Clinical Trials /

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

NCT03620643

Description:

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.

Related Conditions:
  • Diffuse Gastric Adenocarcinoma
  • Lobular Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ROS1 Targeting With Crizotinib in Advanced E-cadherin Negative, ER Positive Lobular Breast Cancer or Diffuse Gastric Cancer Study
  • Official Title: Phase II Study of ROS1 Targeting With Crizotinib in Advanced E-cadherin Negative, ER Positive Lobular Breast Cancer or Diffuse Gastric Cancer

Clinical Trial IDs

  • ORG STUDY ID: CCR4684
  • NCT ID: NCT03620643

Conditions

  • Lobular Breast Carcinoma
  • Gastric Cancer

Interventions

DrugSynonymsArms
Crizotinib Oral Capsule [Xalkori]XalkoriCrizotinib Oral Capsule [Xalkori] monotherapy
Fulvestrant 50 MG/ML Prefilled Syringe [Faslodex]FaslodexCrizotinib Oral Capsule [Xalkori] plus Fulvestrant injection

Purpose

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
    

Trial Arms

NameTypeDescriptionInterventions
Crizotinib Oral Capsule [Xalkori] monotherapyActive ComparatorArm 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.
  • Crizotinib Oral Capsule [Xalkori]
Crizotinib Oral Capsule [Xalkori] plus Fulvestrant injectionActive ComparatorArm 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).
  • Crizotinib Oral Capsule [Xalkori]
  • Fulvestrant 50 MG/ML Prefilled Syringe [Faslodex]

Eligibility Criteria

        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 fulvestrant or 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants With Objective Response Assessed Using RECIST v1.1
Time Frame:From Day 1 to Progressive Disease, assessed up to end of study (up to approximately 48 months)
Safety Issue:
Description:To assess confirmed response rate by RECIST 1.1 of crizotinib and fulvestrant in the breast cohort

Secondary Outcome Measures

Measure:Percentage of Participants With Adverse Events (AEs) and Serious AEs (SAEs)
Time Frame:From Day 1 to 90 days after last dose of study drug, assessed up to end of study (up to approximately 45 months)
Safety Issue:
Description:To assess the overall safety and tolerability of crizotinib with fulvestrant in the breast cancer cohort and as monotherapy in the gastric 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.
Measure:Progression-free survival (PFS) Assessed Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in both gastric and breast cancer cohorts
Time Frame:From Day 1 to disease progression (PD) or death from any cause, assessed up to end of study (up to approximately 48 months)
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Royal Marsden NHS Foundation Trust

Trial Keywords

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

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