ROS1 Targeting With Crizotinib in Advanced E-cadherin Negative, ER Positive Lobular Breast Cancer or Diffuse Gastric Cancer Study

NCT03620643

Last updated date
Study Location
Royal Marsden NHS Foundation Trust
London, , SW3 6JJ, United Kingdom
Contact
0208 915

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Lobular Breast Carcinoma, Gastric Cancer
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

- Patients with histologically or Histological diagnosis of inoperable or metastatic diffuse gastric cancer or recurrent inoperable locally advanced ER positive/HER2 negative lobular breast cancer. Assessment of ER and HER2 status as per local assessment.

- Previously treated with at least one prior line of therapy for advanced disease, but no more than three prior lines of chemotherapy for advanced disease. Patients with breast cancer must have received at least one prior line of hormone therapy 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.

- 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 6 months 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 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
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


- 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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Lobular Breast Carcinoma, Gastric CancerROS1 Targeting With Crizotinib in Advanced E-cadherin Negative, ER Positive Lobular Breast Cancer or Diffuse Gastric Cancer Study
NCT03620643
  1. London,
ALL GENDERS
18 Years+
years
MULTIPLE SITES
Advanced Information
Descriptive Information
Brief Title  ICMJE ROS1 Targeting With Crizotinib in Advanced E-cadherin Negative, ER Positive Lobular Breast Cancer or Diffuse Gastric Cancer Study
Official Title  ICMJE Phase II Study of ROS1 Targeting With Crizotinib in Advanced E-cadherin Negative, ER Positive Lobular Breast Cancer or Diffuse Gastric Cancer
Brief Summary 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.
Detailed Description

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 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.

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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
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 gastric cancer cohorts will take place for this study.
Masking: Single (Participant)
Primary Purpose: Other
Condition  ICMJE
  • Lobular Breast Carcinoma
  • Gastric Cancer
Intervention  ICMJE
  • Drug: Crizotinib Oral Capsule [Xalkori]
    Crizotinib 250 mg Crizotinib 200mg
    Other Name: Xalkori
  • Drug: Fulvestrant 50 MG/ML Prefilled Syringe [Faslodex]
    Fulvestrant (Faslodex) 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.
    Other Name: Faslodex
Study Arms  ICMJE
  • Active Comparator: Crizotinib Oral Capsule [Xalkori] monotherapy
    Arm 1 - Gastric cancer cohort (n=29 participants) will be treated with monotherapy called Crizotinib Oral Capsule [Xalkori] (250 mg b.d) taken on a continuous dosing schedule. One treatment cycle for Crizotinib is 28 days long.
    Intervention: Drug: Crizotinib Oral Capsule [Xalkori]
  • Active Comparator: Crizotinib Oral Capsule [Xalkori] plus Fulvestrant injection
    Arm 2 - Lobular Breast Cancer cohort (n=29 participants) will be treated with combination therapy. The combination therapy includes; Crizotinib Oral Capsule [Xalkori] (250mg b.d.) plus Fulvestrant 50 mg/mL Prefilled Syringe [Faslodex] intramuscular (IM) injection (500 mg per 1 cycle (q28 days, plus loading dose on day 15).
    Interventions:
    • Drug: Crizotinib Oral Capsule [Xalkori]
    • Drug: Fulvestrant 50 MG/ML Prefilled Syringe [Faslodex]
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 3, 2018)
58
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 4, 2022
Estimated Primary Completion Date December 4, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with histologically or Histological diagnosis of inoperable or metastatic diffuse gastric cancer or recurrent inoperable locally advanced ER positive/HER2 negative lobular breast cancer. Assessment of ER and HER2 status as per local assessment.
  • Previously treated with at least one prior line of therapy for advanced disease, but no more than three prior lines of chemotherapy for advanced disease. Patients with breast cancer must have received at least one prior line of hormone therapy 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.
  • 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 6 months 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 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.
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Hanh Nguyen0208 915 ext 6506[email protected]
Contact: Alicia Okines0207 352 ext 2751[email protected]
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03620643
Other Study ID Numbers  ICMJE CCR4684
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD:Undecided
Responsible Party Royal Marsden NHS Foundation Trust
Study Sponsor  ICMJE Royal Marsden NHS Foundation Trust
Collaborators  ICMJE
  • Pfizer
  • Breast Cancer Now
Investigators  ICMJE Not Provided
PRS Account Royal Marsden NHS Foundation Trust
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP