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

NCT03620643 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: CCR4684
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 5

Brief Summary

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.

Conditions

Lobular Breast Carcinoma; Gastric Cancer; Triple Negative Breast Cancer; CDH1 Gene Mutation

Keywords

Advanced E-cadherin negative gastric cancer; Oestrogen receptor positive lobular breast cancer; Crizotinib; Fulvestrant

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  From Day 1 to Progressive Disease, assessed up to end of study (Approximately 57 months)

Secondary Outcomes (3)

• Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs)

  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

  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

  From Day 1 to disease progression (PD) or death from any cause, assessed up to end of study (Approximately 57 months)

Study Arms (2)

Crizotinib Oral Capsule [Xalkori] monotherapy

ACTIVE COMPARATOR

Arm 1 - Basket cohort (n=29 participants) were treated with Crizotinib Oral Capsule \[Xalkori\] (250 mg b.d) taken as monotherapy on a continuous dosing schedule. One treatment cycle for Crizotinib is 28 days long.

Drug: Crizotinib Oral Capsule [Xalkori]

Crizotinib Oral Capsule [Xalkori] plus Fulvestrant injection

ACTIVE COMPARATOR

Arm 2 - Lobular Breast Cancer cohort (n=29 participants) were treated with combination therapy. The combination therapy included; Crizotinib Oral Capsule \[Xalkori\] (250mg b.d.) plus Fulvestrant 50 mg/mL Prefilled Syringe \[Faslodex or generic\] intramuscular (IM) injection (500 mg per 1 cycle (q28 days, plus loading dose on day 15).

Drug: Crizotinib Oral Capsule [Xalkori]; Drug: Fulvestrant 50 MG/ML Prefilled Syringe [Faslodex or generic]

Interventions

Crizotinib Oral Capsule [Xalkori] DRUG

Crizotinib 250 mg Crizotinib 200mg

Also known as: Xalkori

Crizotinib Oral Capsule [Xalkori] monotherapy; Crizotinib Oral Capsule [Xalkori] plus Fulvestrant injection

Fulvestrant 50 MG/ML Prefilled Syringe [Faslodex or generic] DRUG

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.

Also known as: Faslodex

Crizotinib Oral Capsule [Xalkori] plus Fulvestrant injection

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Royal Marsden NHS Foundation Trust: lead
• Pfizer: collaborator
• Breast Cancer Now: collaborator

Study Sites (5)

Beatson West of Scotland Cancer Centre

Glasgow, United Kingdom

Location

Royal Marsden NHS Foundation Trust

London, SW3 6JJ, United Kingdom

Location

Guys and St Thomas NHS Foundation Trust

London, United Kingdom

Location

University College London Hospital

London, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, United Kingdom

Location

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MeSH Terms

Conditions

Carcinoma, Lobular; Stomach Neoplasms; Triple Negative Breast Neoplasms

Interventions

Crizotinib; Fulvestrant; Drugs, Generic

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Ductal, Lobular, and Medullary; Breast Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Stomach Diseases

Intervention Hierarchy (Ancestors)

Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Aminopyridines; Pyridines; Estradiol; Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pharmaceutical Preparations

Results Point of Contact

• Title: Clinical Trial Manager
• Organization: The Royal Marsden NHS Foundation Trust

rolo.trial@rmh.nhs.uk

02078082887

Study Officials

• Professor Peter Schmid

  St Bart's Hospital

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This multi-centre study design will aim to complete recruitment over 18 months from six high volume centres including the Royal Marsden. Parallel recruitment to breast and basket cancer cohorts will take place for this study.

Study Record Dates

• First Submitted: May 4, 2018
• First Posted: August 8, 2018
• Study Start: May 9, 2019
• Primary Completion: August 30, 2024
• Study Completion: August 30, 2024
• Last Updated: October 30, 2025
• Results First Posted: October 30, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

GB (5)