants needed to start (or continue to receive) a monthly injection under the skin to temporarily stop the function of the participant's ovaries to be eligible to take part in the trial. This injection is called goserelin and had to be started at least 4 weeks before the first day of treatment on the trial. The overall aims of this clinical study were 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
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
OTHER
Masking
SINGLE
Enrollment
33
Crizotinib 250 mg Crizotinib 200mg
Fulvestrant (Faslodex or generic) is supplied as two 5-mL clear neutral glass (Type 1) barrels, each containing 250mg/5mL of fulvestrant solution for intramuscular injection and fitted with a tamper evident closure.
Beatson West of Scotland Cancer Centre
Glasgow, United Kingdom
Royal Marsden NHS Foundation Trust
London, United Kingdom
Guys and St Thomas NHS Foundation Trust
London, United Kingdom
University College London Hospital
London, United Kingdom
The Christie NHS Foundation Trust
Manchester, United Kingdom
Percentage of Breast Cancer Cohort Participants With Confirmed Response Assessed Using RECIST v1.1
To assess confirmed response rate by RECIST 1.1 of crizotinib and fulvestrant in advanced E-cadherin negative, ER positive lobular breast cancer.
Time frame: From Day 1 to Progressive Disease, assessed up to end of study (Approximately 57 months)
Percentage of Basket Cohort Participants With Confirmed Response Assessed Using RECIST v1.1
To assess confirmed response rate (CR/PR outcome) by RECIST 1.1 scan of crizotinib monotherapy in advanced E-cadherin negative, diffuse gastric cancer, triple negative lobular breast cancer or CDH1-mutated solid tumour.
Time frame: From Day 1 to Progressive Disease, assessed up to end of study (Approximately 57 months)
Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
To assess the overall safety and tolerability of crizotinib with fulvestrant in the breast cancer cohort and as monotherapy in the basket cancer cohort. Toxicity will be assessed by CTCAE (version 4) every 4 weeks during study treatment. Adverse events, including serious adverse events, will be recorded until 30 days after the last dose of study treatment with crizotinib.
Time frame: From Day 1 to 30 days after last dose of study drug, assessed up to end of study (Approximately 57 months)
Progression-free Survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in Both Basket and Breast Cancer Cohorts
PFS is defined as the time from baseline treatment to the first occurrence of PD, as determined by the investigator using RECIST v1.1, or death from any cause during the study, whichever occurs first. PD is defined as greater than or equal to (\>/=) 20 percent (%) relative increase and \>/=5 millimeter (mm) of absolute increase in the sum of diameters (SD) of target lesions (TLs), taking as reference the smallest SD recorded since treatment started, or appearance of 1 or more new lesions.
Time frame: From Day 1 to disease progression (PD) or death from any cause, assessed up to end of study (Approximately 57 months)
Assessment of Overall Survival in Each Cohort
Overall survival, calculated from day 1 of study treatment to the date of death from any cause.
Time frame: From Day 1 to disease progression (PD) or death from any cause, assessed up to end of study (Approximately 57 months)
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